Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication.
Paraoxon (POX) is an active metabolite of organophosphate (OP) pesticide parathion that has been weaponized and used against civilian populations. Exposure to POX produces high mortality. OP poisoning is often associated with chronic neurological disorders. In this study, we optimize a rat survival model of lethal POX exposures in order to mimic both acute and long-term effects of POX intoxication. Male Sprague-Dawley rats injected with POX (4mg/kg, ice-cold PBS, s.c.) produced a rapid cholinergic crisis that evolved into status epilepticus (SE) and death within 6-8min. The EEG profile for POX induced SE was characterized and showed clinical and electrographic seizures with 7-10Hz spike activity. Treatment of 100% lethal POX intoxication with an optimized three drug regimen (atropine, 2mg/kg, i.p., 2-PAM, 25mg/kg, i.m. and diazepam, 5mg/kg, i.p.) promptly stopped SE and reduced acute mortality to 12% and chronic mortality to 18%. This model is ideally suited to test effective countermeasures against lethal POX exposure. Animals that survived the POX SE manifested prolonged elevations in hippocampal [Ca(2+)]i (Ca(2+) plateau) and significant multifocal neuronal injury. POX SE induced Ca(2+) plateau had its origin in Ca(2+) release from intracellular Ca(2+) stores since inhibition of ryanodine/IP3 receptor lowered elevated Ca(2+) levels post SE. POX SE induced neuronal injury and alterations in Ca(2+) dynamics may underlie some of the long term morbidity associated with OP toxicity.
Departments of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Laxmikant S
LS
Deshpande
Departments of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Dawn S
DS
Carter
Departments of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Kristin F
KF
Phillips
Departments of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Robert E
RE
Blair
Departments of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA; Departments of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA; Departments of Molecular Biophysics and Biochemistry, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: rdeloren@hsc.vcu.edu.
Robert J
RJ
DeLorenzo
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D062025:Organophosphate Poisoning / Q000150:complications* / Q000401:mortality; D010261:Paraoxon / Q000008:administration & dosage*; D011220:Pralidoxime Compounds / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced* / Q000188:drug therapy*
D000927:Anticonvulsants; D011220:Pralidoxime Compounds; D001285:Atropine; C028797:pralidoxime; D003975:Diazepam; D010261:Paraoxon; D002118:Calcium
Ca(2+) dynamics; Paraoxon; Sprague–Dawley rats; Status epilepticus; Survival model