Cholinergic And Non-cholinergic Mechanisms Of Spatial Memory Impairment In Rats Chronically Treated With Low-dose Soman

Background and objectives:Highly toxic organophosphates (OPs) pose potential neurotoxic threats to both military and civilian populations, as evidenced in recent terrorist attacks and in an accident as part of current demilitarization efforts, as well as occupational hazards to individuals exposed to certain insecticides. As one of representative of Ops, Lipophilic soman (0-1, 2, 2-trime thylpropyl methylphosphonofluoridate) can readily cross the blood-brain barrier and lead to neuronal impairment. Soman toxicity results from the irreversible binding to and inactivation of acetylcholinesterase (AChE), the enzyme that normally catalyzes the hydrolysis of acetylcholine (ACh) at neuromuscular junctions and other cholinergic synapses. Accumulation of ACh in the synapse causes repetitive neuronal firing, resulting ultimately in convulsions, respiratory failure, and/or death.Animals dosed with repeated organophosphates(e.g. Diisopropylfluorophosphate, Disulfoton, sarin) have decreased number of muscarinic receptors in central and peripheral nerve tissue, which has been suggested as representing adaptation to prolonged cholinesterase inhibition. Such changes in receptor level may protect against usual signs of acute organophosphates toxicity, but may also result in subtle undesirable effects on senior brain function. Therefore, down-regulation of central neuronal cholinergic function may be responsible for cognitive impairment in animals chronically treated with asymptomatic low-dose organophosphates. However, effects of soman in low dose chronically intoxication on cognition function does not fully understood. In addition, little is known of the non-cholinergic mechanism (e.g. amino-acid neurotransmitter, neuropeptide system, response of stress gene, et al.) involved in the neural damage of soman. The underlying biochemical mechanisms of neurological and neuropsychological effects including the impairments of cognitive function following single or repeated asymptomatic exposures to soman is rarely concerned. The aim of this study is to provide theoretical instruction toprophylaxis and therapy of low-dose nerve agent intoxication, including soman intoxication, through investigation the effect and mechanisms of soman on cognition function in brain of rats chronically treated with low-dose soman.Methods:Wistar rats were given daily subcutaneous injections of soman for 14 days in this study. Spatial memory and LTP (long-term potentiation) of the hippocampus slices were evaluated in rats following repeated soman exposure with the methods of Morris water maze task and eilectrophysiology respectively. Chromatometry and RT-PCR were carried out to investigate the activities of acetylcholinesterase and ml/m4 expression in the brain of rat. In situ hybridization, immunohistochemistry and RT-PCR were employed to evaluate amino acid level, NMDA receptor expression, BDNF immunoreactivity and ERK signal transduction in the brain of rat chronically received low dose of soman. The ultrastructural of neurons in CA1 area of the hippocampus was also observed with electron microscope.Results:1. Effect of chronic administration of soman in low dose on memory in rats(1) In Morris water maze test, escape latency of the rats treated chronically with soman was obviously increased compared with the normal saline treated rats. Both the time percentage and the distance percentage of swimming trace in the former platform quadrant decreased significantly in rats, the frequency of pass through the platform was also decreased obviously.(2) The LTP induction rate of the hippocampus slice was obviously decreased significantly when the rats chronically treated with low dose of soman. Increase of PSA (population spike amplitude) of hippocampal slices recorded after titanic stimulation in rats was also decreased markedly compared with control group.(3) The ultrastructure of neurons in CA1 area of the hippocampus of rats soman intoxicated was changed markedly. In brief, the mitochondria was swelling, the...