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1.
Neuroscience ; 162(4): 1351-65, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19490932

ABSTRACT

The mechanisms of epileptogenesis remain largely unknown and are probably diverse. The aim of this study was to investigate the role of focal cholinergic imbalance in epileptogenesis. To address this question, we monitored electroencephalogram (EEG) activity up to 12 weeks after the injection of a potent cholinesterase (ChE) inhibitor (soman) at different doses (0.53, 0.75, 1, 2, 2.8, 4 and 11 nmol) into the right dorsal hippocampus of C57BL/6 mice. Different parameters were used to choose the dose for a focal model of epileptogenesis (mainly electrographic patterns and peripheral ChE inhibition). The pattern of neuronal activation was studied by Fos immunohistochemistry (IHC). Brain damage was evaluated by hemalun-phloxin, neuronal nuclei antigen IHC and silver staining. Glial fibrillary acidic protein IHC was used to evaluate astroglial reaction. Finally, long-term behavioral consequences were characterized. At the highest dose (11 nmol), soman quickly evoked severe signs, including initial seizures and promoted epileptogenesis in the absence of tissue damage. With lower doses, late-onset seizures were evidenced, after 1-4 weeks depending on the dose, despite the absence of initial overt seizures and of brain damage. Only a weak astroglial reaction was observed. Following injection of 1 nmol, Fos changes were first evidenced in the ipsilateral hippocampus and then spread to extrahippocampal areas. A selective deficit in contextual fear conditioning was also evidenced two months after injection. Our data show that focal hypercholinergy may be a sufficient initial event to promote epilepsy and that major brain tissue changes (cellular damage, edema, neuroinflammation) are not necessary conditions.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors , Epilepsy/enzymology , Hippocampus/enzymology , Soman , Animals , Astrocytes/pathology , Conditioning, Psychological , Dose-Response Relationship, Drug , Electroencephalography , Epilepsy/chemically induced , Epilepsy/pathology , Epilepsy/physiopathology , Fear , Genes, Immediate-Early , Hippocampus/pathology , Hippocampus/physiopathology , Male , Maze Learning , Mice , Mice, Inbred C57BL , Periodicity , Proto-Oncogene Proteins c-fos/biosynthesis , Proto-Oncogene Proteins c-fos/genetics , Rotarod Performance Test , Seizures/chemically induced , Seizures/enzymology , Seizures/pathology , Seizures/physiopathology , Time Factors
2.
Pharmacol Biochem Behav ; 69(3-4): 561-9, 2001.
Article in English | MEDLINE | ID: mdl-11509217

ABSTRACT

Effects of low to mild doses of soman on central and blood cholinesterase (ChE) activities and anxiety behavior were studied in mice 30 min, 24 h and 7 days after poisoning. At these two latter time points, histopathological consequences of soman intoxication were also studied. The 30-microg/kg dose of soman produced 30 min after intoxication, about 35% of central ChE inhibition, and an anxiolytic effect without toxic signs or histopathological changes. The 50-microg/kg dose of soman produced at the same time, about 56% of central ChE inhibition, slight clinical signs of poisoning without convulsions, an anxiogenic effect with a slight hypolocomotion but no brain damage. A mild dose of soman (90 microg/kg) produced at this same time point about 80% of central ChE inhibition, and led to ataxia and tremors in every mouse and to convulsions in some of them. Thirty minutes and 24 h after poisoning, the behavioral tests revealed neither anxiolytic nor anxiogenic responses despite a clear hypolocomotion. Only mice that experienced long-lasting convulsions developed neuropathological changes. The functional implication of our results, as well as the biological relevance of blood vs. brain ChE levels, as an index of intoxication severity are discussed.


Subject(s)
Amygdala/drug effects , Behavior, Animal/drug effects , Cholinesterase Inhibitors/administration & dosage , Cholinesterases/metabolism , Soman/administration & dosage , Amygdala/pathology , Animals , Anxiety/chemically induced , Anxiety/metabolism , Behavior, Animal/physiology , Brain/drug effects , Brain/metabolism , Cholinesterase Inhibitors/adverse effects , Male , Mice , Soman/adverse effects
3.
Neurotoxicology ; 20(4): 535-49, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10499353

ABSTRACT

The effects of soman, a potent irreversible inhibitor of acetylcholinesterase, on central neuropathology in rats were studied in relation with subsequent spatial memory impairments. In a first step, it was found that, without treatment, neuropathology and learning impairment were observed only in rats which experienced convulsions. Then, treatment consisting of atropine sulfate, and/or TCP and/or NBQX was administered to intoxicated animals at infraanticonvulsant doses to obtain a graded subsequent neuropathology and to appreciate an eventual relation between neuropathology and spatial memory impairment. Thus, a correlation between neuropathology in the hippocampal CA1 region and spatial learning performance was found, the degradation of performance of rat being directly related to the amplitude of their neural damage. A threshold was emphasized : below a certain degree of neural loss, no memory impairment was found. Only treatment with tritherapy (atropine + TCP + NBQX) was able to improve the different parameters of spatial learning, despite no effect on the convulsions of the animals.


Subject(s)
Hippocampus/drug effects , Memory Disorders/chemically induced , Phencyclidine/analogs & derivatives , Quinoxalines/pharmacology , Soman/toxicity , Animals , Antidotes/pharmacology , Atropine/pharmacology , Behavior, Animal/drug effects , Cholinergic Antagonists/pharmacology , Convulsants/toxicity , Dose-Response Relationship, Drug , Drug Interactions , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Hippocampus/pathology , Male , Maze Learning/drug effects , Neuroprotective Agents/pharmacology , Phencyclidine/pharmacology , Rats , Rats, Wistar , Spatial Behavior/drug effects , Survival Rate , Time Factors
4.
J Physiol Paris ; 92(5-6): 369-73, 1998.
Article in English | MEDLINE | ID: mdl-9789839

ABSTRACT

Recent studies concerning management of soman-induced seizures are reviewed. While drugs classically used against epilepsy in hospital appear ineffective against soman, muscarinic receptor blockers are shown to be able to prevent or stop seizures within the first 5 min after their onset. Benzodiazepine could also be considered as an emergency treatment useful during the first 10 min of seizure. Comparatively NMDA antagonists appear to be able to terminate soman-induced seizures even if the treatment is delayed after 40 min of epileptic activity. Drugs with both antimuscarinic and anti-NMDA properties may represent the most adequate pharmacological treatment to treat soman intoxication. However, the results obtained until now with these drugs must be completed in relation with their possible efficacy after i.m. administration. Propositions for future studies are reviewed.


Subject(s)
Cholinesterase Inhibitors , Epilepsy/chemically induced , Epilepsy/drug therapy , Soman , Benzodiazepines/therapeutic use , Excitatory Amino Acid Antagonists/therapeutic use , Humans , Muscarinic Antagonists/therapeutic use , N-Methylaspartate/antagonists & inhibitors
5.
Pharmacol Biochem Behav ; 59(4): 1087-92, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9586871

ABSTRACT

NBQX, a specific and potent AMPA receptor antagonist has been found to be neuroprotective in various models of ischemia and to have anticonvulsant properties in different models of epilepsy. In this experiment, the neurobehavioral effects of NBQX were studied. In an open field, an important ataxia was emphasized at a dose of 60 mg/kg. In a swimming task, an increase of the escape latencies was noted on the third day at a dose of 40 mg/kg. In a Morris water maze task, doses devoid of effects on locomotion were used (10, 20, and 30 mg/kg). There was no effect on the acquisition of the task at 10 mg/kg and a slight impairment at 20 mg/kg, but the rats did not learn the task at 30 mg/kg. This impairment was reversible, as shown by the increasing performance of this group without treatment. No impairment was noted in the retention phase of the Morris water maze task. The results are discussed relative to the role of the AMPA receptor in memory processes.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Quinoxalines/pharmacology , Receptors, AMPA/antagonists & inhibitors , Animals , Male , Maze Learning/drug effects , Memory/drug effects , Motor Activity/drug effects , Rats , Rats, Wistar
6.
Pharmacol Biochem Behav ; 51(2-3): 429-34, 1995.
Article in English | MEDLINE | ID: mdl-7667364

ABSTRACT

TCP (N-[1-(2-thienyl)cyclohexyl]piperidine), A PCP (phencyclidine) derivative, has been shown to possess antiepileptic and neuroprotective efficacy against chemically induced seizures. However, it is known that other antagonists of the NMDA receptor impair spatial learning. This study was thus undertaken to explore the eventual effects of TCP on memory. The same study was done with MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ), one of the most studied NMDA receptor antagonists, which can be considered as a reference molecule. Three doses of each drug were chosen: 0.05, 0.1, and 0.2 mg/kg for MK-801 and 0.5, 1, and 2 mg/kg for TCP, the second dosage corresponding to the minimal required for antiseizure activity. The drugs were injected IP 30 min each day before a classical procedure of acquisition in a Morris water maze test. At the highest dose of each drug, the animals did not learn the position of the platform. At 0.1 mg/kg MK-801, the rats used a praxis strategy to find the platform but they did not known where the platform was. Contrary to MK-801, TCP at 1 mg/kg did not induce any memory impairment. At the lowest doses used, no memory impairment was found. It thus appears that, at the minimal therapeutic dose effective against chemically induced seizures (0.1 mg/kg for MK-801 and 1 mg/kg for TCP), TCP, contrary to MK-801, does not induce any memory impairment. Furthermore, at all the doses used, TCP presents the particularity that its locomotor side effects are not long lasting, being no longer observed from 30 min after the injection.


Subject(s)
Dizocilpine Maleate/pharmacology , Illicit Drugs/pharmacology , Memory/drug effects , Phencyclidine/analogs & derivatives , Space Perception/drug effects , Animals , Escape Reaction/drug effects , Male , Maze Learning/drug effects , Motor Activity/drug effects , Phencyclidine/pharmacology , Rats , Rats, Wistar
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