Grauer E

References (17)

Title : Lung damage following whole body, but not intramuscular, exposure to median lethality dose of sarin: findings in rats and guinea pigs - Chapman_2019_Inhal.Toxicol__1
Author(s) : Chapman S , Lazar S , Gez R , Rabinovitz I , Yaakov G , Grauer E
Ref : Inhal Toxicol , :1 , 2019
Abstract : Objective: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic, volatile warfare agent. Rats and guinea pigs exposed to sarin display cholinergic excitotoxicity which includes hyper-salivation, respiratory distress, tremors, seizures, and death. Here we focused on the characterization of the airways injury induced by direct exposure of the lungs to sarin vapor and compared it to that induced by the intramuscularly route. Materials and methods: Rats were exposed to sarin either in vapor ( approximately 1LCT50, 34.2 +/- 0.8 microg/l/min, 10 min) or by i.m. ( approximately 1LD50, 80 microg/kg), and lung injury was evaluated by broncho-alveolar lavage (BAL). Results and discussion: BAL analysis revealed route-dependent effects in rats: vapor exposed animals showed elevation of inflammatory cytokines, protein, and neutrophil cells. These elevations were seen at 24 h and were still significantly higher compared to control values at 1 week following vapor exposure. These elevations were not detected in rats exposed to sarin i.m. Histological evaluation of the brains revealed typical changes following sarin poisoning independent of the route of administration. The airways damage following vapor exposure in rats was also compared to that induced in guinea pigs. The latter showed increased eosinophilia and histamine levels that constitutes an anaphylactic response not seen in rats. Conclusions: These data clearly point out the importance of using the appropriate route of administration in studying the deleterious effects of volatile nerve agents, as well as the selection of the appropriate animal species. Since airways form major target organs for the development of injury following inhalation toxicity, they should be included in any comprehensive evaluation of countermeasures efficacy.
ESTHER : Chapman_2019_Inhal.Toxicol__1
PubMedSearch : Chapman_2019_Inhal.Toxicol__1
PubMedID: 31359796

Title : Optimization of the Ocular Treatment Following Organophosphate Nerve Agent Insult - Egoz_2017_Toxicol.Sci_159_50
Author(s) : Egoz I , Nili U , Grauer E , Gore A
Ref : Toxicol Sci , 159 :50 , 2017
Abstract : Eye exposure to organophosphate (OP) irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. The aim of this study was to find an anticholinergic antidote, which would counteract miosis and visual impairment induced by the nerve agents sarin and VX with minimal untoward side-effects. Rat pupil width and light reflex were evaluated from 15 min up to 2 weeks following topical OP exposure with or without topical ocular treatment of atropine or homatropine or with a combined intramuscular treatment of trimedoxime (TMB-4(Trimedoxime)) and atropine (TA). Visual function following insult and treatment was assessed using a cued Morris water maze task. Topical VX exposure showed a dose-dependent miosis with a significant reduction in visual function similar to the effect seen following sarin exposure. Homatropine (2%; w/v) and atropine (0.1%; w/v) treatment ameliorated both sarin and VX-induced miosis and the resulting visual impairment. TA treatment was sufficient in ameliorating the sarin-induced ocular impairment while an additional ocular treatment with either 0.1% atropine or 2% homatropine was necessary following VX exposure. To conclude the use of 0.1% atropine or 2% homatropine was beneficial in ameliorating the ocular insult following VX or sarin ocular exposure and thus should be considered as universal treatments against this intoxication. The findings also emphasize the necessity of additional ocular treatment to the systemic treatment in visually impaired casualties following VX exposure.
ESTHER : Egoz_2017_Toxicol.Sci_159_50
PubMedSearch : Egoz_2017_Toxicol.Sci_159_50
PubMedID: 28903494

Title : Novel bifunctional hybrid small molecule scavengers for mitigating nerve agents toxicity - Amitai_2016_Chem.Biol.Interact_259_187
Author(s) : Amitai G , Gez R , Raveh L , Bar-Ner N , Grauer E , Chapman S
Ref : Chemico-Biological Interactions , 259 :187 , 2016
Abstract : The antidotal treatment of organophosphates (OP) nerve agents (NA) poisoning is based on anticholinergics (e.g. atropine) combined with oxime reactivators (e.g. 2PAM) of acetylcholinesterase (AChE). This treatment is symptomatic and does not degrade the OP. New small-molecule OP scavengers were developed as bifunctional hybrids. Their molecular design was based on combining a nucleophile that directly degrades OP with a moiety that reactivates OP-inhibited AChE. The OP degrading moiety is either benzhydroxamic acid (BHA) or 4-pyridinehydroxamic acid (4PHA) coupled via (CH2)n, (n = 1 or 3) to 2PAM. Three newly synthesized oxime-hydroxamate hybrids: 2PAMPr4PHA, 2PAMMeBHA and 2,4-DiPAMMeBHA were found to detoxify sarin, cyclosarin and soman in solution at 3-10-fold faster rate than 2PAM and to reactivate OP-AChE in vitro. 2PAMPr4PHA displayed 18-fold faster reactivation than 2-PAM of cyclosarin-inhibited HuAChE (kr = 3.6 x 102 vs. 0.2 x 102 M-1min-1, respectively, 37 degrees C). These hybrids inhibited AChE reversibly, IC50 = 16-48 muM, thereby decreasing the inhibition rates by OPs. The LD50 (im) of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA are >568, 508 and >506 mumol/kg in rats and 144, 203 and >506 mumol/kg in guinea pigs. The rate of blood ChE recovery by the hybrids administered either pre- or post-exposure to 0.8xLD50 sarin was comparable or faster than 2PAM. Antidotal efficacy of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA administered with atropine, as pre-treatment to sarin in rats (im), yielded protection ratios (PR) 11.6, 11.5 and 4.7, respectively, vs. 5.5 with 2PAM. Post-treatment against various OPs in rats and guinea-pigs yielded PRs higher or similar to that of 2 PAM. Our in vivo data indicates that some hybrids may serve as efficient small molecule scavengers for mitigating the toxicity of OP NAs.
ESTHER : Amitai_2016_Chem.Biol.Interact_259_187
PubMedSearch : Amitai_2016_Chem.Biol.Interact_259_187
PubMedID: 27129421

Title : Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes - Lazar_2016_Toxicol.Appl.Pharmacol_310_87
Author(s) : Lazar S , Egoz I , Brandeis R , Chapman S , Bloch-Shilderman E , Grauer E
Ref : Toxicol Appl Pharmacol , 310 :87 , 2016
Abstract : Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80mug/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h. In all brain regions tested, bax mRNA decreased 1h post exposure followed by an increase 24h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous "first response" mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention.
ESTHER : Lazar_2016_Toxicol.Appl.Pharmacol_310_87
PubMedSearch : Lazar_2016_Toxicol.Appl.Pharmacol_310_87
PubMedID: 27639427

Title : Is rivastigmine safe as pretreatment against nerve agents poisoning? A pharmacological, physiological and cognitive assessment in healthy young adult volunteers - Lavon_2015_Neurotoxicol_49_36
Author(s) : Lavon O , Eisenkraft A , Blanca M , Raveh L , Ramaty E , Krivoy A , Atsmon J , Grauer E , Brandeis R
Ref : Neurotoxicology , 49 :36 , 2015
Abstract : Rivastigmine, a reversible cholinesterase inhibitor, approved as a remedy in Alzheimer's disease, was suggested as pretreatment against nerve agents poisoning. We evaluated the pharmacokinetic, pharmacodynamic, physiologic, cognitive and emotional effects of repeated rivastigmine in young healthy male adults, in a double blind, placebo controlled crossover trial. Three groups completed 3 treatment periods: 0, 1.5 and 3mg twice a day, for a total of 5 intakes. Parameters monitored were: vital signs, ECG, laboratory tests, sialometry, visual accommodation, inspiratory peak flow, and cognitive function tests. Adverse reactions were mild. Peak blood levels and peak cholinesterase inhibition increased with repeated intakes, and high variability and non-linear pharmacokinetics were demonstrated. In addition, two cognitive functions were affected (perceptual speed and dynamic tracking). The complicated pharmacological profile and the high inter-personal variability limit the potential use of rivastigmine as pretreatment for war fighters and first responders.
ESTHER : Lavon_2015_Neurotoxicol_49_36
PubMedSearch : Lavon_2015_Neurotoxicol_49_36
PubMedID: 26001567

Title : Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity - Katalan_2013_Arch.Toxicol_87_347
Author(s) : Katalan S , Lazar S , Brandeis R , Rabinovitz I , Egoz I , Grauer E , Bloch-Shilderman E , Raveh L
Ref : Archives of Toxicology , 87 :347 , 2013
Abstract : Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 mug/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic-clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.
ESTHER : Katalan_2013_Arch.Toxicol_87_347
PubMedSearch : Katalan_2013_Arch.Toxicol_87_347
PubMedID: 23052190

Title : Subchronic exposure to low-doses of the nerve agent VX: physiological, behavioral, histopathological and neurochemical studies - Bloch-Shilderman_2008_Toxicol.Appl.Pharmacol_231_17
Author(s) : Bloch-Shilderman E , Rabinovitz I , Egoz I , Raveh L , Allon N , Grauer E , Gilat E , Weissman BA
Ref : Toxicol Appl Pharmacol , 231 :17 , 2008
Abstract : The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 microg/kg/day, 0.05 LD(50)) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition (approximately 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction (approximately 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.
ESTHER : Bloch-Shilderman_2008_Toxicol.Appl.Pharmacol_231_17
PubMedSearch : Bloch-Shilderman_2008_Toxicol.Appl.Pharmacol_231_17
PubMedID: 18485435

Title : Oxotremorine-induced hypothermia as a method for evaluating long-term neuronal changes following poisoning by cholinesterase inhibitors in rats - Grauer_2007_Toxicology_242_1
Author(s) : Grauer E , Levy A
Ref : Toxicology , 242 :1 , 2007
Abstract : Severe poisoning by inhibitors of cholinesterase (ChE) enzymes is often associated with prolonged central or peripheral neuronal damage. Oxotremorine is a cholinergic agonist known to induce acute hypothermia. Central and peripheral cholinergic signaling is involved in the induction of hypothermia as well as in its recovery. These processes were used in the present study to reveal prolonged neuronal abnormalities in poisoned rats, using oxotremorine with and without concomitant administration of the peripheral muscarinic antagonist methyl scopolamine. In non-poisoned naive rats, the hypothermic effect of oxotremorine appeared faster while its recovery was delayed following co-administration of methyl scopolamine, suggesting predominantly peripheral processes in counteracting the hypothermia. One month after exposure to approximately 1LD(50) of the carbamates aldicarb and oxamyl, the hypothermic effect of oxotremorine was similar to that found in saline-treated control group. However, the effect of methyl scopolamine on the recovery process was significantly diminished, indicating that the impaired cholinergic mechanisms were predominantly peripheral. In contrast, 1 month following organophosphate (OP) poisoning by the nerve agents sarin and VX, oxotremorine-induced hypothermia was reduced, indicating mainly impaired central cholinergic mechanisms. The development of severe convulsions during nerve agent poisoning may explain the central neuronal damage in OP-poisoned rats, displayed as reduced hypothermia. As convulsions were not part of the poisoning symptoms with the carbamates tested, their long-term damage was displayed at the recovery stage. This method might be used as a relatively simple means for detecting differential long-term central and peripheral cholinergic injuries, long after toxicity signs have receded.
ESTHER : Grauer_2007_Toxicology_242_1
PubMedSearch : Grauer_2007_Toxicology_242_1
PubMedID: 17931764

Title : Viral neuroinvasion as a marker for BBB integrity following exposure to cholinesterase inhibitors - Grauer_2001_Life.Sci_68_985
Author(s) : Grauer E , Ben Nathan D , Lustig S , Kobiler D , Kapon J , Danenberg HD
Ref : Life Sciences , 68 :985 , 2001
Abstract : Exposure to the nerve agent soman, an irreversible cholinesterase (ChE) inhibitor, results in changes in blood-brain barrier permeability attributed to its seizure-induced activity. However, smaller BBB changes may be independent of convulsions. Such minor injury may escape detection. A nonneuroinvasive neurovirulent Sindbis virus strain (SVN) was used as a marker for BBB permeability. Peripheral inoculation of mice with 2 x 10(3) plaque forming units (PFU) caused up to 10(5) PFU/ml viremia after 24 hours with no signs of central nervous system (CNS) infection and with no virus detected in brain tissue. Intra-cerebral injection of as low as 1-5 PFU of the same virus caused CNS infection, exhibited 5-7 days later as hind limb paralysis and death. Soman (0.1-0.7 of the LD50) was administered at peak viremia (1 day following peripheral inoculation). Sublethal soman exposure at as low as 0.1 LD50 resulted in CNS infection 6-8 days following inoculation in 30-40% of the mice. High virus titer were recorded in brain tissue of sick mice while no virus was detected in healthy mice subjected to the same treatment. No changes in the level of viremia or changes in viral traits were observed in the infected mice. The reversible anticholinesterases physostigmine (0.2 mg/kg, s.c.) and pyridostigmine (0.4 mg/kg, i.m.) injected at a dose equal to 0.1 LD50, induced similar results. Thus, both central and peripheral anticholinesterases (anti-ChEs) induce changes in BBB permeability sufficient to allow, at least in some of the mice, the invasion of this otherwise noninvasive but highly neurovirulent virus. This BBB change is probably due to the presence of cholinesterases in the capillary wall. SVN brain invasion served here as a highly sensitive and reliable marker for BBB integrity.
ESTHER : Grauer_2001_Life.Sci_68_985
PubMedSearch : Grauer_2001_Life.Sci_68_985
PubMedID: 11212873

Title : Stress does not enable pyridostigmine to inhibit brain cholinesterase after parenteral administration - Grauer_2000_Toxicol.Appl.Pharmacol_164_301
Author(s) : Grauer E , Alkalai D , Kapon J , Cohen G , Raveh L
Ref : Toxicol Appl Pharmacol , 164 :301 , 2000
Abstract : The peripherally acting cholinesterase inhibitor pyridostigmine was widely used during the Gulf War as a pretreatment against possible chemical warfare attack. Following consistent reports on long-term illness among Gulf War veterans, pyridostigmine was examined for its possible long-term effects. These effects were suggested to be induced by the combination of pyridostigmine administration and stress exposure that allowed this quaternary compound to enter the brain through stress induced changes in blood-brain barrier (BBB) permeability. Recently, pyridostigmine administration was demonstrated to inhibit brain cholinesterase following acute stress in mice. However, the effect was not replicated under similar conditions in guinea pigs. Because of the significant implication of these findings, we tested brain cholinesterase (ChE) inhibition following the administration of pyridostigmine, or the tertiary carbamate physostigmine, with or without stress in mice. Different experiments were performed to examine the contribution of gender, age (young and adults), stress (type and intensity), or strain (CD-1 and FVB/n) parameters. No inhibition of brain ChE was detected in any of these experiments. At the same time, physostigmine induced the expected decrease in brain ChE in all the experiments. Thus, we could not replicate the findings that suggest pyridostigmine can affect brain cholinesterase following stress.
ESTHER : Grauer_2000_Toxicol.Appl.Pharmacol_164_301
PubMedSearch : Grauer_2000_Toxicol.Appl.Pharmacol_164_301
PubMedID: 10799340

Title : Current Capabilities in Extrapolating from Animal to Human the Capacity of Human Butyrylcholinesterase to Detoxify Organophosphates -
Author(s) : Ashani Y , Grauer E , Grunwald J , Allon N , Raveh L
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :255 , 1998
PubMedID:

Title : Enhanced hemicholinium binding and attenuated dendrite branching in cognitively impaired acetylcholinesterase-transgenic mice - Beeri_1997_J.Neurochem_69_2441
Author(s) : Beeri R , Le Novere N , Mervis R , Huberman T , Grauer E , Changeux JP , Soreq H
Ref : Journal of Neurochemistry , 69 :2441 , 1997
Abstract : In a search for behavioral, neuroanatomical, and metabolic characteristics of Alzheimer's disease that may result from cholinergic malfunction, we used transgenic mice overexpressing acetylcholinesterase (AChE) mRNA and active enzyme in brain neurons. Mapping by in situ hybridization revealed that transgenic and host AChE mRNAs were distributed similarly. In a Morris water maze working memory paradigm, adult transgenic mice did not display the characteristic improvement found in control mice either between or within test days and spent less time than control mice in the platform zone. In 5-week-old transgenic mice, the basilar dendritic trees of layer 5 pyramidal neurons from the frontoparietal cortex were essentially as developed as in age-matched controls. However, branching totally ceased after this age, whereas in control adults it continued up to at least 7 months. Therefore, dendritic arbors became smaller in adult transgenic mice than those of controls. Furthermore, the average number of spines was significantly lower on dendritic branches of 7-month-old but not 5-week-old transgenics as compared with controls. Binding of tritiated hemicholinium-3, a blocker of the high-affinity choline uptake characteristic of active cholinergic terminals, was over twofold enhanced in the brain of transgenic mice. In contrast, no differences were observed in the mRNA and ligand binding levels of several different subtypes of nicotinic and muscarinic acetylcholine receptors. These findings suggest that three different hallmarks associated with Alzheimer's disease--namely, progressive cognitive failure, cessation of dendrite branching and spine formation, and enhanced high-affinity choline uptake--are outcomes of cholinergic malfunction.
ESTHER : Beeri_1997_J.Neurochem_69_2441
PubMedSearch : Beeri_1997_J.Neurochem_69_2441
PubMedID: 9375677

Title : The stoichiometry of protection against soman and VX toxicity in monkeys pretreated with human butyrylcholinesterase - Raveh_1997_Toxicol.Appl.Pharmacol_145_43
Author(s) : Raveh L , Grauer E , Grunwald J , Cohen E , Ashani Y
Ref : Toxicol Appl Pharmacol , 145 :43 , 1997
Abstract : Bioscavengers of organophophates (OP) have been examined as potential substitutes for the currently approved drug treatment against OP toxicity. The present work was designed to assess the ability of butyrylcholinesterase, purified from human serum (HuBChE), to prevent the toxicity induced by soman and VX in rhesus monkeys. The consistency of the data across species was then evaluated as the basis for the extrapolation of the data to humans. The average mean residence time of the enzyme in the circulation of monkeys following an intravenous loading was 34 hr. High bioavailability of HuBChE in blood (>80%) was demonstrated after intramuscular injection. A molar ratio of HuBChE:OP approximately 1.2 protected against an i.v. bolus injection of 2.1 x LD50 VX, while a ratio of 0.62 was sufficient to protect monkeys against an i.v. dose of 3.3 x LD50 of soman, with no additional postexposure therapy. A remarkable protection was also seen against soman-induced behavioral deficits detected in the performance of a spatial discrimination task. The consistency of the results across several species offers a reliable prediction of both the stoichiometry of the scavenging and the extent of prophylaxis with HuBChE against nerve agent toxicity in humans.
ESTHER : Raveh_1997_Toxicol.Appl.Pharmacol_145_43
PubMedSearch : Raveh_1997_Toxicol.Appl.Pharmacol_145_43
PubMedID: 9221822

Title : Biochemical and cognitive studies of apolipoprotein-E-deficient mice - Gordon_1996_Mol.Chem.Neuropathol_28_97
Author(s) : Gordon I , Genis I , Grauer E , Sehayek E , Michaelson DM
Ref : Molecular & Chemical Neuropathology , 28 :97 , 1996
Abstract : Apolipoprotein-E-deficient mice provide a useful model system for studying the role of apolipoprotein E (apoE) in brain function. In the present study, we characterized the cholinergic function of these mice and the extent of phosphorylation of their cytoskeletal protein tau. Morris water maze tasks revealed deficits in working memory that were accompanied by a specific decrease in hippocampal and cortical choline acetyltransferase activities. Immunoblot experiments utilizing native and dephosphorylated tau and antibodies directed against specific phosphorylated and unphosphorylated tau epitopes revealed that tau of the apoE-deficient mice is hyperphosphorylated. These results show that apoE-deficient mice have cognitive cholinergic and cytoskeletal derangements and point out the importance of this model for studying the role of apoE in neuronal function.
ESTHER : Gordon_1996_Mol.Chem.Neuropathol_28_97
PubMedSearch : Gordon_1996_Mol.Chem.Neuropathol_28_97
PubMedID: 8871947

Title : Differential effects of anticholinergic drugs on paired discrimination performance - Grauer_1996_Pharmacol.Biochem.Behav_53_463
Author(s) : Grauer E , Kapon J
Ref : Pharmacol Biochem Behav , 53 :463 , 1996
Abstract : Working and reference memory processes were simultaneously evaluated during the performance of a paired discrimination (PD) task in which visual and spatial discrimination trials were combined within the same session. Atropine (1 and 5 mg/kg), scopolamine (0.02-0.20 mg/kg), benactyzine (1-4 mg/kg), trihexyphenidyl (1-10 mg/kg), and aprophen (5-20 mg/kg) were all found to increase the number of errors performed by overtrained rats during the spatial but not during the visual trials. Although all the anticholinergic drugs tested induced specific working memory impairment at low doses, they differentially affected other, simultaneously recorded, behavioral parameters. Thus, while atropine affected most of the recorded parameters, aprophen induced only a mild effect. Benactyzine was found to have the most specific effect on working memory, with only minimal side effects, a combination that supports its use as the preferred psychopharmacological model of working memory impairment.
ESTHER : Grauer_1996_Pharmacol.Biochem.Behav_53_463
PubMedSearch : Grauer_1996_Pharmacol.Biochem.Behav_53_463
PubMedID: 8808159

Title : Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice - Gordon_1995_Neurosci.Lett_199_1
Author(s) : Gordon I , Grauer E , Genis I , Sehayek E , Michaelson DM
Ref : Neuroscience Letters , 199 :1 , 1995
Abstract : Apolipoprotein E-deficient mice provide a useful system for studying the role of apolipoprotein E (apoE) in the function of distinct neuronal systems. In the present study we focused on the cholinergic system of these mice. This was pursued by measurements of specific biochemical, physiological and cognitive parameters. Morris Water Maze tasks revealed impairments in working memory but not in reference memory of the apoE-deficient mice. Measurements of brain choline acetyltransferase activities revealed them to be markedly lower in the hippocampus and frontal cortex of the apoE-deficient mice than in the corresponding brain areas of the controls, but unaltered in other brain areas. In addition, hypothermia induced by the centrally acting muscarinic agonist, oxotremorine, was reduced in the apoE-deficient mice as compared to controls. These results show that apoE-deficient mice have cholinergic deficits and highlight the importance of this mouse model for studying the interactions between apoE and the cholinergic nervous system.
ESTHER : Gordon_1995_Neurosci.Lett_199_1
PubMedSearch : Gordon_1995_Neurosci.Lett_199_1
PubMedID: 8584214

Title : Human Butyrylcholinesterase as Prophylaxis Treatment against Soman -
Author(s) : Grauer E , Raveh L , Kapon J , Grunwald J , Cohen E , Ashani Y
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :400 , 1995
PubMedID: