title: Gene expression and phosphoprotein profile of certain key neuronal signaling proteins following soman intoxication.
abstract: Nerve agents irreversibly inhibit acetylcholinesterase (AChE), leading to cholinergic crisis and death at acute exposure levels. The complexity, delayed onset, and persistent nature of nerve agent induced CNS effects need to be elucidated to block their multiple effects. In the present study gene expression and phosphoprotein profile of certain key neuronal proteins were studied after soman exposure. Quantitative real time PCR analysis of c-Fos, Bax, CREB and caspase 3 genes in the hippocampus, cortex and cerebellum showed that only c-Fos and Bax mRNA expression was increased significantly. Western blot analysis also confirmed the induction of c-Fos at early time points both at 0.5 and 1.0 LD(50) dose of soman exposure. Acute soman exposure caused perturbations in the phosphorylation status of ERK, JNK, p38 MAPK, CREB, c-Jun and NF-κB in all the three brain regions. The primary target for soman toxicity, AChE was inhibited in blood and brain up to 90%. Therapeutic treatment comprising of HI-6, atropine and diazepam has completely protected animals from death and reactivated soman inhibited AChE up to 40% in the plasma and RBC. This therapeutic regime also reduced soman induced Bax expression to near control levels, but could not reverse the soman induced changes in c-Fos expression and phosphorylation levels completely. Results suggest that exposure to soman caused persistent changes in these key brain proteins, which could lead to the development of complex neurotoxic effects and there is an urgent need for development of better drugs to stop multiple effects of nerve agents poisoning.
authors.affiliation: Defence Research and Development Establishment, Jhansi Road, Gwalior, M.P., India. ramugolime@gmail.com
authors.forename: G
authors.initials: G
authors.lastname: RamaRao
authors.forename: B K
authors.initials: BK
authors.lastname: Bhattacharya
authors.forename: Subodh
authors.initials: S
authors.lastname: Kumar
authors.forename: C K
authors.initials: CK
authors.lastname: Waghmare
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000506:poisoning*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D003975:Diazepam / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D009833:Olfactory Pathways / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000506:poisoning*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride; D003975:Diazepam