Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins.
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.
Pazdernik
T L
TL
Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, KS 66160, USA. tpazdern@kumc.edu
Emerson
M R
MR
Cross
R
R
Nelson
S R
SR
Samson
F E
FE
D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000378:metabolism; D051547:Heme Oxygenase-1; D007501:Iron / Q000032:analysis / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000032:analysis / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D012999:Soman / Q000633:toxicity*
D002619:Chemical Warfare Agents; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D008668:Metallothionein; D012999:Soman; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D005978:Glutathione