Involvement Of Excitatory Amino Acid System (EAAs) In Dimethoate-induced Neurotoxicity

It is estimated that more than 70% of pesticide poisoning cases occur in the country are due to organophosphorus pesticides (OPs), which ranks the top of the acute chemical intoxication. The long history and inappropriate use of OPs leads to excessive exposure and high risk of unintentional poisoning. The non-cholinergic mechanisms might be involved in both acute OPs poisoning and chronic OPs-induced neuropsychiatric disorders (COPIND) besides the well-documented cholinesterase inhibition. Thus the key role of excitatory amino acid (EAA) in the contribution of exitotoxicity in acute epilepticus, cerebral ischemia or traumatic brain injury and in the etiology and progression of several human neurodegenerative diseases, such as Parkinson's disease and Hundtington's disease, it is considerable to investigate the involvement of EAA in both acute and chronic OPs poisoning.The levels of EAA including glutamate and aspartate were determined by HPLC-FLD in brain regions at 0.5h, 2.0h, 8.0h and 24.0h after a single dimethoate administration (0, 38.9mg/kg, 83.7mg/kg or 180.0mg/kg by gavage) in rats. Both in the cerebral cortex and the hippocampus, dimethoate treatment caused significant decreases in EAA in a dose-time-effect manner; early treatment decreased EAA in the stratum while the level of EAA in the brain stem changed about at 24.0h; but the dimethoate administration had no significant effects on either Glu or Asp during the observation period in the rat cerebellum. The decrement of EAA might be a part of compemsatory process to counteract the excessive cholinergic activity and excitotoxicity by the acute dimethoate administration.After 13 weeks of repeated oral exposure to dimethoate (0, 5.0mg/kg, 10.0mg/kg and 20.0mg/kg by gavage), five days a week except weekends, the levels of Glu and Asp decreased in the rat cortex but increased significantly in the hippocampus in the 2 highest dose groups. It might be a compensation modulation of the neurotransmitters in the cortex while the increase of EAA would cause damage to the neurons in the hippocampus which would mediate the alterations of neurobehavior after the long-term repeated exposure to dimethoate in rat.There were some cognitive deficits observed, demonstrated by slightly longer latency during spatial training and decreased preference for the correct quadrant on probe trials in a Morris water maze after the chronic dimethoate administration. The neurobehavioral changes correlated to the alterations of the profiles of the NMDA receptor system statistically. The levels of the receptor ligand Glu, the co-agonist Gly and the interneuronal modulator GABA were increased significantly at the 2 highest doses of dimethoate while the NMDA receptor density and binding affinities were decreased significantly in the hippocampus. The results suggest that the prolonged hippocampus NMDA receptor system hypofunction might contribute the impairments of rat spatial learning and memory after the repeated dimethoate exposure.The non-competitive NMDA receptor antagonist, MK-801, was pretreatment 30min before the dimethoate administration to verify the role of NMDA receptor system in the chronic OPs-induced neurobehavioral impairments. Rats pretreated with MK-801 showed an improved latency and preference in the water maze compared to the correspondent dimethoate treated rats and the control. The beneficial effects from the blockage of the NMDA receptor indicate the secondarily activated non-cholinergic excitatory system might be involved in the chronic dimethate exposure induced spatial learning and memory impairments in rats.It is suggested that the excitatory amino acid system as well as the cholinergic mechanisms appear to play major roles underlying dimethoate-induced neurotoxicity. The investigation on the NMDA receptor system may lead to a better understanding of non-cholinergic mechanisms in OPs intoxication.