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


RESULTS
Therapeutic 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.


CONCLUSIONS
Rats 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.
Biochemistry Division, Defence Research and Development Establishment, Jhansi road, Gwalior, MP, India. ramugolime@gmail.com.
Golime
G
RamaRao
Prachiti
P
Afley
Jyothiranjan
J
Acharya
Bijoy Krishna
BK
Bhattacharya
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage; D001285:Atropine / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000008:administration & dosage; D018757:GABA Modulators / Q000008:administration & dosage; D008297:Male; D008874:Midazolam / Q000008:administration & dosage*; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D010091:Oximes / Q000008:administration & dosage*; D011726:Pyridinium Compounds / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000633:toxicity*; D015996:Survival Rate; D016896:Treatment Outcome
D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018757:GABA Modulators; D018727:Muscarinic Antagonists; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; C022870:asoxime chloride; D008874:Midazolam