Gilat E

References (8)

Title : Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and caramiphen - Raveh_2008_Toxicol.Appl.Pharmacol_227_155
Author(s) : Raveh L , Rabinovitz I , Gilat E , Egoz I , Kapon J , Stavitsky Z , Weissman BA , Brandeis R
Ref : Toxicol Appl Pharmacol , 227 :155 , 2008
Abstract : Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where caramiphen exibited some protection at the 20-min time point. Our results show that caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed.
ESTHER : Raveh_2008_Toxicol.Appl.Pharmacol_227_155
PubMedSearch : Raveh_2008_Toxicol.Appl.Pharmacol_227_155
PubMedID: 18320638

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 : Subcellular alterations of protein kinase C isozymes in the rat brain after organophosphate poisoning - Bloch-Shilderman_2005_J.Pharmacol.Exp.Ther_313_1082
Author(s) : Bloch-Shilderman E , Kadar T , Levy A , Sahar R , Rabinovitz I , Gilat E
Ref : Journal of Pharmacology & Experimental Therapeutics , 313 :1082 , 2005
Abstract : The protein kinase C (PKC) signaling pathway has been associated with modulation of N-metyl-D-aspartate receptor activity, motor behavior, learning, and memory, all of which are severely impaired in organophosphate (OP) intoxication. Nevertheless, the role of PKC in OP intoxication is largely unknown. The present study attempted to characterize alterations in the immunoreactivity levels of PKC isozymes expressed in different brain areas in the rat following exposure to the nerve agent sarin (1x LD(50)). Furthermore, possible neuroprotective effect of selective PKC regulating peptide after such insult was evaluated. The results indicated that a significant reduction in the immunoreactivity level of the conventional betaII-PKC and the atypical zeta-PKC was observed in frontal cortex up to 24 h postsarin and in the striatum up to 5 days postsarin exposure. This reduction was in contrast to the increase in the immuno-reactivity level of both isozymes seen in the hippocampus or thalamus. Treatment with the anticonvulsant midazolam (0.5 mg/kg) 10 min postsarin exposure markedly reduced zeta-PKC immunoreactivity level and betaII-PKC in the membrane fractions in the hippocampus. betaII-PKC peptide (380 ng/kg), known to inhibit PKC translocation and activation, attenuated sarin-induced neuropathology. These observations suggest a role for both conventional and atypical PKC isozymes in OP-induced neuropathy in the rat and further support their involvement in cell death.
ESTHER : Bloch-Shilderman_2005_J.Pharmacol.Exp.Ther_313_1082
PubMedSearch : Bloch-Shilderman_2005_J.Pharmacol.Exp.Ther_313_1082
PubMedID: 15716382

Title : Nasal midazolam as a novel anticonvulsive treatment against organophosphate-induced seizure activity in the guinea pig - Gilat_2003_Arch.Toxicol_77_167
Author(s) : Gilat E , Goldman M , Lahat E , Levy A , Rabinovitz I , Cohen G , Brandeis R , Amitai G , Alkalai D , Eshel G
Ref : Archives of Toxicology , 77 :167 , 2003
Abstract : Seizures and status epilepticus, which may contribute to brain injury, are common consequences of exposure to organophosphorus (OP) cholinesterase inhibitors. Effective management of these seizures is critical. To investigate the efficacy of nasal midazolam as an anticonvulsive treatment for OP exposure, as compared to intramuscular midazolam, guinea pigs were connected to a recording swivel for electrocorticograph (ECoG) monitoring and clinical observation. The experimental paradigm consisted of pyridostigmine pretreatment (0.1 mg/kg i.m.) 20 min prior to sarin exposure (1.2x LD(50,) 56 micro g/kg i.m.). One minute post-exposure, atropine (3 mg/kg i.m.) and TMB-4(Trimedoxime) (1 mg/kg im) were administered. Within 3-8 min after sarin exposure all animals developed electrographic seizure activity (EGSA), with convulsive behavior. Treatment with midazolam (1 mg/kg i.m.) 10 min after the onset of EGSA abolished EGSA within 389+/-181 s. The same dose was not effective, in most cases, when given 30 min after onset. However, a higher dose (2 mg/kg) was found efficacious after 30 min (949+/-466 s). In contrast, nasal application of midazolam (1 mg/kg) was found most effective, with significant advantages, in amelioration of EGSA and convulsive behavior, when given 10 min (216+/-185 s) or 30 min (308+/-122 s) following the onset of EGSA ( P<0.001). Thus, nasal midazolam could be used as a novel, rapid and convenient route of application against seizure activity induced by nerve agent poisoning.
ESTHER : Gilat_2003_Arch.Toxicol_77_167
PubMedSearch : Gilat_2003_Arch.Toxicol_77_167
PubMedID: 12632257

Title : Anticholinergic and antiglutamatergic agents protect against soman-induced brain damage and cognitive dysfunction - Raveh_2003_Toxicol.Sci_75_108
Author(s) : Raveh L , Brandeis R , Gilat E , Cohen G , Alkalay D , Rabinovitz I , Sonego H , Weissman BA
Ref : Toxicol Sci , 75 :108 , 2003
Abstract : Soman, a powerful inhibitor of acetylcholinesterase, causes an array of toxic effects in the central nervous system including convulsions, learning and memory impairments, and, ultimately, death. We report on the protection afforded by postexposure antidotal treatments, combined with pyridostigmine (0.1 mg/kg) pretreatment, against these consequences associated with soman poisoning. Scopolamine (0.1 mg/kg) or caramiphen (10 mg/kg) were administered 5 min after soman (1.2 LD50), whereas TAB (i.e., TMB4, atropine, and benactyzine, 7.5, 3, and 1 mg/kg, respectively) was injected in rats concomitant with the development of toxic signs. Atropine (4 mg/kg) was given to the two former groups at the onset of toxic symptoms. Caramiphen and TAB completely abolished electrographic seizure activity while scopolamine treatment exhibited only partial protection. Additionally, no significant alteration in the density of peripheral benzodiazepine receptors was noted following caramiphen or TAB administration, while scopolamine application resulted in a complex outcome: a portion of the animals demonstrated no change in the number of these sites whereas the others exhibited markedly higher densities. Cognitive functions (i.e., learning and memory processes) evaluated using the Morris water maze improved considerably by the three treatments when compared to soman-injected animals; the following rank order was observed: caramiphen > TAB > scopolamine. Additionally, statistically significant correlations (r = 0.72, r = 0.73) were demonstrated between two learning parameters and [3H]Ro5-4864 binding to brain membrane. These results show that drugs with a pharmacological profile consisting of anticholinergic and antiglutamatergic properties such as caramiphen and TAB, have a substantial potential as postexposure therapies against intoxication by organophosphates.
ESTHER : Raveh_2003_Toxicol.Sci_75_108
PubMedSearch : Raveh_2003_Toxicol.Sci_75_108
PubMedID: 12832655

Title : The involvement of the NMDA receptor complex in the protective effect of anticholinergic drugs against soman poisoning - Raveh_1999_Neurotoxicol_20_551
Author(s) : Raveh L , Chapman S , Cohen G , Alkalay D , Gilat E , Rabinovitz I , Weissman BA
Ref : Neurotoxicology , 20 :551 , 1999
Abstract : Organophosphate poisoning is associated with adverse effects on the central nervous system such as seizure/convulsive activity and long term changes in neuronal networks. This study reports on investigations designed to assess the consequences of soman exposure on excitatory amino acids receptors in the rat brain. In addition, the protective effects of caramiphen which acts at these receptors, and scopolamine, which does not, was determined on soman-induced alteration in rat brain functions. Administration of soman (1xLD50) to pyridostigmine pretreated rats produced seizure activity (measured by EEG monitoring) in all animals tested. Estimation of [3H]MK-801 binding to brain membranes from intoxicated rats revealed a marked decrease in Bmax value 24 but not 2 hrs following soman administration. The specific nature of these effects of soman was demonstrated by the findings that [3H]flunitrazepam binding to central benzodiazepine receptors remained unchanged in soman-poisoned rat brain membranes. Both scopolamine and caramiphen, when used prophylactically prevented the lethal effect of soman and completely blocked the development of electrographic seizure activity (EGSA). In contrast, only caramiphen abolished soman-induced modifications in NMDA/ion channel characteristics. Caramiphen displaced [3H]MK-801 bound to the NMDA/ion channel complex, possibly by interacting with the Zn2+ site whereas scopolamine did not. Moreover, caramiphen, but not scopolamine, partially protected mice from NMDA-induced lethality. Thus, it is suggested that an important component of the protective efficacy of caramiphen against organophosphate poisoning might be attributed to its ability to modulate NMDA receptors in addition to its anticholinergic properties.
ESTHER : Raveh_1999_Neurotoxicol_20_551
PubMedSearch : Raveh_1999_Neurotoxicol_20_551
PubMedID: 10499354

Title : Prophylaxis against soman inhalation toxicity in guinea pigs by pretreatment alone with human serum butyrylcholinesterase - Allon_1998_Toxicol.Sci_43_121
Author(s) : Allon N , Raveh L , Gilat E , Cohen E , Grunwald J , Ashani Y
Ref : Toxicol Sci , 43 :121 , 1998
Abstract : Human butyrylcholinesterase (HuBChE) has previously been shown to protect mice, rats, and monkeys against multiple lethal toxic doses of organophosphorus (OP) anticholinesterases that were challenged by i.v. bolus injections. This study examines the concept of using a cholinesterase scavenger as a prophylactic measure against inhalation toxicity, which is the more realistic simulation of exposure to volatile OPs. HuBChE-treated awake guinea pigs were exposed to controlled concentration of soman vapors ranging from 417 to 430 micrograms/liter, for 45 to 70 s. The correlation between the inhibition of circulating HuBChE and the dose of soman administered by sequential i.v. injections and by respiratory exposure indicated that the fraction of the inhaled dose of soman that reached the blood was 0.29. HuBChE to soman molar ratio of 0.11 was sufficient to prevent the manifestation of toxic signs in guinea pigs following exposure to 2.17x the inhaled LD50 dose of soman (ILD50, 101 micrograms/kg). A slight increase in HuBChE:soman ratio (0.15) produced sign-free animals after two sequential respiratory exposures with a cumulative dose of 4.5x ILD50. Protection was exceptionally high and far superior to the currently used traditional approach that consisted of pretreatment with pyridostigmine and postexposure combined administration of atropine, benactyzine, and an oxime reactivator. Quantitative analysis of the results suggests that in vivo sequestration of soman, and presumably other OPs, by exogenously administered HuBChE, is independent of the species used or the route of challenge entry. This assuring conclusion significantly expands the database of the bioscavenger strategy that now offers a dependable extrapolation from animals to human.
ESTHER : Allon_1998_Toxicol.Sci_43_121
PubMedSearch : Allon_1998_Toxicol.Sci_43_121
PubMedID: 9710953

Title : Protection of Guinea Pigs against Soman Inhalation by Pretreatment Alone with Human Butyrylcholinesterase -
Author(s) : Allon N , Raveh L , Gilat E , Grunwald J , Manistersky E , 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. :398 , 1995
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