Journal
COUNTERMEASURES AGAINST CHEMICAL THREATS
Volume 1374, Issue -, Pages 176-183Publisher
BLACKWELL SCIENCE PUBL
DOI: 10.1111/nyas.13122
Keywords
paraoxon; status epilepticus; cell death; calcium; dantrolene; carisbamate
Categories
Funding
- NINDS NIH HHS [U01 NS058213, R56 NS092494, R01 NS052529] Funding Source: Medline
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Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP-based chemical attacks against civilians. Current antidotes are essential in limiting immediate mortality associated with OP exposure. However, further research is needed to identify the molecular mechanisms underlying long-term neurological deficits following survival of OP toxicity in order to develop effective therapeutics. We have developed rat survival models of OP-induced status epilepticus (SE) that mimic chronic mortality and morbidity following OP intoxication. We have observed significant elevations in hippocampal calcium levels after OP SE that persisted for weeks following initial survival. Drugs inhibiting intracellular calcium-induced calcium release, such as dantrolene, levetiracetam, and carisbamate, lowered OP SE-mediated protracted calcium elevations. Given the critical role of calcium signaling in modulating behavior and cell death mechanisms, drugs targeted at preventing the development of the calcium plateau could enhance neuroprotection, help reduce morbidity, and improve outcomes following survival of OP SE.
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