Long-term cognitive deficits accompanied by reduced neurogenesis after soman poisoning
article
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.
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.
Topics
LearningMemoryNeurogenesisOlanzapineOrganophosphateSomanacetylcholineacetylcholinesteraseatropinedoublecortinolanzapinesomananimal experimentanimal modelanimal tissuearticlebody weightcell survivalcognitive defectcontrolled studycorpus striatumdevelopmental disorderdrug efficacydrug treatment failurehistopathologylearning disordermalemaze testmemory disordernervous system developmentneurotoxicitynonhumanosmotic minipumppriority journalratrecurrent diseaseseizureAcetylcholineAcetylcholinesteraseAnimalsAtropineBenzodiazepinesCholinesterase ReactivatorsCorpus StriatumHippocampusMaleMaze LearningNeurogenesisPyridinium CompoundsRatsRats, Sprague-DawleySeizuresSomanAnimaliaRattus
TNO Identifier
27867
Source
NeuroToxicology, 30, pp. 72-80.
Pages
72-80
Files
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