Garcia ML

References (4)

Title : Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP\/PS1 Mice - Viayna_2021_J.Med.Chem_64_812
Author(s) : Viayna E , Coquelle N , Cieslikiewicz-Bouet M , Cisternas P , Oliva CA , Sanchez-Lopez E , Ettcheto M , Bartolini M , De Simone A , Ricchini M , Rendina M , Pons M , Firuzi O , Perez B , Saso L , Andrisano V , Nachon F , Brazzolotto X , Garcia ML , Camins A , Silman I , Jean L , Inestrosa NC , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 64 :812 , 2021
Abstract : The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Abeta42/Abeta40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
ESTHER : Viayna_2021_J.Med.Chem_64_812
PubMedSearch : Viayna_2021_J.Med.Chem_64_812
PubMedID: 33356266
Gene_locus related to this paper: human-ACHE

Title : Memantine for the Treatment of Dementia: A Review on its Current and Future Applications - Folch_2018_J.Alzheimers.Dis_62_1223
Author(s) : Folch J , Busquets O , Ettcheto M , Sanchez-Lopez E , Castro-Torres RD , Verdaguer E , Garcia ML , Olloquequi J , Casadesus G , Beas-Zarate C , Pelegri C , Vilaplana J , Auladell C , Camins A
Ref : J Alzheimers Dis , 62 :1223 , 2018
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-beta protein (Abeta) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Abeta production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.
ESTHER : Folch_2018_J.Alzheimers.Dis_62_1223
PubMedSearch : Folch_2018_J.Alzheimers.Dis_62_1223
PubMedID: 29254093

Title : Development of a Nasal Donepezil-loaded Microemulsion for the Treatment of Alzheimer's Disease: in vitro and ex vivo Characterization - Espinoza_2018_CNS.Neurol.Disord.Drug.Targets_17_43
Author(s) : Espinoza LC , Vacacela M , Clares B , Garcia ML , Fabrega MJ , Calpena AC
Ref : CNS Neurol Disord Drug Targets , 17 :43 , 2018
Abstract : BACKGROUND: Donepezil (DPZ) is widely prescribed as a specific and reversible acetylcholinesterase inhibitor for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). OBJECTIVE: Considering the therapeutic potential of DPZ and the advantages offered by the intranasal route as an alternative for drug administration, the aim of this study was the development and characterization of a DPZ microemulsion (ME) for nose-to-brain delivery. METHOD: The ME was developed by construction of pseudoternary phase diagrams and characterized by dynamic light scattering and transmission electron microscopy. Flow properties and viscosity, as well as optical stability and stability under storage at different temperatures were evaluated. Finally, in vitro release and ex vivo permeation studies through porcine nasal mucosa were accomplished. RESULTS: A transparent and homogeneous DPZ-ME (12.5 mg/ml) was obtained. The pH and viscosity were 6.38 and 44.69 mPa.s, respectively, indicating nasal irritation prevention and low viscosity. The mean droplet size was 58.9+/-3.2 nm with a polydispersity index of 0.19+/-0.04. The morphological analysis revealed the spherical shape of droplets, as well as their smooth and regular surface. Optical stability evidenced no destabilization processes. DPZ release profile indicated that the ME followed a hyperbolic kinetic model while the ex vivo permeation profile showed that the highest permeation occurred during initial 4 h and the maximum permeated amount was approximately 2000 microg, which corresponds to 80% of the starting amount of drug. CONCLUSION: We conclude that our nasal ME could be considered as a new potential tool for further investigation in the AD.
ESTHER : Espinoza_2018_CNS.Neurol.Disord.Drug.Targets_17_43
PubMedSearch : Espinoza_2018_CNS.Neurol.Disord.Drug.Targets_17_43
PubMedID: 29299992

Title : Insecticidal activity of an essential oil of Tagetes patula L. (Asteraceae) on common bed bug Cimex lectularius L. and molecular docking of major compounds at the catalytic site of ClAChE1 - Politi_2017_Parasitol.Res_116_415
Author(s) : Politi FA , Nascimento JD , da Silva AA , Moro IJ , Garcia ML , Guido RV , Pietro RC , Godinho AF , Furlan M
Ref : Parasitol Res , 116 :415 , 2017
Abstract : Emerging resistance to insecticides has influenced pharmaceutical research and the search for alternatives to control the common bed bug Cimex lectularius. In this sense, natural products can play a major role. Tagetes patula, popularly known as dwarf marigold, is a plant native to North America with biocide potential. The aim of this work was to evaluate the biological activity of T. patula essential oil (EO) against adult common bed bugs via exposure to dry residues by the Impregnated Paper Disk Test (IPDT) using cypermethrin as a positive control. We selected the enzyme acetylcholinesterase as a target for modeling studies, with the intent of investigating the molecular basis of any biological activity of the EO. Chemical analysis of the EO was performed using gas chromatography coupled to mass spectrometry (GC-MS). Additionally, oral and dermal acute toxicity tests were performed according to Organization for Economic Cooperation and Development (OECD) guidelines. The sulforhodamine B assay (SRB) was performed to verify the cytotoxicity of EO to HaCaT cells. The EO eliminated 100 % of the bed bugs at 100 mg mL-1 with an LC50 value of 15.85 mg mL-1. GC-MS analysis identified alpha-terpinolene, limonene, piperitenone, and piperitone as major components of the mixture. Molecular modeling studies of these major compounds suggested that they are acetylcholinesterase inhibitors with good steric and electronic complementarity. The in vitro cytotoxicity evaluation revealed a LC50 = 37.06 mug mL-1 and in vivo acute toxicity showed an LC50 >4000 mg kg-1, indicating that the EO presents low risk of toxic side effects in humans. The T. patula essential oil components provide a promising strategy for controlling bed bug populations with low mammalian toxicity. These findings pave the way for further in vivo studies aimed at developing a safe and effective insecticide.
ESTHER : Politi_2017_Parasitol.Res_116_415
PubMedSearch : Politi_2017_Parasitol.Res_116_415
PubMedID: 27838836