Title
Long-term cognitive deficits accompanied by reduced neurogenesis after soman poisoning
Author
Joosen, M.J.A.
Jousma, E.
van den Boom, T.M.
Kuijpers, W.C.
Smit, A.B.
Lucassen, P.J.
van Helden, H.P.M.
TNO Defensie en Veiligheid
Publication year
2009
Abstract
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.
Subject
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 reference this document use:
http://resolver.tudelft.nl/uuid:a1f6e7de-82f2-47a7-9df9-692b34d38168
DOI
https://doi.org/10.1016/j.neuro.2008.11.010
TNO identifier
27867
Source
NeuroToxicology, 30, 72-80
Document type
article