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1.
Ann Pharm Fr ; 62(4): 247-52, 2004 Jul.
Article in French | MEDLINE | ID: mdl-15243343

ABSTRACT

Amongst organophosphate compounds, both pesticides and warfare neurotoxics are probably the most representative. These compounds are irreversible acetylcholinesterase inhibitors. Usual clinical signs observed after acute poisoning are mainly respiratory distress, convulsions and seizures. Following acute poisoning, an emergency treatment must be provided as soon as possible (maximum delay of 1 hour post-poisoning), to prevent irreversible brain damage and patient death. At the present time, there is no efficient delayed treatment which could be provided if this 1 hour latency is overpassed. However, neurogenesis by stem cell engraftment, eventually complemented by gene therapy strategy, could be a potential therapeutic approach to repair organophosphate-induced brain damage. Main stem cell engraftement strategies successfully used for brain damage of various origins are reviewed in this Article.


Subject(s)
Brain Diseases/chemically induced , Brain Diseases/therapy , Neurotoxicity Syndromes/therapy , Organophosphate Poisoning , Stem Cell Transplantation , Animals , Brain Diseases/pathology , Chemical Warfare Agents/poisoning , Humans , Neurons/transplantation , Neurotoxicity Syndromes/pathology
2.
Neurotoxicology ; 22(1): 29-37, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11307848

ABSTRACT

Huperzine A (HUP), an alkaloid isolated from the Chinese club moss, Huperzia serrata is a reversible inhibitor of cholinesterases which crosses the blood-brain barrier and shows high specificity for acetylcholinesterase (AChE) and a prolonged biological half-life. We tested, in vivo, its efficiency in protecting cortical AChE from soman inhibition and preventing subsequent seizures. The release of acetylcholine (ACh) was also followed in the cortex of freely moving rats using microdialysis techniques. We previously found that soman-induced seizures occurred in rodents only when the cortical AChE inhibition was over 65% and when the increase of ACh level was over 200 times the baseline level. This was verified in the present study in control animals intoxicated by 1 LD50 of soman (90 microg/kg). Using the same dose of soman in rats pre-treated with 500 microg/kg of HUP, we observed that 93% of the animals survived and none of them had seizures. This dose of HUP reduced AChE inhibition to 54% and increase of ACh level to 230 times baseline value. HUP thus appears as a promising compound to protect subjects against organophosphorus intoxication.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Seizures/prevention & control , Sesquiterpenes/pharmacology , Soman/antagonists & inhibitors , Acetylcholine/metabolism , Acetylcholinesterase/metabolism , Alkaloids , Animals , Brain/enzymology , Electroencephalography/drug effects , Kinetics , Male , Microdialysis , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Soman/toxicity
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.
Arch Toxicol ; 72(2): 84-92, 1998.
Article in English | MEDLINE | ID: mdl-9456079

ABSTRACT

Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.


Subject(s)
Anticonvulsants/therapeutic use , Chemical Warfare Agents/toxicity , Cholinesterase Inhibitors/toxicity , Cholinesterase Reactivators/therapeutic use , Cyclohexanes/therapeutic use , Excitatory Amino Acid Antagonists/therapeutic use , Neuroprotective Agents/therapeutic use , Piperidines/therapeutic use , Soman/toxicity , Animals , Anticonvulsants/pharmacology , Atropine/administration & dosage , Atropine/therapeutic use , Brain/drug effects , Brain/pathology , Cholinesterase Reactivators/administration & dosage , Cyclohexanes/administration & dosage , Cyclohexenes , Diazepam/administration & dosage , Diazepam/therapeutic use , Drug Combinations , Excitatory Amino Acid Antagonists/administration & dosage , Injections, Intravenous , Macaca fascicularis , Male , Muscarinic Antagonists/administration & dosage , Muscarinic Antagonists/therapeutic use , Neuroprotective Agents/pharmacology , Piperidines/administration & dosage , Pralidoxime Compounds/administration & dosage , Pralidoxime Compounds/therapeutic use , Seizures/prevention & control , Staining and Labeling , Time Factors
5.
Fundam Clin Pharmacol ; 11(5): 387-94, 1997.
Article in English | MEDLINE | ID: mdl-9342591

ABSTRACT

Huperzine A (HUP) is a potent reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. Its ability to prevent seizures and subsequent hippocampal neuropathological changes induced by the organophosphate soman was studied in guinea pigs. Results were compared to guinea pigs treated with pyridostigmine (PYR, 0.2 mg/kg, subcutaneously). HUP pretreatment at 0.5 mg/kg, intraperitoneally, totally prevented seizures and ensured the survival of all animals for 24 h after intoxication. Hippocampal tissue was then free of any neuronal damage. Comparatively, all animals pretreated with PYR exhibited epileptic activity after soman poisoning and five of six animals died. Examination of the hippocampus of the only surviving guinea pig pretreated with PYR showed extensive neuropathological changes. Although HUP or PYR induced similar inhibitions of blood AChE activity, only HUP pretreatment led to a decrease in central AChE activity. In binding studies on guinea-pig brain homogenates, HUP had no affinity for muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and gamma-aminobutyric acid (GABA)A receptors and only a very low one for N-methyl-D-aspartate (NMDA) receptors. In conclusion, HUP, unlike PYR, protects against soman-induced convulsions and neuropathological changes in the hippocampus. This efficacy seems to be related to a protection by HUP of both peripheral and central stores of AChE.


Subject(s)
Cholinesterase Inhibitors/therapeutic use , Hippocampus/pathology , Neuroprotective Agents/therapeutic use , Seizures/drug therapy , Sesquiterpenes/therapeutic use , Alkaloids , Animals , Brain/metabolism , Cholinesterase Inhibitors/metabolism , Electroencephalography , Guinea Pigs , Male , Pyridostigmine Bromide/therapeutic use , Receptors, N-Methyl-D-Aspartate/metabolism , Seizures/chemically induced , Seizures/pathology , Sesquiterpenes/metabolism , Soman
6.
C R Acad Sci III ; 316(10): 1250-4, 1993 Oct.
Article in French | MEDLINE | ID: mdl-8062133

ABSTRACT

The objective of the present study was to evaluate the anticonvulsant and neuroprotective activities of propentofylline against soman, an irreversible acetylcholinesterase inhibitor. In a first step, the ability of propentofylline to inhibit in vitro the hippocampal evoked release of acetylcholine (ACh) and glutamate (Glu), the two major neurotransmitters involved during soman intoxication, was demonstrated. Propentofylline was then given either at single doses from 0.5 to 25 mg/kg or with repetitive injections at 10 mg/kg to mice subjected to soman. Neither tonic-clonic convulsions induced by soman nor subsequent hippocampal damage were reduced in propentofylline-treated mice. This observation suggested that propentofylline did not inhibit the long-lasting hippocampal release of ACh and Glu under soman.


Subject(s)
Anticonvulsants/pharmacology , Soman/toxicity , Xanthines/pharmacology , Acetylcholine/pharmacokinetics , Animals , Drug Evaluation, Preclinical , Glutamates/pharmacokinetics , Male , Neurons/drug effects , Rats , Rats, Wistar
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