Development of a rat pilocarpine model of seizure/status epilepticus that mimics chemical warfare nerve agent exposure.
We developed a rat pilocarpine seizure/status epilepticus (SE) model, which closely resembles 1.6-2.0 x LD50 soman exposure, to analyse the molecular mechanism of neuronal damage and to screen effective neuroprotectants against cholinergic agonist and chemical warfare nerve agent (CWNA) exposure. Rats implanted with radiotelemetry probes capable of recording electroencephalogram (EEG), electrocardiogram (ECG), temperature, and physical activity were treated with lithium chloride (5 mEq/kg, im), followed 24 h later by (ip) doses of pilocarpine hydrochloride. Based on radiotelemetry analysis, a dose of 240 mg/kg (ip) pilocarpine generated seizure/SE analogous to 1.6-2.0 x LD50 of soman. The model was refined by reducing the peripheral convulsions without affecting the central nervous system (CNS) by administering methylscopolamine bromide (1 mg/kg, ip), an anti-cholinergic that does not cross the blood-brain barrier. However, when methylscopolamine bromide was administered, a higher dose of pilocarpine (320 mg/kg, ip) was required to generate the equivalent seizure/SE. Histopathology data indicated that pilocarpine induces significant damage to the hippocampal region of the brain, with similar neuropathology to that of 1.6-2.0 x LD50 soman exposure. There was a reduction in body temperature after the administration of pilocarpine, as observed in organophosphate (OP) nerve agents exposure. The heart-rate of pilocarpine-treated animals increased compared to the normal range. The pilocarpine seizure/SE model was also reproducible in the absence of lithium chloride. These results support that pilocarpine seizure/SE model is useful in studying the molecular mechanisms of neuropathology and screening neuroprotectants following cholinergic agonist and CWNA exposure.
Tetz
Lauren M
LM
Department of Biochemical Pharmacology/Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.
Rezk
Peter E
PE
Ratcliffe
Ruthie H
RH
Gordon
Richard K
RK
Steele
Keith E
KE
Nambiar
Madhusoodana P
MP
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004569:Electroencephalography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007928:Lethal Dose 50; D018021:Lithium Chloride; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists; D019832:N-Methylscopolamine / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000503:physiopathology; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D012999:Soman / Q000633:toxicity; D013226:Status Epilepticus / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D018680:Cholinergic Antagonists; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D010862:Pilocarpine; D012999:Soman; D018021:Lithium Chloride; D019832:N-Methylscopolamine