Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes

Abstract

BackgroundRecent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas.ResultsTherapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2 × LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus.ConclusionRats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents.

Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population

“…The data reported so far show that midazolam can protect against nerve agent-induced brain damage in adult or young-adult rats, if it is administered at the time of exposure (Chapman et al, 2015), at the onset of seizures (RamaRao et al, 2014), or after 5 min of seizure activity (Gilat et al, 2005); however, if it is given 1 h after exposure, it does not prevent histological damage, despite its antiseizure efficacy and beneficial effects on behavioral performance and inflammatory responses (Chapman et al, 2015). More studies are needed to understand the neuroprotective efficacy of midazolam when administered at different time points after nerve agent exposure, and direct comparisons must be made with LY293558 under the same experimental conditions for two drugs.…”

Midazolam as an anticonvulsant antidote for organophosphate intoxication—A pharmacotherapeutic appraisal

“…Midazolam has been suggested as a better anticonvulsant than diazepam for nerve agent seizures. Midazolam has been tested extensively in a variety of animal models of OP exposure . Most experiments are conducted in a guinea‐pig model that is designed to closely simulate the military antidote regimen (pyridostigmine pretreatment and atropine sulfate + 2‐PAM).…”

“…Midazolam has been tested extensively in a variety of animal models of OP exposure. 4,43,[55][56][57][58] Most experiments are conducted in a guinea-pig model that is designed to closely simulate the military antidote regimen (pyridostigmine pretreatment and atropine sulfate + 2-PAM). Rat and primate models were also utilized for testing the anticonvulsant therapies for OP intoxication.…”

Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents

“…Midazolam (MDZ) has been proposed as a replacement anticonvulsant to diazepam for OP intoxication (Gilbert et al, 1999;Glauser et al, 2016;Smith and Brown, 2017). MDZ is an effective anticonvulsant in experimental paradigms (McDonough et al, 1999(McDonough et al, , 2009Koplovitz et al, 2001;Capacio et al, 2004;RamaRao et al, 2014). The RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial, a NIH-sponsored clinical trial) study showed that MDZ can control SE in outpatient settings (Silbergleit et al, 2011(Silbergleit et al, , 2012.…”