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Long-term cognitive deficits accompanied by reduced neurogenesis after soman poisoning

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Author: Joosen, M.J.A. · Jousma, E. · Boom, T.M. van den · Kuijpers, W.C. · Smit, A.B. · Lucassen, P.J. · Helden, H.P.M. van
Institution: TNO Defensie en Veiligheid
Source:NeuroToxicology, 30, 72-80
Identifier: 27867
doi: doi:j.neuro.2008.11.010
Keywords: Toxicology · Learning · Memory · Neurogenesis · Olanzapine · Organophosphate · Soman · acetylcholine · acetylcholinesterase · atropine · doublecortin · olanzapine · soman · animal experiment · animal model · animal tissue · article · body weight · cell survival · cognitive defect · controlled study · corpus striatum · developmental disorder · drug efficacy · drug treatment failure · histopathology · learning disorder · male · maze test · memory disorder · nervous system development · neurotoxicity · nonhuman · osmotic minipump · priority journal · rat · recurrent disease · seizure · Acetylcholine · Acetylcholinesterase · Animals · Atropine · Benzodiazepines · Cholinesterase Reactivators · Corpus Striatum · Hippocampus · Male · Maze Learning · Neurogenesis · Pyridinium Compounds · Rats · Rats, Sprague-Dawley · Seizures · Soman · Animalia · Rattus


To date, treatment of organophosphate (OP) poisoning shows several shortcomings, and OP-victims might suffer from lasting cognitive deficits and sleep–wake disturbances. In the present study, long-term effects of soman poisoning on learning ability, memory and neurogenesis were investigated in rats, treated with the anticholinergic atropine and the oxime HI-6 for reactivation of soman-inhibited acetylcholinesterase. We also investigated whether sub-chronic treatment with the reported neurogenesis enhancer olanzapine would stimulate neurogenesis and possibly normalize the anticipated long-term deleterious effects of soman intoxication. Animals were treated with HI-6 (125 mg/kg i.p.), followed after 30 min by soman (200 mg/kg s.c.) and atropine sulphate (16 mg/kg i.m.) 1 min thereafter. Soman poisoning led to an elevation of extracellular acetylcholine levels to 1500% over baseline values as assessed by striatal microdialysis. Brain acetylcholinesterase was inhibited over 95%. This was accompanied by short recurrent seizures lasting for 40 min. Osmotic minipumps releasing olanzapine (7.5 mg/kg/day) or vehicle were subcutaneously implanted 24 h post-intoxication. After drug delivery for 4 weeks, newborn cells were BrdU labeled. Learning and memory performance were assessed 8 weeks after soman poisoning, followed by analysis of surviving newborn cells (BrdU) and neurogenesis (doublecortin, DCX). Eight weeks after soman-intoxication a significantly impaired learning ability was found that was paralleled by significantly lower numbers of DCX-positive cells but no changes in the number of BrdU-labeled cells. Apparently, the present Olanzapine regime was ineffective. We conclude that soman poisoning has long lasting effects on learning ability, a finding that was accompanied by impaired neurogenesis. Although we confirm a correlation between impaired neurogenesis and cognitive deficits, establishing the true causal relationship between these processes in OP exposed animals awaits future research.