Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity.
Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 μg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic-clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.
Department of Pharmacology, Israel Institute for Biological Research, 74100 Ness-Ziona, Israel. shahafk@iibr.gov.il
Shahaf
S
Katalan
Shlomi
S
Lazar
Rachel
R
Brandeis
Ishai
I
Rabinovitz
Inbal
I
Egoz
Ettie
E
Grauer
Eugenia
E
Bloch-Shilderman
Lily
L
Raveh
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000931:Antidotes / Q000494:pharmacology*; D001930:Brain Injuries / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002619:Chemical Warfare Agents / Q000506:poisoning*; D003517:Cyclopentanes / Q000494:pharmacology; D004830:Epilepsy, Tonic-Clonic; D008278:Magnesium Sulfate / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000506:poisoning*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013686:Telemetry
D000927:Anticonvulsants; D000931:Antidotes; D002619:Chemical Warfare Agents; D003517:Cyclopentanes; D008278:Magnesium Sulfate; C004519:caramiphen; D012524:Sarin; D008874:Midazolam