Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins

Abstract

Soman, a potent acetylcholinesterase inhibitor, induces status epilepticus in rats followed by conspicuous neuropathology, most prominent in piriform cortex and the CA3 region of the hippocampus. Cholinergic seizures originate in striatal-nigral pathways and with fast-acting agents (soman) rapidly spread to limbic related areas and finally culminate in a full-blown status epilepticus. This leads to neurochemical changes, some of which may be neuroprotective whereas others may cause brain damage. Pretreatment with lithium sensitizes the brain to cholinergic seizures. Likewise, other agents that increase limbic hyperactivity may sensitize the brain to cholinergic agents. The hyperactivity associated with the seizure state leads to an increase in intracellular calcium, cellular edema and metal delocalization producing an oxidative stress. These changes induce the synthesis of stress-related proteins such as heat shock proteins, metallothioneins and heme oxygenases. We show that soman-induced seizures cause a depletion in tissue glutathione and an increase in tissue 'catalytic' iron, metallothioneins and heme oxygenase-1. The oxidative stress induces the synthesis of stress-related proteins, which are indicators of 'stress' and possibly provide neuroprotection. These findings suggest that delocalization of iron may catalyze Fenton-like reactions, causing progressive cellular damage via free radical products. Published in

Alterations in brain glutathione homeostasis induced by the nerve gas soman

“…An oxidative stress is likely associated with the marked increase in metabolic activity (1 h post soman exposure) that occurs during the seizure phase and by metal delocalization during the pathology phase (24 h post soman exposure) (Pazdernik et al, 2001). This oxidative stress alters glutathione homeostasis in the brain dramatically, suggesting that the supplementation of antioxidants may be efficacious in addition to currently prescribed antidotes to soman exposure.…”

“…Oxidative stress has been implicated in the neuropathology associated with status epilepticus induced by soman (Jacobsson et al, 1999, Pazdernik et al, 2001). Here we demonstrate that soman-induced seizures alter the thiol status of those brain regions known to have a marked increase in metabolic activity and progress to have neuropathology.…”

“…Cholinergic seizures originate in striatal-nigral pathways (initiation sites) and with fast-acting agents (soman) rapidly spread to limbic related areas and finally culminate in full-blown status epilepticus (Pazdernik et al, 2001). Activation of muscarinic receptors initiates a cascade of biochemical events that culminate in a glutamate-driven limbic status epilepticus (Wade et al, 1987;Lallement et al, 1991;Shih and McDonough, 1997;Solberg and Belkin, 1997).…”

“…The hyperactivity associated with the seizure state leads to an increase in intracellular calcium, cellular edema and metal delocalization producing an oxidative stress (Pazdernik et al, 2001). It is known that glutamate stimulation of NMDA receptors is associated with the production of reactive oxygen species (Kucukkaya et al, 1996).…”

Effect of Soman on JNK and P38 Mitogen Activated Protein Kinase (Mapk) Pathways

“…Nerve agents are highly toxic organophosphates representing potential threats to both military and toxic effects of nerve agents (4,5). Therefore, finding the mechanisms of nerve agent-induced non-specific effects might contribute to early diagnosis and complex treatment of nerve agent poisoning.…”