Darvesh S

General

Full name : Darvesh Sultan

First name : Sultan

Mail : Dalhousie University\; Sir Charles Tupper Building\; Rm. 12D\; 5850 College Street\; Halifax\; B3H 1X5

Zip Code :

City :

Country : Canada

Email : sultan.darvesh@dal.ca

Phone : +19024732490

Fax :

Website : \/\/geriatricresearch.medicine.dal.ca\/darvesh.htm

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References (63)

Title : Interaction of Exogenous Acetylcholinesterase and Butyrylcholinesterase with Amyloid-beta Plaques in Human Brain Tissue - Reid_2024_Chem.Biol.Interact__111012
Author(s) : Reid GA , Darvesh S
Ref : Chemico-Biological Interactions , :111012 , 2024
Abstract : Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are associated with amyloid-beta (Abeta) plaques and exhibit altered biochemical properties in human Alzheimer's disease (AD), as well as in the transgenic 5XFAD mouse model of AD amyloidosis. In the brains of the 5XFAD mouse model devoid of BChE enzyme (5XFAD/BChE-KO), incubation of tissue sections with exogenous BChE purified from human plasma (pl-BChE) leads to its association with Abeta plaques and its biochemical properties are comparable to those reported for endogenous BChE associated with plaques in both human AD and in 5XFAD mouse brain tissue. We sought to determine whether these observations in 5XFAD/BChE-KO mice also apply to human brain tissues. To do so, endogenous ChE activity in human AD brain tissue sections was quenched with 50% aqueous acetonitrile (MeCN(aq)) leaving the tissue intact for further studies. Quenched sections were then incubated with recombinant AChE (r-AChE) or pl-BChE and stained for each enzymes' activity. Exogenous r-AChE or pl-BChE became associated with Abeta plaques, and when bound, had properties that were comparable to the endogenous ChE enzymes associated with plaques in AD brain tissues without acetonitrile treatment. These findings in human AD brain tissue extend previous observations in the 5XFAD/BChE-KO mouse model and demonstrate that exogenously applied r-AChE and pl-BChE have high affinity for Abeta plaques in human brain tissues. This association alters the biochemical properties of these enzymes, most likely due a conformational change. If incorporation of AChE and BChE in Abeta plaques facilitates AD pathogenesis, blocking this association could lead to disease-modifying approaches to AD. This work provides a method to study the mechanism of AChE and BChE interaction with Abeta plaque pathology in post-mortem human brain tissue.
ESTHER : Reid_2024_Chem.Biol.Interact__111012
PubMedSearch : Reid_2024_Chem.Biol.Interact__111012
PubMedID: 38648920

Title : Solvents and detergents compatible with enzyme kinetic studies of cholinesterases - Sands_2023_Chem.Biol.Interact_14ChEPon_110667
Author(s) : Sands D , Davis A , Banfield S , Pottie IR , Darvesh S
Ref : Chemico-Biological Interactions , :110667 , 2023
Abstract : Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that serve a wide range of physiological functions including the hydrolysis of the neurotransmitter acetylcholine and several other xenobiotics. The development of inhibitors for these enzymes has been the focus for the treatment of several conditions, such as Alzheimer's disease. Novel chemical entities are evaluated as potential inhibitors of AChE and BChE using enzyme kinetics. A common issue encountered in these studies is low aqueous solubility of the possible inhibitor. Additives such as cosolvents or detergents can be included in these studies improve the aqueous solubility. Typical cosolvents include acetonitrile or dimethyl sulfoxide while typical detergents include Polysorbate 20 (Tween 20) or 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate (CHAPS). When solubility is not improved, these molecules are often not evaluated further. To address this issue eleven cosolvents and six detergents that could facilitate aqueous solubility were evaluated to understand how they would affect cholinesterase enzymes using Ellman's assay. These studies show that propylene glycol, acetonitrile, methanol, Tween 20, Polysorbate 80 (Tween 80), polyoxyethylene 23 lauryl ether (Brij 35) and polyoxyethylene 10 oleoyl ether (Brij 96v) have the least inhibitory effects towards cholinesterase activity. It is concluded that these cosolvents and detergents should be considered as solubilizing agents for evaluation of potential cholinesterase inhibitors with low aqueous solubility.
ESTHER : Sands_2023_Chem.Biol.Interact_14ChEPon_110667
PubMedSearch : Sands_2023_Chem.Biol.Interact_14ChEPon_110667
PubMedID: 37579937

Title : A method for the efficient evaluation of substrate-based cholinesterase imaging probes for Alzheimer's disease - Darvesh_2023_J.Enzyme.Inhib.Med.Chem_38_2225797
Author(s) : Darvesh S , Banfield S , Dufour M , Forrestall KL , Maillet H , Reid GA , Sands D , Pottie IR
Ref : J Enzyme Inhib Med Chem , 38 :2225797 , 2023
Abstract : Cholinesterase (ChE) enzymes have been identified as diagnostic markers for Alzheimer disease (AD). Substrate-based probes have been synthesised to detect ChEs but they have not detected changes in ChE distribution associated with AD pathology. Probes are typically screened using spectrophotometric methods with pure enzyme for specificity and kinetics. However, the biochemical properties of ChEs associated with AD pathology are altered. The present work was undertaken to determine whether the Karnovsky-Roots (KR) histochemical method could be used to evaluate probes at the site of pathology. Thirty thioesters and esters were synthesised and evaluated using enzyme kinetic and KR methods. Spectrophotometric methods demonstrated all thioesters were ChE substrates, yet only a few provided staining in the brain with the KR method. Esters were ChE substrates with interactions with brain ChEs. These results suggest that the KR method may provide an efficient means to screen compounds as probes for imaging AD-associated ChEs.
ESTHER : Darvesh_2023_J.Enzyme.Inhib.Med.Chem_38_2225797
PubMedSearch : Darvesh_2023_J.Enzyme.Inhib.Med.Chem_38_2225797
PubMedID: 38061987

Title : Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites - Meier-Stephenson_2022_Alzheimers.Dement.(N.Y)_8_e12283
Author(s) : Meier-Stephenson FS , Meier-Stephenson VC , Carter MD , Meek AR , Wang Y , Pan L , Chen Q , Jacobo S , Wu F , Lu E , Simms GA , Fisher L , McGrath AJ , Fermo V , Barden CJ , Clair HDS , Galloway TN , Yadav A , Campagna-Slater V , Hadden M , Reed M , Taylor M , Kelly B , Diez-Cecilia E , Kolaj I , Santos C , Liyanage I , Sweeting B , Stafford P , Boudreau R , Reid GA , Noyce RS , Stevens L , Staniszewski A , Zhang H , Murty M , Lemaire P , Chardonnet S , Richardson CD , Gabelica V , DePauw E , Brown R , Darvesh S , Arancio O , Weaver DF
Ref : Alzheimers Dement (N Y) , 8 :e12283 , 2022
Abstract : INTRODUCTION: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Abeta) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. METHODS: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Abeta-mediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. RESULTS: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Abeta is released as an early responder immunopeptide triggering an innate immunity cascade in which Abeta exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Abeta. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Abeta, leading to a chronic self-perpetuating autoimmune cycle. AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. DISCUSSION: Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.
ESTHER : Meier-Stephenson_2022_Alzheimers.Dement.(N.Y)_8_e12283
PubMedSearch : Meier-Stephenson_2022_Alzheimers.Dement.(N.Y)_8_e12283
PubMedID: 35415204

Title : Neuropathology and cholinesterase expression in the brains of octogenarians and older - Maxwell_2022_Chem.Biol.Interact__110065
Author(s) : Maxwell SP , Cash MK , Darvesh S
Ref : Chemico-Biological Interactions , :110065 , 2022
Abstract : A subset of octogenarians and older maintain normal cognitive function (CNOO) despite high prevalence and incidence of cognitive decline attributed to neurodegeneration or aging in the population. The rostral prefrontal cortex (rPFC) and hippocampal formation are brain regions integral to cognition, namely attention and memory, facilitated in part by cholinergic innervation. We hypothesized that preserved cholinergic neurotransmission in these regions contributes to intact cognition in the CNOO. To test this, we evaluated the burden of neuropathological and cholinesterase-associated protein aggregates in the rPFC and hippocampal formation. Tissues from age- and sex-matched CNOO and Alzheimer's disease (AD) rPFC and hippocampal formation were stained for beta-amyloid (Abeta), tau, alpha-synuclein, phosphorylated TAR DNA-binding protein 43 (pTDP-43), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The relative abundance of neuropathological aggregates was semi-quantitatively scored. Deposition of Abeta plaques, tau neurofibrillary tangles (NFT) and pTDP-43 inclusions were comparable between CNOO and AD cases. Intraneuronal Abeta and tau-positive thorny astrocytes consistent with aging-related tau astrogliopathy, were also noted in the rPFC. Abundance of BChE-positive plaque pathology was significantly higher in AD than in CNOO cases in most regions of interest, followed closely by abundance of AChE-positive plaque pathology. BChE- and AChE-activities were also associated with varied NFT morphologies. CNOO cases maintained cognition despite a high neuropathological burden in the rPFC and hippocampal formation. BChE-positive and, to a lesser extent, AChE-positive pathologies were significantly lower in most regions in the CNOO compared to AD. This suggests a specificity of cholinesterase-associated neuropathology with AD. We conclude that while CNOO have cholinesterase-associated neuropathology in the rPFC and hippocampal formation, abundance in this population is significantly lower compared to AD which may contribute to their intact cognition.
ESTHER : Maxwell_2022_Chem.Biol.Interact__110065
PubMedSearch : Maxwell_2022_Chem.Biol.Interact__110065
PubMedID: 35872043

Title : Interaction of Exogenous Butyrylcholinesterase with beta-Amyloid Plaques in 5XFAD\/Butyrylcholinesterase-Knockout Mouse Brain - Reid_2021_Curr.Alzheimer.Res__
Author(s) : Reid GA , Darvesh S
Ref : Curr Alzheimer Res , : , 2021
Abstract : BACKGROUND: In Alzheimer's disease (AD), and amyloid models such as the 5XFAD mouse, butyrylcholinesterase (BChE) is associated with beta-amyloid (Abeta) plaques and has unique biochemical features which distinguish it from that found in neurons. It has been suggested that BChE associated with Abeta plaques may be involved in the maturation of this structure and thus dis- ease progression. OBJECTIVE: Currently, it is unknown whether BChE bound to Abeta plaques has altered biochemical properties due to a different primary structure or because of the association of this enzyme with Abeta plaques. Also, the source and binding mechanism of this BChE remains unknown. METHODS: Brain tissue sections from the 5XFAD/BChE-KO mouse were incubated with exogenous sources of BChE and stained for this enzyme's activity. Efforts were made to determine what re- gion of BChE or Abeta may be involved in this association. RESULTS: We found that incubation of 5XFAD/BChE-KO brain tissues with exogenous BChE led to this enzyme becoming associated with Abeta plaques and neurons. In contrast to neuronal BChE, the BChE bound to Abeta plaques had similar biochemical properties to those seen in AD. Mutations to BChE and efforts to block Abeta epitomes failed to prevent this association. CONCLUSION: The association of BChE with Abeta plaques, and the resultant biochemical changes, suggests that BChE may undergo a conformational change when bound to Abeta plaques but not neurons. The 5XFAD/BChE-KO model is ideally suited to explore the binding mechanism of BChE to Abeta plaques as well as the involvement of BChE in AD pathogenesis.
ESTHER : Reid_2021_Curr.Alzheimer.Res__
PubMedSearch : Reid_2021_Curr.Alzheimer.Res__
PubMedID: 34455970

Title : Clinical and neuropathological variability in the rare IVS10 + 14 tau mutation - Maxwell_2021_Neurobiol.Aging_101_298 e1
Author(s) : Maxwell SP , Cash MK , Rockwood K , Fisk JD , Darvesh S
Ref : Neurobiology of Aging , 101 :298 e1 , 2021
Abstract : Mutations in the microtubule-associated protein tau gene are known to cause progressive neurodegenerative disorders with variable clinical and neuropathological phenotypes, including the intronic 10 + 14 (IVS10 + 14) splice site mutation. Three families have been reported with the IVS10 + 14 microtubule-associated protein tau mutation. Here, we describe the clinical and neuropathological data from an additional family. Neuropathological data were available for 2 of the 3 cases, III-4, and III-5. While III-5 had widespread tau deposition and atrophy, III-4 exhibited more mild neuropathological changes except for the substantia nigra. The previously reported families that express the IVS10 + 14 mutation exhibited significant interfamilial heterogeneity, with symptoms including amyotrophy, dementia, disinhibition, parkinsonism, and breathing problems. In addition to expressing many of these symptoms, members of this fourth family experienced profound sensory abnormalities and sleep disturbance. Although there were probable clinicopathological correlates for the symptoms expressed by the earlier families and III-5 from our cohort, pathology in III-4 did not appear sufficient to explain symptom severity. This indicates the need to explore alternate mechanisms of tau-induced brain dysfunction.
ESTHER : Maxwell_2021_Neurobiol.Aging_101_298 e1
PubMedSearch : Maxwell_2021_Neurobiol.Aging_101_298 e1
PubMedID: 33612310

Title : Distribution of acetylcholinesterase in the hippocampal formation of the Atlantic white-sided dolphin (Lagenorhynchus acutus) - Reid_2021_J.Comp.Neurol_529_1029
Author(s) : Reid GA , Darvesh S
Ref : Journal of Comparative Neurology , 529 :1029 , 2021
Abstract : The cetacean hippocampal formation has been noted to be one of the smallest relative to brain size of all mammals studied. This region, comprised of the dentate gyrus, hippocampus proper, subiculum, presubiculum, parasubiculum and the entorhinal cortex, is important in learning, memory, and navigation. There have been a number of studies detailing the distribution of acetylcholinesterase (AChE) in the hippocampal formation of terrestrial mammals with the goal of gaining a greater understanding of some aspects of the cholinergic innervation to this region, as well as its parcellation. The present study was undertaken to describe the organization, cytoarchitecture, and distribution of AChE in the hippocampal formation of the Atlantic white-sided dolphin (AWSD) with the view to understand similarities and differences between this aquatic mammal and terrestrial mammals. Nissl-staining demonstrated cytoarchitecture of the hippocampal formation in the AWSD comparable to that reported in other cetaceans. In addition, the AWSD had a rich pattern of AChE staining that distinctly varied between regions and laminae. A number of differences in the distribution of AChE staining in areas comparable to those of terrestrial species reported suggested possible alterations in connectivity of this region. Overall, however, AChE-staining suggested that cholinergic innervation, neural pathways and function of the hippocampal formation of the AWSD is conserved, similar to other mammals.
ESTHER : Reid_2021_J.Comp.Neurol_529_1029
PubMedSearch : Reid_2021_J.Comp.Neurol_529_1029
PubMedID: 32779183

Title : Clinicopathological correlations and cholinesterase expression in early-onset familial Alzheimer's disease with the presenilin 1 mutation, Leu235Pro - Cash_2021_Neurobiol.Aging_103_31
Author(s) : Cash MK , Rockwood K , Fisk JD , Darvesh S
Ref : Neurobiology of Aging , 103 :31 , 2021
Abstract : In sporadic Alzheimer's disease (SpAD), acetylcholinesterase and butyrylcholinesterase, co-regulators of acetylcholine, are associated with beta-amyloid plaques and tau neurofibrillary tangles in patterns suggesting a contribution to neurotoxicity. This association has not been explored in early-onset familial Alzheimer's disease (FAD). We investigated whether cholinesterases are observed in the neuropathological hallmarks in FAD expressing the presenilin 1 Leu235Pro mutation. Brain tissues from three FAD cases and one early-onset SpAD case were stained and analyzed for beta-amyloid, tau, alpha-synuclein, acetylcholinesterase and butyrylcholinesterase. AD pathology was prominent throughout the rostrocaudal extent of all 4 brains but alpha-synuclein-positive neurites were present in only one familial case. In FAD and SpAD cases, cholinergic activity was associated with plaques and tangles but not with alpha-synuclein pathology. Both cholinesterases showed similar or decreased plaque staining than detected with beta-amyloid immunostaining but greater plaque deposition than observed with thioflavin-S histofluorescence. Acetylcholinesterase and butyrylcholinesterase are highly associated with AD pathology in inherited disease and both may represent specific diagnostic and therapeutic targets for all AD forms.
ESTHER : Cash_2021_Neurobiol.Aging_103_31
PubMedSearch : Cash_2021_Neurobiol.Aging_103_31
PubMedID: 33789210

Title : Imaging Butyrylcholinesterase in Multiple Sclerosis - Thorne_2021_Mol.Imaging.Biol_23_127
Author(s) : Thorne MWD , Cash MK , Reid GA , Burley DE , Luke D , Pottie IR , Darvesh S
Ref : Mol Imaging Biol , 23 :127 , 2021
Abstract : PURPOSE: Molecular imaging agents targeting butyrylcholinesterase (BChE) have shown promise in other neurodegenerative disorders and may have utility in detecting changes to normal appearing white matter in multiple sclerosis (MS). BChE activity is present in white matter and localizes to activated microglia associated with MS lesions. The purpose of this study was to further characterize changes in the cholinergic system in MS pathology, and to explore the utility of BChE radioligands as potential diagnostic and treatment monitoring agents in MS. PROCEDURE: Cortical and white matter lesions were identified using myelin staining, and lesions were classified based on microglial activation patterns. Adjacent brain sections were used for cholinesterase histochemistry and in vitro autoradiography using phenyl 4-[(123)I]-iodophenylcarbamate ((123)I-PIP), a previously described small-molecule cholinesterase-binding radioligand. RESULTS: BChE activity is positively correlated with microglial activation in white matter MS lesions. There is no alteration in cholinesterase activity in cortical MS lesions. (123)I-PIP autoradiography revealed uptake of radioactivity in normal white matter, absence of radioactivity within demyelinated MS lesions, and variable uptake of radioactivity in adjacent normal-appearing white matter. CONCLUSIONS: BChE imaging agents have the potential to detect MS lesions and subtle pathology in normal-appearing white matter in postmortem MS brain tissue. The possibility of BChE imaging agents serving to supplement current diagnostic and treatment monitoring strategies should be evaluated.
ESTHER : Thorne_2021_Mol.Imaging.Biol_23_127
PubMedSearch : Thorne_2021_Mol.Imaging.Biol_23_127
PubMedID: 32926288

Title : 1-(3-Tert-Butylphenyl)-2,2,2-Trifluoroethanone as a Potent Transition-State Analogue Slow-Binding Inhibitor of Human Acetylcholinesterase: Kinetic, MD and QM\/MM Studies - Zueva_2020_Biomolecules_10_1608
Author(s) : Zueva IV , Lushchekina SV , Pottie IR , Darvesh S , Masson P
Ref : Biomolecules , 10 : , 2020
Abstract : Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with K(i) = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with K(i)* = 0.53 nM. Reversible binding of TFK provides a long residence time, = 20 min, on AChE. After binding, TFK acylates the active serine, forming an hemiketal. Then, disruption of hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the "isomerization" step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called "transition state analog", followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer's disease and protection of central AChE against organophosphorus compounds.
ESTHER : Zueva_2020_Biomolecules_10_1608
PubMedSearch : Zueva_2020_Biomolecules_10_1608
PubMedID: 33260981

Title : Evidence for Cholinergic Dysfunction in Autosomal Dominant Kufs Disease - Jarrett_2018_Can.J.Neurol.Sci_45_150
Author(s) : Jarrett P , Easton A , Rockwood K , Dyack S , McCollum A , Siu V , Mirsattari SM , Massot-Tarrus A , Beis MJ , D'Souza N , Darvesh S
Ref : Can Journal of Neurology Sci , 45 :150 , 2018
Abstract : OBJECTIVE: Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal lipopigments form lysosomal inclusion bodies in neurons. Kufs disease is rare, and clinical symptoms include seizures, progressive cognitive impairment, and myoclonus. Most cases of Kufs disease are autosomal recessive; however, there have been a few case reports of an autosomal dominant form linked to mutations within the DNAJC5 gene. METHODS: We describe a family with Kufs disease in which the proband and three of her four children presented with cognitive impairment, seizures, and myoclonus. RESULTS: Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene. The proband brain had an abundance of neuronal lipofuscin in the cerebral cortex, striatum, amygdala, hippocampus, substantia nigra, and cerebellum. There were no amyloid plaques or neurofibrillary tangles. Immunohistochemistry demonstrated that the cholinergic neurons and cholinergic projection fibers were spared, but there was a profound loss of choline acetyltransferase within the caudate, putamen, and basal forebrain. This suggests a loss of choline acetyltransferase as opposed to a loss of the neurons. CONCLUSIONS: This report describes the clinical history of autosomal dominant Kufs disease, the genetic mutation within the DNAJC5 gene, and the neuropathological findings demonstrating depletion of choline acetyltransferase in the brain.
ESTHER : Jarrett_2018_Can.J.Neurol.Sci_45_150
PubMedSearch : Jarrett_2018_Can.J.Neurol.Sci_45_150
PubMedID: 29506599

Title : The cholinergic system in the basal forebrain of the Atlantic white-sided dolphin (Lagenorhynchus acutus) - Reid_2018_J.Comp.Neurol_526_1910
Author(s) : Reid GA , Geula C , Darvesh S
Ref : Journal of Comparative Neurology , 526 :1910 , 2018
Abstract : The basal forebrain (BFB) cholinergic neurotransmitter system is important in a number of brain functions including attention, memory, and the sleep-wake cycle. The size of this region has been linked to the increase in encephalization of the brain in a number of species. Cetaceans, particularly those belonging to the family Delphinidae, have a relatively large brain compared to its body size and it is expected that the cholinergic BFB in the dolphin would be a prominent feature. However, this has not yet been explored in detail. This study examines and maps the neuroanatomy and cholinergic chemoarchitecture of the BFB in the Atlantic white-sided dolphin (Lagenorhynchus acutus). As in some other mammals, the BFB in this species is a prominent structure along the medioventral surface of the brain. The parcellation and distribution of cholinergic neural elements of the dolphin BFB was comparable to that observed in other mammals in that it has a medial septal nucleus, a nucleus of the vertical limb of the diagonal band of Broca, a nucleus of the horizontal limb of the diagonal band of Broca, and a nucleus basalis of Meynert. The observed BFB cholinergic system of this dolphin is consistent with evolutionarily conserved and important functions for survival.
ESTHER : Reid_2018_J.Comp.Neurol_526_1910
PubMedSearch : Reid_2018_J.Comp.Neurol_526_1910
PubMedID: 29700823

Title : Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus - Hamodat_2017_Neuropathol.Appl.Neurobiol_43_571
Author(s) : Hamodat H , Cash MK , Fisk JD , Darvesh S
Ref : Neuropathol Appl Neurobiol , 43 :571 , 2017
Abstract : AIMS: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and deposition of beta-amyloid (Abeta) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD. METHODS: Cytoarchitecture of the POG was studied using Nissl staining in normal (n = 8) and AD (n = 6) brains. Distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using histochemical methods. Abeta plaques and tau NFTs were detected using immunohistochemistry. Abundance of AD pathology was assessed using a semi-quantitative approach. RESULT: Nissl staining showed pyramidal cells in the AON and paleocortical organization of the OA. AChE stained neurons and neuropil in the AON and OA, while BChE activity was noted in the olfactory tract and in AON and OA neurons. Pathology was frequent in the AD POG and the abundance of BChE-associated AD pathology was greater than that associated with AChE. CONCLUSIONS: AChE and BChE activities in normal POG recapitulated their distributions in other cortical regions. Greater abundance of BChE-associated, in comparison to AChE-associated, AD pathology in the POG suggests preferential involvement of BChE in olfactory dysfunction in AD.
ESTHER : Hamodat_2017_Neuropathol.Appl.Neurobiol_43_571
PubMedSearch : Hamodat_2017_Neuropathol.Appl.Neurobiol_43_571
PubMedID: 28644906

Title : Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study - Rosenberry_2017_Molecules_22_
Author(s) : Rosenberry TL , Brazzolotto X , Macdonald IR , Wandhammer M , Trovaslet-Leroy M , Darvesh S , Nachon F
Ref : Molecules , 22 : , 2017
Abstract : Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.
ESTHER : Rosenberry_2017_Molecules_22_
PubMedSearch : Rosenberry_2017_Molecules_22_
PubMedID: 29186056
Gene_locus related to this paper: human-BCHE

Title : Targeting butyrylcholinesterase for preclinical single photon emission computed tomography (SPECT) imaging of Alzheimer's disease - DeBay_2017_Alzheimers.Dement.(N.Y)_3_166
Author(s) : DeBay DR , Reid GA , Pottie IR , Martin E , Bowen CV , Darvesh S
Ref : Alzheimers Dement (N Y) , 3 :166 , 2017
Abstract : INTRODUCTION: Diagnosis of Alzheimer's disease (AD) in vivo, by molecular imaging of amyloid or tau, is constrained because similar changes can be found in brains of cognitively normal individuals. Butyrylcholinesterase (BChE), which becomes associated with these structures in AD, could elevate the accuracy of AD diagnosis by focusing on BChE pathology in the cerebral cortex, a region of scant BChE activity in healthy brain.
METHODS: N-methylpiperidin-4-yl 4-[123I]iodobenzoate, a BChE radiotracer, was injected intravenously into B6SJL-Tg(APPSwFlLon, PSEN1 *M146 L *L286 V) 6799Vas/Mmjax (5XFAD) mice and their wild-type (WT) counterparts for comparative single photon emission computed tomography (SPECT) studies. SPECT, computed tomography (CT), and magnetic resonance imaging (MRI) enabled comparison of whole brain and regional retention of the BChE radiotracer in both mouse strains.
RESULTS: Retention of the BChE radiotracer was consistently higher in the 5XFAD mouse than in WT, and differences were particularly evident in the cerebral cortex. DISCUSSION: Cerebral cortical BChE imaging with SPECT can distinguish 5XFAD mouse model from the WT counterpart.
ESTHER : DeBay_2017_Alzheimers.Dement.(N.Y)_3_166
PubMedSearch : DeBay_2017_Alzheimers.Dement.(N.Y)_3_166
PubMedID: 29067326

Title : Butyrylcholinesterase-knockout reduces fibrillar beta-amyloid and conserves (18)FDG retention in 5XFAD mouse model of Alzheimer's disease - DeBay_2017_Brain.Res_1671_102
Author(s) : DeBay DR , Reid GA , Macdonald IR , Mawko G , Burrell S , Martin E , Bowen CV , Darvesh S
Ref : Brain Research , 1671 :102 , 2017
Abstract : Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of beta-amyloid (Abeta) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Abeta pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Abeta plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Abeta than 5XFAD mice at the same age. Therefore, BChE may have a role in Abeta pathogenesis. Furthermore, in AD, diminished glucose metabolism in the brain can be detected in vivo with positron emission tomography (PET) imaging following 2-deoxy-2-((18)F)fluoro-D-glucose ((18)FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Abeta burden, whole brain and regional uptake of (18)FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT5XFAD and WTBChE-KO) strains at 5months. Diminished fibrillar Abeta burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain (18)FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in (18)FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT5XFAD. Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WTBChE-KO, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Abeta, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice.
ESTHER : DeBay_2017_Brain.Res_1671_102
PubMedSearch : DeBay_2017_Brain.Res_1671_102
PubMedID: 28729192

Title : Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer's Disease - Macdonald_2017_J.Alzheimers.Dis_58_491
Author(s) : Macdonald IR , Maxwell SP , Reid GA , Cash MK , DeBay DR , Darvesh S
Ref : J Alzheimers Dis , 58 :491 , 2017
Abstract : Amyloid-beta (Abeta) plaques are a neuropathological hallmark of Alzheimer's disease (AD); however, a significant number of cognitively normal older adults can also have Abeta plaques. Thus, distinguishing AD from cognitively normal individuals with Abeta plaques (NwAbeta) based on Abeta plaque detection is challenging. It has been observed that butyrylcholinesterase (BChE) accumulates in plaques preferentially in AD. Thus, detecting BChE-associated plaques has the potential as an improved AD biomarker. We present Abeta, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (n = 8), NwAbeta (n = 6), cognitively normal without plaques (n = 8), and other common dementias including corticobasal degeneration, frontotemporal dementia with tau, dementia with Lewy bodies, and vascular dementia. Pathology burden in the orbitofrontal cortex, entorhinal cortex, amygdala, and hippocampal formation was determined and compared. The predictive value of Abeta and BChE quantification was determined, via receiver-operating characteristic plots, to evaluate their AD diagnostic performance using sensitivity, specificity, and area under curve (AUC) metrics. In general, Abeta and BChE-associated pathology were greater in AD, particularly in the orbitofrontal cortex. In this region, the largest increase (9.3-fold) was in BChE-associated pathology, observed between NwAbeta and AD, due to the virtual absence of BChE-associated plaques in NwAbeta brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided better diagnostic performance (AUC = 1.0, sensitivity/specificity = 100% /100%) when compared to Abeta (AUC = 0.98, 100% /85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management.
ESTHER : Macdonald_2017_J.Alzheimers.Dis_58_491
PubMedSearch : Macdonald_2017_J.Alzheimers.Dis_58_491
PubMedID: 28453492

Title : Reduced fibrillar beta-amyloid in subcortical structures in a butyrylcholinesterase-knockout Alzheimer disease mouse model - Darvesh_2016_Chem.Biol.Interact_259_307
Author(s) : Darvesh S , Reid GA
Ref : Chemico-Biological Interactions , 259 :307 , 2016
Abstract : The serine hydrolase, butyrylcholinesterase (BChE) is known to have a variety of enzymatic and non-enzymatic functions. In the brain, BChE is expressed mainly in glia, white matter and in distinct populations of neurons in areas important in cognition. In Alzheimer's disease (AD), many beta-amyloid (Abeta) plaques become associated with BChE activity, the significance of which is unclear. A mouse model of AD containing five familial AD genes (5XFAD) also exhibits Abeta plaques associated with BChE. We developed a comparable strain (5XFAD/BChE-KO) that is unable to synthesize BChE and reported diminished fibrillar Abeta deposits in the cerebral cortex of 5XFAD/BChE-KO mice, compared to 5XFAD counterparts at the same age. This effect was most significant in male mice. The present study extends comparison of the two strains with a detailed examination of fibrillar Abeta plaque burden in other regions of the brain that typically accumulate pathology and exhibit neurodegeneration. This work demonstrates that, as in the cerebral cortex, the absence of BChE leads to diminished fibrillar Abeta deposition in amygdala, hippocampal formation, thalamus and basal ganglia. This reduction is statistically significant in males, with a trend towards such reduction in female mice.
ESTHER : Darvesh_2016_Chem.Biol.Interact_259_307
PubMedSearch : Darvesh_2016_Chem.Biol.Interact_259_307
PubMedID: 27091549

Title : Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer's Disease - Darvesh_2016_Curr.Alzheimer.Res_13_1173
Author(s) : Darvesh S
Ref : Curr Alzheimer Res , 13 :1173 , 2016
Abstract : The serine hydrolase butyrylcholinesterase (BChE), like the related enzyme acetylcholinesterase (AChE), co-regulates metabolism of the neurotransmitter acetylcholine. In the human brain BChE is mainly expressed in white matter and glia and in distinct populations of neurons in regions that are important in cognition and behavior, functions compromised in Alzheimer's disease (AD). AD is a neurodegenerative disorder causing dementia with no cure nor means for definitive diagnosis during life. In AD, BChE is found in association with pathology, such as beta-amyloid (Abeta) plaques, particularly in the cerebral cortex where BChE is not normally found in quantity. Up to 30% of cognitively normal older adults have abundant Abeta deposition in the brain. We have designed an imaging agent that can detect, through autoradiography, BChE-associated Abeta plaques in the cerebral cortex of AD brains, but does not visualize Abeta plaques in brains of cognitively normal individuals. Furthermore, in an AD mouse model with BChE gene knocked out, there are up to 70% fewer fibrillar Abeta brain plaques, suggesting diminished BChE activity could prove beneficial as a curative approach to AD. To that end, we have examined numerous N-10-carbonyl phenothiazines that are specific inhibitors of human BChE, revealing important details of the enzyme's active site gorge. These phenothiazines can be designed without potential side effects caused by neurotransmitter receptor interactions. In conclusion, BChE is potentially an important target for diagnosis and treatment of AD.
ESTHER : Darvesh_2016_Curr.Alzheimer.Res_13_1173
PubMedSearch : Darvesh_2016_Curr.Alzheimer.Res_13_1173
PubMedID: 27040140

Title : Development of acetophenone ligands as potential neuroimaging agents for cholinesterases - Jollymore-Hughes_2016_Bioorg.Med.Chem_24_5270
Author(s) : Jollymore-Hughes CT , Pottie IR , Martin E , Rosenberry TL , Darvesh S
Ref : Bioorganic & Medicinal Chemistry , 24 :5270 , 2016
Abstract : Association of cholinesterase with beta-amyloid plaques and tau neurofibrillary tangles in Alzheimer's disease offers an opportunity to detect disease pathology during life. Achieving this requires development of radiolabelled cholinesterase ligands with high enzyme affinity. Various fluorinated acetophenone derivatives bind to acetylcholinesterase with high affinity, including 2,2,2-trifluoro-1-(3-dimethylaminophenyl)ethanone (1) and 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (2). Such compounds also offer potential for incorporation of radioactive fluorine (18F) for Positron Emission Tomography (PET) imaging of cholinesterases in association with Alzheimer's disease pathology in the living brain. Here we describe the synthesis of two meta-substituted chlorodifluoroacetophenones using a Weinreb amide strategy and their rapid conversion to the corresponding trifluoro derivatives through nucleophilic substitution by fluoride ion, in a reaction amenable to incorporating 18F for PET imaging. In vitro kinetic analysis indicates tight binding of the trifluoro derivatives to cholinesterases. Compound 1 has a Ki value of 7nM for acetylcholinesterase and 1300nM for butyrylcholinesterase while for compound 2 these values are 0.4nM and 26nM, respectively. Tight binding of these compounds to cholinesterase encourages their development for PET imaging detection of cholinesterase associated with Alzheimer's disease pathology.
ESTHER : Jollymore-Hughes_2016_Bioorg.Med.Chem_24_5270
PubMedSearch : Jollymore-Hughes_2016_Bioorg.Med.Chem_24_5270
PubMedID: 27637382

Title : Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology - Macdonald_2016_J.Nucl.Med_57_297
Author(s) : Macdonald IR , Reid GA , Pottie IR , Martin E , Darvesh S
Ref : J Nucl Med , 57 :297 , 2016
Abstract : Acetylcholinesterase and butyrylcholinesterase accumulate with brain beta-amyloid (Abeta) plaques in Alzheimer disease (AD). The overall activity of acetylcholinesterase is found to decline in AD, whereas butyrylcholinesterase has been found to either increase or remain the same. Although some cognitively normal older adults also have Abeta plaques within the brain, cholinesterase-associated plaques are generally less abundant in such individuals. Thus, brain imaging of cholinesterase activity associated with Abeta plaques has the potential to distinguish AD from cognitively normal older adults, with or without Abeta accumulation, during life. Current Abeta imaging agents are not able to provide this distinction. To address this unmet need, synthesis and evaluation of a cholinesterase-binding ligand, phenyl 4-(123)I-iodophenylcarbamate ((123)I-PIP), is described.
METHODS: Phenyl 4-iodophenylcarbamate was synthesized and evaluated for binding potency toward acetylcholinesterase and butyrylcholinesterase using enzyme kinetic analysis. This compound was subsequently rapidly radiolabeled with (123)I and purified by high-performance liquid chromatography. Autoradiographic analyses were performed with (123)I-PIP using postmortem orbitofrontal cortex from cognitively normal and AD human brains. Comparisons were made with an Abeta imaging agent, 2-(4'-dimethylaminophenyl)-6-(123)I-iodo-imidazo[1,2-a]pyridine ((123)I-IMPY), in adjacent brain sections. Tissues were also stained for Abeta and cholinesterase activity to visualize Abeta plaque load for comparison with radioligand uptake.
RESULTS: Synthesized and purified PIP exhibited binding to cholinesterases. (123)I was successfully incorporated into this ligand. (123)I-PIP autoradiography with human tissue revealed accumulation of radioactivity only in AD brain tissues in which Abeta plaques had cholinesterase activity. (123)I-IMPY accumulated in brain tissues with Abeta plaques from both AD and cognitively normal individuals. CONCLUSION: Radiolabeled ligands specific for cholinesterases have potential for use in neuroimaging AD plaques during life. The compound herein described, (123)I-PIP, can detect cholinesterases associated with Abeta plaques and can distinguish AD brain tissues from those of cognitively normal older adults with Abeta plaques. Imaging cholinesterase activity associated with Abeta plaques in the living brain may contribute to the definitive diagnosis of AD during life.
ESTHER : Macdonald_2016_J.Nucl.Med_57_297
PubMedSearch : Macdonald_2016_J.Nucl.Med_57_297
PubMedID: 26541777

Title : Butyrylcholinesterase-knockout reduces brain deposition of fibrillar beta-amyloid in an Alzheimer mouse model - Reid_2015_Neurosci_298_424
Author(s) : Reid GA , Darvesh S
Ref : Neuroscience , 298 :424 , 2015
Abstract : In Alzheimer's disease (AD), numerous beta-amyloid (Abeta) plaques are associated with butyrylcholinesterase (BChE) activity, the significance of which is unclear. A mouse model, containing five human familial AD genes (5XFAD), also develops Abeta plaques with BChE activity. Knock-out of BChE in this model showed diminished fibrillar Abeta plaque deposition, more so in males than females. This suggests that lack of BChE reduces deposition of fibrillar Abeta in AD and this effect may be influenced by sex.
ESTHER : Reid_2015_Neurosci_298_424
PubMedSearch : Reid_2015_Neurosci_298_424
PubMedID: 25931333

Title : Cholinesterase inhibition in Alzheimer's disease: is specificity the answer? - Macdonald_2014_J.Alzheimers.Dis_42_379
Author(s) : Macdonald IR , Rockwood K , Martin E , Darvesh S
Ref : J Alzheimers Dis , 42 :379 , 2014
Abstract : Cholinesterase inhibitors are the standard of care for Alzheimer's disease (AD). Acetylcholinesterase (AChE) catalyzes the hydrolysis of the cholinergic neurotransmitter acetylcholine. However, the related enzyme butyrylcholinesterase (BCHE) also breaks down acetylcholine and is likewise targeted by the same clinical cholinesterase inhibitors. The lack of clinical efficacy for the highly specific and potent AChE inhibitor, (-) huperzine A, is intriguing, given the known cholinergic deficit in AD. Based on the proven efficacy of inhibitors affecting both cholinesterases and the apparent failure of specific AChE inhibition, focused BCHE inhibition seems important for more effective treatment of AD. Therefore, BCHE-selective inhibitors provide promise for improved benefit.
ESTHER : Macdonald_2014_J.Alzheimers.Dis_42_379
PubMedSearch : Macdonald_2014_J.Alzheimers.Dis_42_379
PubMedID: 24898642

Title : Selectivity of phenothiazine cholinesterase inhibitors for neurotransmitter systems - Darvesh_2013_Bioorg.Med.Chem.Lett_23_3822
Author(s) : Darvesh S , Macdonald IR , Martin E
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :3822 , 2013
Abstract : Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer's disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer's disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer's disease.
ESTHER : Darvesh_2013_Bioorg.Med.Chem.Lett_23_3822
PubMedSearch : Darvesh_2013_Bioorg.Med.Chem.Lett_23_3822
PubMedID: 23707254

Title : Thioesters for the in vitro evaluation of agents to image brain cholinesterases - Macdonald_2013_J.Enzyme.Inhib.Med.Chem_28_447
Author(s) : Macdonald IR , Jollymore CT , Reid GA , Pottie IR , Martin E , Darvesh S
Ref : J Enzyme Inhib Med Chem , 28 :447 , 2013
Abstract : Cholinesterases are associated with pathology characteristic of conditions such as Alzheimer's disease and are therefore, considered targets for neuroimaging. Ester derivatives of N-methylpiperidinol are promising potential imaging agents; however, methodology is lacking for evaluating these compounds in vitro. Here, we report the synthesis and evaluation of a series of N-methylpiperidinyl thioesters, possessing comparable properties to their corresponding esters, which can be directly evaluated for cholinesterase kinetics and histochemical distribution in human brain tissue. N-methylpiperidinyl esters and thioesters were synthesized and they demonstrated comparable cholinesterase kinetics. Furthermore, thioesters were capable, using histochemical method, to visualize cholinesterase activity in human brain tissue. N-methylpiperidinyl thioesters can be rapidly evaluated for cholinesterase kinetics and visualization of enzyme distribution in brain tissue which may facilitate development of cholinesterase imaging agents for application to conditions such as Alzheimer's disease.
ESTHER : Macdonald_2013_J.Enzyme.Inhib.Med.Chem_28_447
PubMedSearch : Macdonald_2013_J.Enzyme.Inhib.Med.Chem_28_447
PubMedID: 22233541

Title : Butyrylcholinesterase and the cholinergic system - Reid_2013_Neurosci_234_53
Author(s) : Reid GA , Chilukuri N , Darvesh S
Ref : Neuroscience , 234 :53 , 2013
Abstract : The cholinergic system plays important roles in neurotransmission in both the peripheral and central nervous systems. The cholinergic neurotransmitter acetylcholine is synthesized by choline acetyltransferase (ChAT) and its action terminated by acetylcholinesterase (AChE) and butyrylcholinesterase (BCHE). The predominance of AChE has focused much attention on understanding the relationship of this enzyme to ChAT-positive cholinergic neurons. However, there is ample evidence that BCHE also plays an important role in cholinergic regulation. To elucidate the relationship of BCHE to neural elements that are producing acetylcholine, the distribution of this enzyme was compared to that of ChAT in the mouse CNS. Brain tissues from 129S1/SvImJ mice were stained for BCHE and ChAT using histochemical, immunohistochemical and immunofluorescent techniques. Both BCHE and ChAT were found in neural elements throughout the CNS. BCHE staining with histochemistry and immunohistochemistry produced the same distribution of labeling throughout the brain and spinal cord. Immunofluorescent double labeling demonstrated that many nuclei in the medulla oblongata, as well as regions of the spinal cord, had neurons that contained both BCHE and ChAT. BCHE-positive neurons without ChAT were found in close proximity with ChAT-positive neuropil in areas such as the thalamus and amygdala. BCHE-positive neuropil was also found closely associated with ChAT-positive neurons, particularly in tegmental nuclei of the pons. These observations provide further neuroanatomical evidence of a role for BCHE in the regulation of acetylcholine levels in the CNS.
ESTHER : Reid_2013_Neurosci_234_53
PubMedSearch : Reid_2013_Neurosci_234_53
PubMedID: 23305761

Title : Butyrylcholinesterase radioligands to image Alzheimer's disease brain - Darvesh_2013_Chem.Biol.Interact_203_354
Author(s) : Darvesh S
Ref : Chemico-Biological Interactions , 203 :354 , 2013
Abstract : Butyrylcholinesterase (BCHE) is found to have a brain distribution pattern that is distinct from that of acetylcholinesterase (AChE). Neurons containing BCHE are particularly located in the amygdala, hippocampal formation and the thalamus, structures involved in the normal functions of cognition and behavior that typically become compromised in Alzheimer's disease (AD). Progress of this disease is thought to result, at least in part, from the accumulation of beta-amyloid (Abeta) plaques and neurofibrillary tangles (NFTs) in the brain. These structures characteristically become associated with cholinesterase activity, and are major determinants of AD diagnosis post-mortem. Early definitive AD diagnosis in the living brain could greatly facilitate specific timely treatment of the disorder and the search for novel drugs to preempt progress of this disease. Radioligands have been developed to detect deposition of Abeta plaques in the brain; however, since many cognitively normal individuals also exhibit Abeta plaque deposition, this approach has inherent disadvantages for definitive AD diagnosis during life. The association of BCHE with Abeta plaques appears to be a characteristic of AD. This has prompted the search for radioligands that target BCHE in association with Abeta plaques that accumulate in cortical grey matter, a region normally with very little of this enzyme activity. A number of BCHE radioligands have been synthesized and preliminary testing indicates that some such radioligands enter the brain and accumulate in regions known to contain BCHE. Radioligands targeting unusual BCHE activity in the brain may represent a means for early diagnosis and treatment monitoring of AD.
ESTHER : Darvesh_2013_Chem.Biol.Interact_203_354
PubMedSearch : Darvesh_2013_Chem.Biol.Interact_203_354
PubMedID: 22935510

Title : Probing the peripheral site of human butyrylcholinesterase - Macdonald_2012_Biochemistry_51_7046
Author(s) : Macdonald IR , Martin E , Rosenberry TL , Darvesh S
Ref : Biochemistry , 51 :7046 , 2012
Abstract : Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) catalyze the hydrolysis of the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. For both enzymes, hydrolysis takes place near the bottom of a 20 deep active site gorge. A number of amino acid residues within the gorge have been identified as important in facilitating efficient catalysis and inhibitor binding. Of particular interest is the catalytic triad, consisting of serine, histidine, and glutamate residues, that mediates hydrolysis. Another site influencing the catalytic process is located above the catalytic triad toward the periphery of the active site gorge. This peripheral site (P-site) contains a number of aromatic amino acid residues as well as an aspartate residue that is able to interact with cationic substrates and guide them down the gorge to the catalytic triad. In human AChE, certain aryl residues in the vicinity of the anionic aspartate residue (D74), such as W286, have been implicated in ligand binding and have therefore been considered part of the P-site of the enzyme. The present study was undertaken to explore the P-site of human BuChE and determine whether, like AChE, aromatic side chains near the peripheral aspartate (D70) of this enzyme contribute to ligand binding. Results obtained, utilizing inhibitor competition studies and BuChE mutant species, indicate the participation of aryl residues (F329 and Y332) in the E-helix component of the BuChE active site gorge, along with the anionic aspartate residue (D70), in binding ligands to the P-site of the enzyme.
ESTHER : Macdonald_2012_Biochemistry_51_7046
PubMedSearch : Macdonald_2012_Biochemistry_51_7046
PubMedID: 22901043

Title : Butyrylcholinesterase is associated with beta-amyloid plaques in the transgenic APPSWE\/PSEN1dE9 mouse model of Alzheimer disease - Darvesh_2012_J.Neuropathol.Exp.Neurol_71_2
Author(s) : Darvesh S , Cash MK , Reid GA , Martin E , Mitnitski A , Geula C
Ref : J Neuropathol Experimental Neurology , 71 :2 , 2012
Abstract : Histochemical analysis of Alzheimer disease (AD) brain tissues indicates that butyrylcholinesterase (BuChE) is present in beta-amyloid (Abeta) plaques. The role of BuChE in AD pathology is unknown, but an animal model developing similar BuChE-associated Abeta plaques could provide insights. The APPSWE/PSEN1dE9 transgenic mouse (ADTg), which develops Abeta plaques, was examined to determine if BuChE associates with these plaques, as in AD. We found that in mature ADTg mice, BuChE activity associated with Abeta plaques. The Abeta-, thioflavin-S- and BuChE-positive plaques mainly accumulated in the olfactory structures, cerebral cortex, hippocampal formation, amygdala, and cerebellum. No plaques were stained for acetylcholinesterase activity. The distribution and abundance of plaque staining in ADTg closely resembled many aspects of plaque staining in AD. Butyrylcholinesterase staining consistently showed fewer plaques than were detected with Abeta immunostaining but a greater number of plaques than were visualized with thioflavin-S. Double-labeling experiments demonstrated that all BuChE-positive plaques were Abeta positive, whereas only some BuChE-positive plaques were thioflavin-S positive. These observations suggest that BuChE is associated with a subpopulation of Abeta plaques and may play a role in AD plaque maturation. A further study of this animal model could clarify the role of BuChE in AD pathology.
ESTHER : Darvesh_2012_J.Neuropathol.Exp.Neurol_71_2
PubMedSearch : Darvesh_2012_J.Neuropathol.Exp.Neurol_71_2
PubMedID: 22157615

Title : Synergistic inhibition of butyrylcholinesterase by galantamine and citalopram - Walsh_2011_Biochim.Biophys.Acta_1810_1230
Author(s) : Walsh R , Rockwood K , Martin E , Darvesh S
Ref : Biochimica & Biophysica Acta , 1810 :1230 , 2011
Abstract : BACKGROUND: Many persons with Alzheimer's disease (AD) treated with galantamine appear to receive additional cognitive benefit from citalopram. Both drugs inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These enzymes co-regulate acetylcholine catabolism. In AD brain, AChE is diminished while BuChE is not, suggesting BuChE inhibition may be important in raising acetylcholine levels. BuChE is subject to activation at high acetylcholine levels reached at the synaptic cleft. The present study explores one way combining galantamine and citalopram could be beneficial in AD. METHODS: Spectrophotometric studies of BuChE catalysis in the absence or presence of galantamine or citalopram or both, were performed using the Ellman method. Data analysis involved expansion of our previous equation describing BuChE catalysis. RESULTS: Galantamine almost completely inhibited BuChE at low substrate concentrations (V(S)=43.6 muM/min; V(S(gal))=0.34 muM/min) without influencing the substrate-activated form of the enzyme (V(SS)=64.0 muM/min;V(SS(gal))=62.3 muM/min). Conversely, citalopram inhibited both un-activated (V(S)=43.6 muM/min; V(S(cit))=10.2 muM/min) and substrate-activated (V(SS)=64.0 muM/min; V(SS(cit))=47.3 muM/min) forms of BuChE. Combined galantamine and citalopram increased inhibition of un-activated BuChE (V(S)=43.6 muM/min; V(S(gal)(cit))=2.73 muM/min) and substrate-activated form (V(SS)=64.0 muM/min; V(SS(gal)(cit))=42.2 muM/min). CONCLUSION: Citalopram and galantamine produce a combined inhibition of BuChE that is considered to be synergistic. GENERAL SIGNIFICANCE: Clinical benefit from combined galantamine and citalopram may be related to a synergistic inhibition of BuChE, facilitating cholinergic neurotransmission. This emphasizes the importance of further study into use of drug combinations in AD treatment.
ESTHER : Walsh_2011_Biochim.Biophys.Acta_1810_1230
PubMedSearch : Walsh_2011_Biochim.Biophys.Acta_1810_1230
PubMedID: 21872646

Title : Potentially procholinergic effects of medications commonly used in older adults - Rockwood_2011_Am.J.Geriatr.Pharmacother_9_80
Author(s) : Rockwood K , Walsh R , Martin E , Darvesh S
Ref : Am J Geriatr Pharmacother , 9 :80 , 2011
Abstract : BACKGROUND: Older adults are susceptible to a variety of illnesses, many of which can be treated with medications that may need to be used for the long term. Considerable attention has been paid to drugs that, in addition to their intended function, may have an anticholinergic effect that results in undesirable side effects, including impairment in cognition. Cholinesterase inhibitors are used as procholinergic drugs to improve cognitive dysfunction in Alzheimer's disease. We hypothesized that some of the drugs commonly used by older adults might, in addition to their intended function, also have procholinergic effects by virtue of inhibiting cholinesterases. OBJECTIVE: To determine the potential procholinergic nature of some of the commonly used drugs by examining their cholinesterase inhibiting properties. METHODS: The Ellman spectrophotometric method was used with human acetylcholinesterase and butyrylcholinesterase, in the absence and presence of increasing concentrations of each test drug. To compare inhibition potencies, from enzyme kinetic data, we determined half maximal inhibitory concentration (IC(50) values) for each cholinesterase by each drug. RESULTS: Of the 28 drugs examined, over half (17/28) inhibited one or both of the human cholinesterases. The inhibition potencies were often within 1 to 2 orders of magnitude of reversible cholinesterase inhibitors currently used to treat Alzheimer's disease. These included trazodone, quetiapine, risperidone, indapamide, and perindopril. CONCLUSIONS: Many drugs used by older adults for other reasons have potentially clinically relevant procholinergic effects. The effect of cumulative cholinesterase inhibition merits clinical evaluation.
ESTHER : Rockwood_2011_Am.J.Geriatr.Pharmacother_9_80
PubMedSearch : Rockwood_2011_Am.J.Geriatr.Pharmacother_9_80
PubMedID: 21459311

Title : Synthesis and preliminary evaluation of piperidinyl and pyrrolidinyl iodobenzoates as imaging agents for butyrylcholinesterase - Macdonald_2011_Mol.Imaging.Biol_13_1250
Author(s) : Macdonald IR , Reid GA , Joy EE , Pottie IR , Matte G , Burrell S , Mawko G , Martin E , Darvesh S
Ref : Mol Imaging Biol , 13 :1250 , 2011
Abstract : PURPOSE: The purpose of this study is to synthesize and evaluate specific agents for molecular imaging of butyrylcholinesterase (BuChE), known to be associated with neuritic plaques and neurofibrillary tangles in Alzheimer's disease (AD). In this study, these agents were tested in a normal rat model. The distribution of radiolabel was compared with known BuChE histochemical distribution in the rat brain. PROCEDURES: Iodobenzoate esters were synthesized and tested, through spectrophotometric analysis, as specific substrates for BuChE. These compounds were converted to the corresponding (123)I esters from tributyltin intermediates and purified for studies in the rat model. Whole body dynamic scintigraphic images were obtained for biodistribution studies. Autoradiograms of brain sections were obtained and compared to histochemical distribution of the enzyme in this model system. RESULTS: The three iodobenzoate esters studied were specific substrates for BuChE. Whole body biodistribution studies with (123)I-labeled compounds showed rapid disappearance from the body while radioactivity was retained in the head region. Brain section autoradiography of animals injected with these labeled compounds indicated that most areas known to contain BuChE corresponded to areas of radioactivity accumulation. CONCLUSION: BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.
ESTHER : Macdonald_2011_Mol.Imaging.Biol_13_1250
PubMedSearch : Macdonald_2011_Mol.Imaging.Biol_13_1250
PubMedID: 20976626

Title : Butyrylcholinesterase activity in multiple sclerosis neuropathology - Darvesh_2010_Chem.Biol.Interact_187_425
Author(s) : Darvesh S , Leblanc AM , Macdonald IR , Reid GA , Bhan V , Macaulay RJ , Fisk JD
Ref : Chemico-Biological Interactions , 187 :425 , 2010
Abstract : Butyrylcholinesterase (BuChE) is an enzyme capable of hydrolysing a wide variety of esters including acetylcholine, a molecule involved in neurotransmission and modulation of immune cell activity. In the brain, BuChE is expressed in white matter and certain populations of neurons and glia. Multiple sclerosis (MS) is an autoimmune disease affecting white matter characterized by neuroinflammation and neurodegeneration in the central nervous system. Here we demonstrate alterations in BuChE activity in MS white matter lesions, including diminished enzyme activity associated with myelin and an increased activity in cells with microglial morphology. Increased BuChE activity within MS lesions could contribute to the pro-inflammatory immune responses through hydrolysis of acetylcholine and to demyelination through hydrolytic deacylation of myelin proteins such as proteolipid protein. This suggests that BuChE could be a potential target for novel disease-modifying strategies for MS.
ESTHER : Darvesh_2010_Chem.Biol.Interact_187_425
PubMedSearch : Darvesh_2010_Chem.Biol.Interact_187_425
PubMedID: 20122907

Title : Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants - Darvesh_2010_Bioorg.Med.Chem_18_2232
Author(s) : Darvesh S , Pottie IR , Darvesh KV , McDonald RS , Walsh R , Conrad S , Penwell A , Mataija D , Martin E
Ref : Bioorganic & Medicinal Chemistry , 18 :2232 , 2010
Abstract : A series of N-10 urea derivatives of phenothiazine was synthesized and each compound was evaluated for its ability to inhibit human cholinesterases. Most were specific inhibitors of BuChE. However, the potent inhibitory effects on both cholinesterases of one sub-class, the cationic aminoureas, provide an additional binding mechanism to cholinesterases for these compounds. The comparative effects of aminoureas on wild-type BuChE and several BuChE mutants indicate a binding process involving salt linkage with the aspartate of the cholinesterase peripheral anionic site. The effect of such compounds on cholinesterase activity at high substrate concentration supports ionic interaction of aminoureas at the peripheral anionic site.
ESTHER : Darvesh_2010_Bioorg.Med.Chem_18_2232
PubMedSearch : Darvesh_2010_Bioorg.Med.Chem_18_2232
PubMedID: 20181484

Title : Biochemical and histochemical comparison of cholinesterases in normal and Alzheimer brain tissues - Darvesh_2010_Curr.Alzheimer.Res_7_386
Author(s) : Darvesh S , Reid GA , Martin E
Ref : Curr Alzheimer Res , 7 :386 , 2010
Abstract : Cholinesterase activity associated with neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains exhibit altered histochemical properties, such as requiring lower pH (6.8) for optimal cholinesterase staining compared to the pH (8.0) for best visualization of cholinesterases in neurons. Furthermore, visualization of NPs and NFTs can be prevented by agents like the peptidase inhibitor/metalloantibiotic bacitracin. The anomalous behavior of cholinesterases associated with pathological lesions needs to be elucidated because of the putative links between these enzymes and the disease process in AD. In this study, cholinesterases were extracted from AD and normal brain tissue to determine whether the differences observed in histochemical analyses in the two sources were reflected in kinetic properties measured in solubilized enzymes. Isolated brain enzymes from both these sources exhibited comparable kinetic parameters with respect to pH dependence, substrate affinity and inhibitor sensitivity and were not significantly affected by other agents that blocked cholinesterase histochemical visualization, such as the structurally diverse metal-chelating antibiotics bacitracin, doxycycline, minocycline and rifampicin. Although the cholinesterases from AD brain tissue examined here represented a total pool of these enzymes from AD brain, rather than enzymes specifically from NPs and NFTs, their kinetic behavior being comparable to cholinesterases isolated from normal brain tissues implies that these enzymes do not undergo disease-related modification in their primary structures. This suggests that the atypical histochemical behavior of cholinesterases in NPs and NFTs may result from interaction of cholinesterases with other molecules within these lesions, mediated by transition metal ions known to be present in AD pathology lesions.
ESTHER : Darvesh_2010_Curr.Alzheimer.Res_7_386
PubMedSearch : Darvesh_2010_Curr.Alzheimer.Res_7_386
PubMedID: 19939227

Title : Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase - Darvesh_2008_J.Med.Chem_51_4200
Author(s) : Darvesh S , Darvesh KV , McDonald RS , Mataija D , Walsh R , Mothana S , Lockridge O , Martin E
Ref : Journal of Medicinal Chemistry , 51 :4200 , 2008
Abstract : Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to pi-pi interaction of the phenothiazine moiety with F329 and Y332 in butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the butyrylcholinesterase active site gorge, such as the peripheral anionic site and the pi-cationic site of the Omega-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dementias.
ESTHER : Darvesh_2008_J.Med.Chem_51_4200
PubMedSearch : Darvesh_2008_J.Med.Chem_51_4200
PubMedID: 18570368

Title : Aryl acylamidase activity of human serum albumin with o-nitrotrifluoroacetanilide as the substrate - Masson_2007_J.Enzyme.Inhib.Med.Chem_22_463
Author(s) : Masson P , Froment MT , Darvesh S , Schopfer LM , Lockridge O
Ref : J Enzyme Inhib Med Chem , 22 :463 , 2007
Abstract : Albumin is generally regarded as an inert protein with no enzyme activity. However, albumin has esterase activity as well as aryl acylamidase activity. A new acetanilide substrate, o-nitrotrifluoroacetanilide (o-NTFNAC), which is more reactive than the classical o-nitroacetanilide, made it possible to determine the catalytic parameters for hydrolysis by fatty-acid free human serum albumin. Owing to the low enzymatic activity of albumin, kinetic studies were performed at high albumin concentration (0.075 mM). The albumin behavior with this substrate was Michaelis-Menten like. Kinetic analysis was performed according to the formalism used for catalysis at high enzyme concentration. This approach provided values for the turnover and dissociation constant of the albumin-substrate complex: k(cat) = 0.13 +/- 0.02 min(-1) and Ks = 0.67 +/- 0.04 mM. MALDI-TOF experiments showed that unlike the ester substrate p-nitrophenyl acetate, o-NTFNAC does not form a stable adduct (acetylated enzyme). Kinetic analysis and MALDI-TOF experiments demonstrated that hydrolysis of o-NTFNAC by albumin is fully rate-limited by the acylation step (k(cat) = k2). Though the aryl acylamidase activity of albumin is low (k(cat)/Ks = 195 M(-1)min(-1)), because of its high concentration in human plasma (0.6-1 mM), albumin may participate in hydrolysis of aryl acylamides through second-order kinetics. This suggests that albumin may have a role in the metabolism of endogenous and exogenous aromatic amides, including drugs and xenobiotics.
ESTHER : Masson_2007_J.Enzyme.Inhib.Med.Chem_22_463
PubMedSearch : Masson_2007_J.Enzyme.Inhib.Med.Chem_22_463
PubMedID: 17847714

Title : Kinetic analysis of butyrylcholinesterase-catalyzed hydrolysis of acetanilides - Masson_2007_Biochim.Biophys.Acta_1774_1139
Author(s) : Masson P , Froment MT , Gillon E , Nachon F , Darvesh S , Schopfer LM
Ref : Biochimica & Biophysica Acta , 1774 :1139 , 2007
Abstract : The aryl-acylamidase (AAA) activity of butyrylcholinesterase (BuChE) has been known for a long time. However, the kinetic mechanism of aryl-acylamide hydrolysis by BuChE has not been investigated. Therefore, the catalytic properties of human BuChE and its peripheral site mutant (D70G) toward neutral and charged aryl-acylamides were determined. Three neutral (o-nitroacetanilide, m-nitroacetanilide, o-nitrophenyltrifluoroacetamide) and one positively charged (3-(acetamido) N,N,N-trimethylanilinium, ATMA) acetanilides were studied. Hydrolysis of ATMA by wild-type and D70G enzymes showed a long transient phase preceding the steady state. The induction phase was characterized by a hysteretic "burst". This reflects the existence of two enzyme states in slow equilibrium with different catalytic properties. Steady-state parameters for hydrolysis of the three acetanilides were compared to catalytic parameters for hydrolysis of esters giving the same acetyl intermediate. Wild-type BuChE showed substrate activation while D70G displayed a Michaelian behavior with ATMA as with positively charged esters. Owing to the low affinity of BuChE for amide substrates, the hydrolysis kinetics of neutral amides was first order. Acylation was the rate-determining step for hydrolysis of aryl-acetylamide substrates. Slow acylation of the enzyme, relative to that by esters may, in part, be due suboptimal fit of the aryl-acylamides in the active center of BuChE. The hypothesis that AAA and esterase active sites of BuChE are non-identical was tested with mutant BuChE. It was found that mutations on the catalytic serine, S198C and S198D, led to complete loss of both activities. The silent variant (FS117) had neither esterase nor AAA activity. Mutation in the peripheral site (D70G) had the same effect on esterase and AAA activities. Echothiophate inhibited both activities identically. It was concluded that the active sites for esterase and AAA activities are identical, i.e. S198. This excludes any other residue present in the gorge for being the catalytic nucleophile pole.
ESTHER : Masson_2007_Biochim.Biophys.Acta_1774_1139
PubMedSearch : Masson_2007_Biochim.Biophys.Acta_1774_1139
PubMedID: 17690023

Title : Sensitivity of butyrylcholinesterase knockout mice to (--)-huperzine A and donepezil suggests humans with butyrylcholinesterase deficiency may not tolerate these Alzheimer's disease drugs and indicates butyrylcholinesterase function in neurotransmission - Duysen_2007_Toxicology_233_60
Author(s) : Duysen EG , Li B , Darvesh S , Lockridge O
Ref : Toxicology , 233 :60 , 2007
Abstract : Butyrylcholinesterase (EC 3.1.1.8 BChE) is present in all human and mouse tissues, and is more abundant than acetylcholinesterase (EC 3.1.1.7 AChE) in all tissues except brain. People who have no BChE activity due to a genetic variation are healthy. This has led to the hypothesis that BChE has no physiological function. We tested this hypothesis by challenging BChE and AChE knockout mice, as well as wild-type mice, with the AChE specific inhibitors, (--)-huperzine A and donepezil, and with serine hydrolase inhibitors, echothiophate and chlorpyrifos oxon. (--)-Huperzine A and donepezil caused mortality and significant toxicity in the BChE-/- animals. The BChE heterozygote (BCHE+/-) mice with approximately one-half the BChE activity of the BChE wild type (BChE+/+) exhibited intermediate toxic symptoms, and survived a longer period. The BChE+/+ animals displayed comparatively minor toxic symptoms and recovered by 24h post-dosing. Plasma AChE activity was inhibited to the same extent in BChE-/-, +/-, and +/+ mice, whereas BChE activity was not inhibited. This indicated that the protective effect of BChE was not due to scavenging (--)-huperzine A. AChE-/- mice were unaffected by (--)-huperzine A and donepezil, demonstrating the specificity of these inhibitors for AChE. AChE-/- mice treated with chlorpyrifos oxon lost all BChE activity, had severe cholinergic symptoms and died of convulsions. This showed that BChE activity was essential for survival of AChE-/- mice. In conclusion, we propose that the protective effect of BChE is explained by hydrolysis of excess acetylcholine in physiologically relevant regions such as diaphragm, cardiac muscle, and brain. Thus, BChE has a function in neurotransmission. People with BChE deficiency are expected to be intolerant of standard doses of the anti-Alzheimer's drugs, (--)-huperzine A and donepezil.
ESTHER : Duysen_2007_Toxicology_233_60
PubMedSearch : Duysen_2007_Toxicology_233_60
PubMedID: 17194517

Title : Human serum cholinesterase from liver pathological samples exhibit highly elevated aryl acylamidase activity - Boopathy_2007_Clin.Chim.Acta_380_151
Author(s) : Boopathy R , Rajesh RV , Darvesh S , Layer PG
Ref : Clinica Chimica Acta , 380 :151 , 2007
Abstract : BACKGROUND: Although aspartate aminotransferase (AST) and gamma-glutamyltransferase (gamma GT) enzymes are widely used as markers for liver disorders, the ubiquitous enzyme butyrylcholinesterase (BChE), synthesized in liver is also used as marker in the assessment of liver pathophysiology. This BChE enzyme in addition to its esterase activity has yet another enzymatic function designated as aryl acylamidase (AAA) activity. It is determined in in vitro based on the hydrolysis of the synthetic substrate o-nitroacetanilide. In the present study, human serum cholinesterase (BChE) activity was studied with respect to its AAA activity on the BChE protein (AAA(BChE)) in patients with liver disorders. AST and gamma GT values were taken into account in this study as known markers for liver disorders. METHODS: Blood samples were grouped into 3 based on esterase activity associated with BChE protein. They are normal, low, and very low BChE activity but with markedly increased AST and gamma GT levels. These samples were tested for their respective AAA function. Association of AAA with BChE from samples was proved using BChE monoclonal antibody precipitation experiment. RESULTS: The absolute levels of AAA were increased as BChE activity decreased while deviating from normal samples and such deviation was directly proportional to the severity of the liver disorder. Differences between these groups became prominent after determining the ratios of AAA(BChE) to BChE activities. Samples showing very high AAA(BChE) to BChE ratio were also showing high to very high gamma GT values. CONCLUSIONS: These findings establish AAA(BChE) as an independently regulated enzymatic activity on BChE especially in liver disorders. Moreover, since neither the low esterase activity of BChE by itself nor increased levels of AST/gamma GT are sufficient pathological indicators, this pilot study merits replication with large sample numbers.
ESTHER : Boopathy_2007_Clin.Chim.Acta_380_151
PubMedSearch : Boopathy_2007_Clin.Chim.Acta_380_151
PubMedID: 17379201

Title : A versatile equation to describe reversible enzyme inhibition and activation kinetics: modeling beta-galactosidase and butyrylcholinesterase - Walsh_2007_Biochim.Biophys.Acta_1770_733
Author(s) : Walsh R , Martin E , Darvesh S
Ref : Biochimica & Biophysica Acta , 1770 :733 , 2007
Abstract : Current treatments for Alzheimer's disease involve inhibiting cholinesterases. Conversely, cholinesterase stimulation may be deleterious. Homocysteine is a known risk factor for Alzheimer's and vascular diseases and its active metabolite, homocysteine thiolactone, stimulates butyrylcholinesterase. Considering the opposing effects on butyrylcholinesterase of homocysteine thiolactone and cholinesterase inhibitors, understanding how these molecules alter this enzyme may provide new insights in the management of dementia. Butyrylcholinesterase does not strictly adhere to Michaelis-Menten parameters since, at higher substrate concentrations, enzyme activation occurs. The substrate activation equation for butyrylcholinesterase does not describe the effects of inhibitors or non-substrate activators. To address this, global data fitting was used to generate a flexible equation based on Michaelis-Menten principles. This methodology was first tested to model complexities encountered in inhibition by imidazole of beta-galactosidase, an enzyme that obeys Michaelis-Menten kinetics. The resulting equation was sufficiently flexible to permit expansion for modeling activation or inhibition of butyrylcholinesterase, while accounting for substrate activation of this enzyme. This versatile equation suggests that both the inhibitor and non-substrate activator examined here have little effect on the substrate-activated form of butyrylcholinesterase. Given that butyrylcholinesterase inhibition can antagonize stimulation of this enzyme by homocysteine thiolactone, cholinesterase inhibition may have a role in treating Alzheimer and vascular diseases related to hyperhomocysteinemia.
ESTHER : Walsh_2007_Biochim.Biophys.Acta_1770_733
PubMedSearch : Walsh_2007_Biochim.Biophys.Acta_1770_733
PubMedID: 17307293

Title : Selective reversible inhibition of human butyrylcholinesterase by aryl amide derivatives of phenothiazine - Darvesh_2007_Bioorg.Med.Chem_15_6367
Author(s) : Darvesh S , McDonald RS , Darvesh KV , Mataija D , Conrad S , Gomez G , Walsh R , Martin E
Ref : Bioorganic & Medicinal Chemistry , 15 :6367 , 2007
Abstract : Evidence suggests that specific inhibition of butyrylcholinesterase may be an appropriate focus for the development of more effective drugs to treat dementias such as Alzheimer's disease. Butyrylcholinesterase is a co-regulator of cholinergic neurotransmission and its activity is increased in Alzheimer's disease, and is associated with all neuropathological lesions in this disease. Some selective butyrylcholinesterase inhibitors have already been reported to increase acetylcholine levels and to reduce the formation of abnormal amyloid found in Alzheimer's disease. Synthesized N-(10)-aryl and N-(10)-alkylaryl amides of phenothiazine are specific inhibitors of butyrylcholinesterase. In some cases, inhibition constants in the nanomolar range are achieved. Enzyme specificity and inhibitor potency of these molecules can be related to molecular volumes, steric and electronic factors. Computed logP values indicate high potential for these compounds to cross the blood-brain barrier. Use of such butyrylcholinesterase inhibitors could provide direct evidence for the importance of this enzyme in the normal nervous system and in Alzheimer's disease.
ESTHER : Darvesh_2007_Bioorg.Med.Chem_15_6367
PubMedSearch : Darvesh_2007_Bioorg.Med.Chem_15_6367
PubMedID: 17681768

Title : Comparison of cognitive functions between people with silent and wild-type butyrylcholinesterase - Manoharan_2007_J.Neural.Transm.(Vienna)_114_939
Author(s) : Manoharan I , Kuznetsova A , Fisk JD , Boopathy R , Lockridge O , Darvesh S
Ref : J Neural Transm (Vienna) , 114 :939 , 2007
Abstract : In the human brain, butyrylcholinesterase (BuChE) is expressed in neurons and glia. For example, many nuclei in the human thalamus, with projections to the cerebral cortex, contain a large number of neurons with intense BuChE activity. Thalamocortical projections subserve a variety of cognitive functions. Due to genetic mutations, there are individuals who do not have detectable BuChE activity (silent BuChE). While the prevalence of silent BuChE is only 1:100,000 in European and American populations, it is 1:24 in the Vysya community in Coimbatore, India. To examine whether there are differences in cognitive functions between individuals with silent BuChE and those expressing normal BuChE (wild-type), twelve healthy individuals with silent BuChE and thirteen healthy individuals with wild-type BuChE, all from the Vysya community in Coimbatore, were tested for cognitive function using the Automated Neuropsychological Assessment Metrics test battery. The silent BuChE group was slightly faster on simple reaction tasks, but slower on a visual perceptual matching task. Furthermore, discriminant function analyses correctly classified 11/12 silent and 8/13 wild-type BuChE subjects (76% correct classification overall) based on BuChE status. Different profiles of cognitive test performance between individuals with silent and wild-type BuChE were observed. These observations suggest a function for BuChE in cognition.
ESTHER : Manoharan_2007_J.Neural.Transm.(Vienna)_114_939
PubMedSearch : Manoharan_2007_J.Neural.Transm.(Vienna)_114_939
PubMedID: 17318303

Title : A medical health report on individuals with silent butyrylcholinesterase in the Vysya community of India - Manoharan_2007_Clin.Chim.Acta_378_128
Author(s) : Manoharan I , Boopathy R , Darvesh S , Lockridge O
Ref : Clinica Chimica Acta , 378 :128 , 2007
Abstract : BACKGROUND: Butyrylcholinesterase (BChE; gi:116353) deficiency has adverse effects on the response to succinylcholine and mivacurium. A physiological function of BChE is to inactivate octanoyl ghrelin. We determined the health effect of complete absence of BChE in humans.
METHODS: Clinical tests of cardiac, lung, liver, and kidney function, body weight, sperm counts and motility were performed on 5 men, age 20-32 y, in the Vysya community of Coimbatore, India who had silent BChE. Postmortem tissues from 2 cadavers with wild-type BChE were assayed.
RESULTS: Test results were normal, except for lung function, which indicated mild obstruction in silent as well as in wild-type BChE subjects. Creatine kinase-MB levels were high in 2 subjects, but there were no other indications of damage to the heart. Body weight was normal. Family histories revealed no trend in disease susceptibility. The human body contains 10 times more BChE than acetylcholinesterase molecules. CONCLUSION: Individuals completely deficient in BChE have only minor abnormalities in clinical test results. However, they respond abnormally to standard doses of succinylcholine and mivacurium. It is expected, but not proven, that they are unusually susceptible to the toxicity of cocaine and organophosphorus pesticides, and resistant to bambuterol and irinotecan. Their normal body weight suggests alternative routes for deactivation of octanoyl ghrelin.
ESTHER : Manoharan_2007_Clin.Chim.Acta_378_128
PubMedSearch : Manoharan_2007_Clin.Chim.Acta_378_128
PubMedID: 17182021

Title : Homocysteine thiolactone and human cholinesterases - Darvesh_2007_Cell.Mol.Neurobiol_27_33
Author(s) : Darvesh S , Walsh R , Martin E
Ref : Cellular Molecular Neurobiology , 27 :33 , 2007
Abstract : 1. The cholinergic system is important in cognition and behavior as well as in the function of the cerebral vasculature. 2. Hyperhomocysteinemia is a risk factor for development of both dementia and cerebrovascular disease. 3. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are serine hydrolase enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine, a key process in the regulation of the cholinergic system. 4. It has been hypothesized that the deleterious effects of elevated homocysteine may, in part, be due to its actions on cholinesterases. 5. To further test this hypothesis, homocysteine and a number of its metabolites and analogues were examined for effects on the activity of human cholinesterases. 6. Homocysteine itself did not have any measurable effect on the activity of these enzymes. 7. Homocysteine thiolactone, the cyclic metabolite of homocysteine, slowly and irreversibly inhibited the activity of human AChE. 8. Conversely, this metabolite and some of its analogues significantly enhanced the activity of human BuChE. 9. Structure-activity studies indicated that the unprotonated amino group of homocysteine thiolactone and related compounds represents the essential feature for activation of BuChE, whereas the thioester linkage appears to be responsible for the slow AChE inactivation. 10. It is concluded that hyperhomocysteinemia may exert its adverse effects, in part, through the metabolite of homocysteine, homocysteine thiolactone, which is capable of altering the activity of human cholinesterases, the most pronounced effect being BuChE activation.
ESTHER : Darvesh_2007_Cell.Mol.Neurobiol_27_33
PubMedSearch : Darvesh_2007_Cell.Mol.Neurobiol_27_33
PubMedID: 16955366

Title : On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases - Darvesh_2006_Bioorg.Med.Chem_14_4586
Author(s) : Darvesh S , McDonald RS , Darvesh KV , Mataija D , Mothana S , Cook H , Carneiro KM , Richard N , Walsh R , Martin E
Ref : Bioorganic & Medicinal Chemistry , 14 :4586 , 2006
Abstract : Cholinesterases, in addition to their well-known esterase action, also show an aryl acylamidase (AAA) activity whereby they catalyze the hydrolysis of amides of certain aromatic amines. The biological function of this catalysis is not known. Furthermore, it is not known whether the esterase catalytic site is involved in the AAA activity of cholinesterases. It has been speculated that the AAA activity, especially that of butyrylcholinesterase (BuChE), may be important in the development of the nervous system and in pathological processes such as formation of neuritic plaques in Alzheimer's disease (AD). The substrate generally used to study the AAA activity of cholinesterases is N-(2-nitrophenyl)acetamide. However, use of this substrate requires high concentrations of enzyme and substrate, and prolonged periods of incubation at elevated temperature. As a consequence, difficulties in performing kinetic analysis of AAA activity associated with cholinesterases have hampered understanding this activity. Because of its potential biological importance, we sought to develop a more efficient and specific substrate for use in studying the AAA activity associated with BuChE, and for exploring the catalytic site for this hydrolysis. Here, we describe the structure-activity relationships for hydrolysis of anilides by cholinesterases. These studies led to a substrate, N-(2-nitrophenyl)trifluoroacetamide, that was hydrolyzed several orders of magnitude faster than N-(2-nitrophenyl)acetamide by cholinesterases. Also, larger N-(2-nitrophenyl)alkylamides were found to be more rapidly hydrolyzed by BuChE than N-(2-nitrophenyl)acetamide and, in addition, were more specific for hydrolysis by BuChE. Thus, N-(2-nitrophenyl)alkylamides with six to eight carbon atoms in the acyl group represent suitable specific substrates to investigate further the function of the AAA activity of BuChE. Based on the substrate structure-activity relationships and kinetic studies, the hydrolysis of anilides and esters of choline appears to utilize the same catalytic site in BuChE.
ESTHER : Darvesh_2006_Bioorg.Med.Chem_14_4586
PubMedSearch : Darvesh_2006_Bioorg.Med.Chem_14_4586
PubMedID: 16504521

Title : Improved prediction of early-onset coronary artery disease using APOE epsilon4, BChE-K, PPARgamma2 Pro12 and ENOS T-786C in a polygenic model - Nassar_2006_Clin.Biochem_39_109
Author(s) : Nassar BA , Rockwood K , Kirkland SA , Ransom TP , Darvesh S , MacPherson K , Johnstone DE , O'Neill BJ , Bata IR , Andreou P , Jeffery JS , Cox JL , Title LM
Ref : Clinical Biochemistry , 39 :109 , 2006
Abstract : OBJECTIVES: Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD [apolipoprotein E (APOE) epsilon4, butyrylcholinesterase (BChE) K, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala and endothelial nitric oxide synthase (ENOS) T-786C]. DESIGN AND
METHODS: We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD (n = 150; <50 years), late-onset CAD (n = 150; >65 years) and healthy controls (n = 150, age range 47-93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes.
RESULTS: Early-onset CAD patients had increased, but non-significant, frequencies of PPARgamma2 Pro12/Pro12 (P = 0.39) and ENOS T-786C (P = 0.72), while BChE-K was only significantly higher in early-onset CAD patients compared to controls (P = 0.03). There were significantly more APOE epsilon4 alleles alone (P = 0.02) or in combination with BChE-K (P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%, P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for PPARgamma2 to 1.70 for APOE epsilon4). This increased to 2.78 (1.44-5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%.
CONCLUSIONS: While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.
ESTHER : Nassar_2006_Clin.Biochem_39_109
PubMedSearch : Nassar_2006_Clin.Biochem_39_109
PubMedID: 16298355

Title : Tomographic visualization of cholinesterase -
Author(s) : Kuljis RO , Darvesh S , Greig NH , Geula C
Ref : Annals of Neurology , 60 :745 , 2006
PubMedID: 17111417

Title : Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives - Darvesh_2005_Bioorg.Med.Chem_13_211
Author(s) : Darvesh S , McDonald RS , Penwell A , Conrad S , Darvesh KV , Mataija D , Gomez G , Caines A , Walsh R , Martin E
Ref : Bioorganic & Medicinal Chemistry , 13 :211 , 2005
Abstract : Several lines of evidence indicate that inhibition of butyrylcholinesterase (BuChE) is important in the treatment of certain dementias. Further testing of this concept requires inhibitors that are both BuChE-selective and robust. N-alkyl derivatives (2, 3, 4) of phenothiazine (1) have previously been found to inhibit only BuChE in a mechanism involving pi-pi interaction between the phenothiazine tricyclic ring system and aromatic residues in the active site gorge. To explore features of phenothiazines that affect the selectivity and potency of BuChE inhibition, a series of N-carbonyl derivatives (5-25) was synthesized and examined for the ability to inhibit cholinesterases. Some of the synthesized derivatives also inhibited AChE through a different mechanism involving carbonyl interaction within the active site gorge. Binding of these derivatives takes place within the gorge, since this inhibition disappears when the molecular volume of the derivative exceeds the estimated active site gorge volume of this enzyme. In contrast, BuChE, with a much larger active site gorge, exhibited inhibition that increased directly with the molecular volumes of the derivatives. This study describes two distinct mechanisms for binding phenothiazine amide derivatives to BuChE and AChE. Molecular volume was found to be an important parameter for BuChE-specific inhibition.
ESTHER : Darvesh_2005_Bioorg.Med.Chem_13_211
PubMedSearch : Darvesh_2005_Bioorg.Med.Chem_13_211
PubMedID: 15582466

Title : Cholinesterases: roles in the brain during health and disease - Ballard_2005_Curr.Alzheimer.Res_2_307
Author(s) : Ballard CG , Greig NH , Guillozet-Bongaarts AL , Enz A , Darvesh S
Ref : Curr Alzheimer Res , 2 :307 , 2005
Abstract : The cholinergic hypothesis of decline in dementia, whereby deficits in learning, memory and behavior are caused, at least in part, by decreased levels of acetylcholine (ACh) in the brain, first emerged more than 20 years ago. The role for acetylcholinesterase (AChE) and its inhibition in this scheme has long been accepted, but findings from preclinical experiments and clinical trials have placed butyrylcholinesterase (BuChE) alongside AChE as an important contributor to the occurrence, symptoms, progression and responses to treatment in dementia. A number of new lines of evidence suggest that both cholinesterase inhibitors (ChEs) may have broader functions in the CNS than previously thought, which relate to both 'classical' esterase activities of the enzymes as well as non-classical actions unrelated to their enzymatic function. Data suggest involvement of the ChEs in modulating glial activation, cerebral blood flow, the amyloid cascade, and tau phosphorylation. It has therefore been speculated that some actions of the ChEs could affect the underlying disease processes in Alzheimer's disease (AD), and that pharmacological manipulation with ChE inhibitors may affect long-term disease progression. Focusing on new findings relating to BuChE, we review recent evidence that has extended knowledge into the roles of ChEs in health, disease and aging.
ESTHER : Ballard_2005_Curr.Alzheimer.Res_2_307
PubMedSearch : Ballard_2005_Curr.Alzheimer.Res_2_307
PubMedID: 15974896

Title : Cholinesterase inhibitors modify the activity of intrinsic cardiac neurons - Darvesh_2004_Exp.Neurol_188_461
Author(s) : Darvesh S , Arora RC , Martin E , Magee D , Hopkins DA , Armour JA
Ref : Experimental Neurology , 188 :461 , 2004
Abstract : Cholinesterase inhibitors used to treat the symptoms of Alzheimer's disease (AD) inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), albeit to different degrees. Because central and peripheral neurons, including intrinsic cardiac neurons located on the surface of the mammalian heart, express both BuChE and AChE, we studied spontaneously active intrinsic cardiac neurons in the pig as a model to assess the effects of inhibition of AChE compared to BuChE. Neuroanatomical experiments showed that some porcine intrinsic cardiac neurons expressed AChE and/or BuChE. Enzyme kinetic experiments with cholinesterase inhibitors, namely, donepezil, galantamine, (+/-) huperzine A, metrifonate, rivastigmine, and tetrahydroaminoacridine, demonstrated that these compounds differentially inhibited porcine AChE and BuChE. Donepezil and (+/-) huperzine A were better reversible inhibitors of AChE, and galantamine equally inhibited both the enzymes. Tetrahydroaminoacridine was a better reversible inhibitor of BuChE. Rivastigmine caused more rapid inactivation of BuChE as compared to AChE. Neurophysiological studies showed that acetylcholine and butyrylcholine increase or decrease the spontaneous activity of the intrinsic cardiac neurons. Donepezil, galantamine, (+/-) huperzine A, and tetrahydroaminoacridine changed spontaneous neuronal activity by about 30-35 impulses per minute, while rivastigmine changed it by approximately 100 impulses per minute. It is concluded that (i) inhibition of AChE and BuChE directly affects the porcine intrinsic cardiac nervous system, (ii) the intrinsic cardiac nervous system represents a suitable model for examining the effects of cholinesterase inhibitors on mammalian neurons in vivo, and (iii) the activity of intrinsic cardiac neurons may be affected by pharmacological agents that inhibit cholinesterases.
ESTHER : Darvesh_2004_Exp.Neurol_188_461
PubMedSearch : Darvesh_2004_Exp.Neurol_188_461
PubMedID: 15246845

Title : Differential effects of lipid-lowering agents on human cholinesterases - Darvesh_2004_Clin.Biochem_37_42
Author(s) : Darvesh S , Martin E , Walsh R , Rockwood K
Ref : Clinical Biochemistry , 37 :42 , 2004
Abstract : OBJECTIVES: Epidemiologic reports indicate that lipid-lowering agents (LLAs) protect against dementia. We hypothesized that LLAs might affect cholinergic systems. The effects of LLAs on the activity of cholinesterases were examined. DESIGN AND
METHODS: Odds ratios and relative risks were calculated from clinical studies of LLAs and dementia and compared with their impacts on human cholinesterases. Representative LLAs were examined for their effects on the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using Ellman's assay.
RESULTS: Epidemiological studies, but not clinical trials, showed lower odds of dementia in patients taking "statins". Comparison of LLAs indicated that "statins" most consistently produced apparent protection. Individual "statins" showed differential cholinesterase inhibition. Lovastatin and simvastatin significantly inhibited butyrylcholinesterase, while mevastatin, pravastatin and the "non-statins" did not. None of the LLAs inhibited acetylcholinesterase.
CONCLUSIONS: Some "statins" inhibit butyrylcholinesterase. This inhibition suggests a possible means whereby "statins" could protect against dementia.
ESTHER : Darvesh_2004_Clin.Biochem_37_42
PubMedSearch : Darvesh_2004_Clin.Biochem_37_42
PubMedID: 14675561

Title : Butyrylcholinesterase, cholinergic neurotransmission and the pathology of Alzheimer's disease - Geula_2004_Drugs.Today.(Barc)_40_711
Author(s) : Geula C , Darvesh S
Ref : Drugs Today (Barc) , 40 :711 , 2004
Abstract : Butyrylcholinesterase is a serine hydrolase biochemically related to the cholinergic enzyme acetylcholinesterase. It is capable of hydrolyzing esters of choline. Butyrylcholinesterase has unique enzymatic properties and is widely distributed in the nervous system, raising the possibility of its involvement in neural function. In particular, recent evidence indicates that along with acetylcholinesterase, butyrylcholinesterase catalyzes the hydrolysis of acetylcholine, and thus serves as a co-regulator of cholinergic transmission. Accumulating evidence also indicates that butyrylcholinesterase is likely to be involved in neurodegenerative disorders such as Alzheimer's disease. Therefore, inhibition of butyrylcholinesterase will not only lead to enhanced cholinergic transmission but also has the potential to interfere with the disease process in Alzheimer's disease and other dementing disorders.
ESTHER : Geula_2004_Drugs.Today.(Barc)_40_711
PubMedSearch : Geula_2004_Drugs.Today.(Barc)_40_711
PubMedID: 15510242

Title : Neurobiology of butyrylcholinesterase -
Author(s) : Darvesh S , Hopkins DA , Geula C
Ref : Nat Rev Neurosci , 4 :131 , 2003
PubMedID: 12563284

Title : Differential distribution of butyrylcholinesterase and acetylcholinesterase in the human thalamus - Darvesh_2003_J.Comp.Neurol_463_25
Author(s) : Darvesh S , Hopkins DA
Ref : Journal of Comparative Neurology , 463 :25 , 2003
Abstract : It has been hypothesized that acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are coregulators of the duration of action of acetylcholine in cholinergic neurotransmission, suggesting that BuChE may also have an important role in the brain. To compare the expression of cholinesterases in the human thalamus, the distributions of BuChE and AChE activity were studied by using a modified Karnovsky-Roots method. BuChE activity was present mainly in neurons, whereas AChE activity was present in both neurons and axons. There was intense staining for BuChE or AChE throughout the thalamus, with some nuclei primarily expressing one or the other cholinesterase. BuChE staining was most intense and widespread in neurons in the anteroventral, mediodorsal, ventral, lateral, and pulvinar thalamic nuclei. AChE was predominantly expressed in neurons of the anterodorsal, midline, ventral, intralaminar, and reticular nuclei. Many nuclei contained both cholinesterases. Considering the overall patterns of labeling in the thalamus for the two cholinesterases, there were both complementary and overlapping relationships of BuChE and AChE activity. Neuronal staining in the subthalamic nucleus and hypothalamus was predominantly positive for AChE activity. The distinct distribution of BuChE activity in neurons in the human thalamus is consistent with an important role for this enzyme in neurotransmission in the human nervous system. Furthermore, BuChE activity, like AChE activity, is found in certain thalamic nuclei related to cognitive and behavioral functions. Involvement of thalamic nuclei in diseases of the nervous system such as Alzheimer's disease and schizophrenia suggests that BuChE could be a potential target for therapeutic intervention in these disorders.
ESTHER : Darvesh_2003_J.Comp.Neurol_463_25
PubMedSearch : Darvesh_2003_J.Comp.Neurol_463_25
PubMedID: 12811800

Title : Inhibition of human cholinesterases by drugs used to treat Alzheimer disease - Darvesh_2003_Alzheimer.Dis.Assoc.Disord_17_117
Author(s) : Darvesh S , Walsh R , Kumar R , Caines A , Roberts S , Magee D , Rockwood K , Martin E
Ref : Alzheimer Disease & Associated Disorders , 17 :117 , 2003
Abstract : Current approaches to the treatment of cognitive and behavioral symptoms of Alzheimer disease emphasize the use of cholinesterase inhibitors. The kinetic effects of the cholinesterase inhibitors donepezil, galantamine, metrifonate, physostigmine, rivastigmine, and tetrahydroaminoacridine were examined with respect to their action on the esterase and aryl acylamidase activities of human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE). Each of these drugs inhibited both AChE and BuChE, but to different degrees. Inhibition of BuChE by these compounds was approximately the same, or better, when acetylthiocholine, the analog of the neurotransmitter acetylcholine, was used as the substrate, instead of butyrylthiocholine. In addition, for these drugs, the inhibition of aryl acylamidase activity paralleled that observed for inhibition of esterase activity of AChE and BuChE. Given that drugs that are currently in use for the treatment of Alzheimer disease inhibit both AChE and BuChE, the development of drugs targeted toward the exclusive inhibition of one or the other cholinesterase may be important for understanding the relative importance of inhibition of BuChE and AChE in the treatment of this disease.
ESTHER : Darvesh_2003_Alzheimer.Dis.Assoc.Disord_17_117
PubMedSearch : Darvesh_2003_Alzheimer.Dis.Assoc.Disord_17_117
PubMedID: 12794390

Title : Enantiomer effects of huperzine A on the aryl acylamidase activity of human cholinesterases - Darvesh_2003_Cell.Mol.Neurobiol_23_93
Author(s) : Darvesh S , Walsh R , Martin E
Ref : Cellular Molecular Neurobiology , 23 :93 , 2003
Abstract : 1. Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) are serine hydrolase enzymes that catalyze the hydrolysis of acetylcholine. 2. (-) Huperzine A is an inhibitor of AChE and is being considered for the treatment of Alzheimer's disease. 3. In addition to esterase activity, AChE and BuChE have intrinsic aryl acylamidase activity. 4. The function of aryl acylamidase is unknown but has been speculated to be important in Alzheimer pathology. 5. Kinetic effects of (-) huperzine A and (+/-) huperzine A on the aryl acylamidase activity of human cholinesterases were examined. 6. (-) Huperzine A inhibited the aryl acylamidase activities of both AChE and BuChE. 7. (+/-) Huperzine A inhibited this function in AChE but stimulated BuChE aryl acylamidase suggesting that the (+) enantiomer is a powerful activator of this enzyme activity. 8. The two huperzine enantiomers may prove to be useful tools to examine the function of aryl acylamidase activity, including its role in Alzheimer pathology.
ESTHER : Darvesh_2003_Cell.Mol.Neurobiol_23_93
PubMedSearch : Darvesh_2003_Cell.Mol.Neurobiol_23_93
PubMedID: 12701885

Title : Relation between butyrylcholinesterase K variant, paraoxonase 1 (PON1) Q and R and apolipoprotein E epsilon 4 genes in early-onset coronary artery disease - Nassar_2002_Clin.Biochem_35_205
Author(s) : Nassar BA , Darvesh S , Bevin LD , Rockwood K , Kirkland SA , O'Neill BJ , Bata IR , Johnstone DE , Title LM
Ref : Clinical Biochemistry , 35 :205 , 2002
Abstract : OBJECTIVES: The common K variant of butyrylcholinesterase (BChE-K), an enzyme which metabolizes acetylcholine and organophosphates, has been associated with Alzheimer's disease, especially in the presence of the apolipoprotein E epsilon 4 allele (APOE-epsilon 4). Although APOE-epsilon 4 has been associated with the development of coronary artery disease (CAD), an association between the BChE-K variant and CAD has not been explored. Paraoxonase 1 (PON1), located within HDL, is an enzyme which also metabolizes organophosphates and may be antiatherogenic. The R192 variant of PON1 (PON1-R) has been associated with CAD. DESIGN AND
METHODS: To determine whether BChE-K is also associated with premature CAD, we examined the frequency of BChE-K among patients with early-onset CAD (n = 150; < 50 yr) vs. late-onset CAD (n = 150; > 65 yr) by molecular analysis. We also examined the frequency of the PON1-R allele in both groups, and explored whether there was synergism between BChE-K and APOE-epsilon 4, BChE-K and PON1-R or PON1-R and APOE-epsilon 4.
RESULTS: The frequency of the BChE-K allele tended to be greater among early-onset CAD patients compared to late-onset CAD patients (41.3% vs. 31.3%; p = 0.07), but without any significant difference between males and females. There was no difference in the prevalence of the PON1-R allele between those with early- or late-onset CAD (46.0% vs. 52.7%; p = 0.25). Twenty-two patients with early-onset CAD had both the BChE-K plus APOE-epsilon 4 alleles (14.7%) compared to 11 late-onset CAD patients (7.3%) (p = 0.04). There was no such association between BChE-K and PON1-R, nor PON1-R and APOE-epsilon 4.
CONCLUSIONS: Our study suggests that there is a minor association between BChE-K and early-onset CAD, especially in the presence of the APOE-epsilon 4 allele.
ESTHER : Nassar_2002_Clin.Biochem_35_205
PubMedSearch : Nassar_2002_Clin.Biochem_35_205
PubMedID: 12074828

Title : Butyrylcholinesterase and cognitive function - Darvesh_2001_Int.Psychogeriatr_13_461
Author(s) : Darvesh S , MacKnight C , Rockwood K
Ref : Int Psychogeriatr , 13 :461 , 2001
Abstract : Butyrylcholinesterase (BuChE) is expressed in brain structures involved in cognition, but the effect of selective BuChE inhibitors on human cognitive function is unknown. We report a patient whose cognitive function deteriorated following a reduction and improved following reinstitution of ethopropazine, a selective BuChE inhibitor. We suggest that, because neurons expressing BuChE may be involved in cognition, there is merit to further evaluation of selective BuChE inhibitors in treating cognitive dysfunction.
ESTHER : Darvesh_2001_Int.Psychogeriatr_13_461
PubMedSearch : Darvesh_2001_Int.Psychogeriatr_13_461
PubMedID: 12003252

Title : Butyrylcholinesterase-Mediated enhancement of the enzymatic activity of trypsin - Darvesh_2001_Cell.Mol.Neurobiol_21_285
Author(s) : Darvesh S , Kumar R , Roberts S , Walsh R , Martin E
Ref : Cellular Molecular Neurobiology , 21 :285 , 2001
Abstract : 1. Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) are enzymes that catalyze the hydrolysis of esters of choline. 2. Both AChE and BuChE have been shown to copurify with peptidases. 3. BuChE has also been shown to copurify with other proteins such as transferrin, with which it forms a stable complex. In addition, BuChE is found in association with beta-amyloid protein in Alzheimer brain tissues. 4. Since BuChE copurifies with peptidases, we hypothesized that BuChE interacts with these enzymes and that this association had an influence on their catalytic activities. One of the peptidases that copurifies with cholinesterases has specificity similar to trypsin, hence, this enzyme was used as a model to test this hypothesis. 5. Purified BuChE causes a concentration-dependent enhancement of the catalytic activity of trypsin while trypsin does not influence the catalytic activity of BuChE. 6. We suggest that, in addition to its esterase activity, BuChE may assume a regulatory role by interacting with other proteins.
ESTHER : Darvesh_2001_Cell.Mol.Neurobiol_21_285
PubMedSearch : Darvesh_2001_Cell.Mol.Neurobiol_21_285
PubMedID: 11569538

Title : Cholinesterases in cardiac ganglia and modulation of canine intrinsic cardiac neuronal activity - Darvesh_1998_J.Auton.Nerv.Syst_71_75
Author(s) : Darvesh S , MacDonald SE , Losier AM , Martin E , Hopkins DA , Armour JA
Ref : J Auton Nerv Syst , 71 :75 , 1998
Abstract : Cholinergic neurotransmission plays a significant role in intrinsic cardiac ganglia with the action of acetylcholine being terminated by acetylcholinesterase (AChE, EC 3.1.1.7). Anatomical studies were performed to characterize neurons associated with AChE and a closely related enzyme, butyrylcholinesterase (BuChE, EC 3.1.1.8), in canine intrinsic cardiac ganglia. Histochemical staining for AChE and BuChE in canine right atrial neurons showed that there were four neuronal populations, namely, those that contained AChE only, BuChE only, both AChE and BuChE, and those that did not contain either enzymes. The neuronal activity of intrinsic cardiac neurons in response to substrates and inhibitors of cholinesterases were studied in anesthetized dogs. The activity of intrinsic cardiac neurons, as measured by changes in the number of action potentials, increased by local application of acetylcholine. However, local application of butyrylcholine led to a considerably greater increase in the activity of intrinsic cardiac neurons. In keeping with the neurochemical heterogeneity in intrinsic cardiac ganglia with respect to cholinesterases, the activity generated by most butyrylcholine-sensitive neurons was not influenced by acetylcholine and the activity generated by the most acetylcholine-sensitive neurons was not influenced by butyrylcholine. This suggests that these two agents preferentially influence different populations of intrinsic cardiac neurons. Enzyme kinetic studies demonstrated that canine AChE preferentially catalyzed the hydrolysis of acetylcholine while canine BuChE preferentially catalyzed the hydrolysis of butyrylcholine. Cholinesterase inhibitors Ro 2-1250 and Ro 2-0638 inhibited both canine cholinesterases, while huperzine A preferentially inhibited canine AChE and ethopropazine inhibited canine BuChE. The activity of neurons in the intrinsic cardiac ganglia significantly increased when Ro 2-1250 or Ro 2-0638 was administered locally. The activity of neurons was not affected when huperzine A or ethopropazine was administered, indicating that both cholinesterases must be inhibited to increase neuronal activity. In summary, these data show that in addition to AChE, intrinsic cardiac ganglia also contain distinct populations of neurons that are associated with BuChE, and the activity generated by these neurons is differentially influenced by their substrates. Because simultaneous inhibition of AChE and BuChE leads to increased neuronal activity, it is concluded that AChE- and BuChE-positive intrinsic cardiac neurons may act synergistically to influence the overall tonic activity of intrinsic cardiac ganglia.
ESTHER : Darvesh_1998_J.Auton.Nerv.Syst_71_75
PubMedSearch : Darvesh_1998_J.Auton.Nerv.Syst_71_75
PubMedID: 9760044

Title : Distribution of butyrylcholinesterase in the human amygdala and hippocampal formation - Darvesh_1998_J.Comp.Neurol_393_374
Author(s) : Darvesh S , Grantham DL , Hopkins DA
Ref : Journal of Comparative Neurology , 393 :374 , 1998
Abstract : The distribution of the major cholinergic regulatory enzyme acetylcholinesterase (AChE, EC 3.1.1.7) has been extensively studied in the human brain, but the distribution of the closely related enzyme butyrylcholinesterase (BCHE, EC 3.1.1.8) is largely unknown. Because of the importance of BCHE and AChE in Alzheimer's disease, we have studied the distribution of BCHE in the normal human amygdala and hippocampal formation and compared it with that of AChE by using histochemical techniques. In the amygdala, the distribution of BCHE differed significantly from that of AChE in that BCHE was found primarily in neurons and their dendritic processes, whereas AChE was found predominantly in the neuropil. BCHE-positive neurons were present in up to 10% of the neuronal profiles in lateral, basolateral (basal), basomedial (accessory basal), central, cortical, and medial amygdaloid nuclei. AChE was found primarily in the neuropil in these nuclei with only a few AChE-positive neurons. In the hippocampal formation, BCHE was also found in neurons and not in the neuropil, whereas AChE was found in both neurons and in the neuropil. BCHE and AChE neurons were present in the polymorphic layer of the dentate gyrus, as well as the stratum oriens and stratum pyramidale of the hippocampus proper. There was considerable overlap in shapes, sizes, and numbers of BCHE- and AChE-positive neurons, suggesting that the enzymes were colocalized in neurons of the hippocampal formation. The distinct distribution of BCHE suggests that it may have specific functions including coregulation of cholinergic and noncholinergic neurotransmission in human amygdala and hippocampal formation.
ESTHER : Darvesh_1998_J.Comp.Neurol_393_374
PubMedSearch : Darvesh_1998_J.Comp.Neurol_393_374
PubMedID: 9548556