Soman And Hypoxia On The Role Of The Cholinergic Nerve Signaling

Study on the combined effects of hypoxia and somanintoxication on cholinergic signal transduction inrats brain and PC12 cellsAbstractSoman, an organophosphorus compound, is one of the most famous nerve agents for its high toxicity in animals and human beings, difficulty in prevention and treatment. In previous studies we found that the toxicity of soman was increased by hypoxia exposure and the mechanism was not clearly underlined. To further clarify the features and the mechanism of brain injury induced by soinan intoxication combined with hypoxia, two correlated models were employed in this study: the whole animal model of soman intoxication at simulated high altitude and cultured PC 12 cells model of soman intoxication in a hypoxia chamber.Results from biochemical measurements and radioactive binding assay with [3H]-QNB revealed a decreased AChE activity, a decreased M receptor affinity and a increased ACh concentration in brain tissues of the control rats. However. the inhibitory effect of soman on brain AChE activity was slightly reduced by hypoxia exposure. The M receptor affinity in the brain regions was also significantly up-regulated by the combined injury of sonian intoxication and hypoxia exposure. In all of the brain regions studied in this project, increased Gqc~ expression, cAMP concentration and PKA activity were discovered respectively in the animals treated by soman only, treated by hypoxia exposure only and treated by the combined injury. Otherwise, Gia expression was suppressed by both hypoxia or soman and combind treatments. The increased PKA activity induced by soman or hypoxia or combined treatment was fully or partially reversed by atropine pretreatment. In the studies with PC-12 cells, soman intoxication or/and hypoxia induced significant enhancement of AC activity, cAMP concentration andthe level of [Ca2~]1.. Nimodipine, a calcium channel blocker, effectively declined the increasing of [Ca2~I1 of PC12 cells induced by soman intoxication or/and hypoxia. These results strongly suggest a enhancing effect of soman intoxication combined with hypoxia on central cholinergic signal transduction system confirmed by M receptor up-regulation, Gia expression suppress,Gqcc expression increase, cAMP formation and calcium mobilization. This enhancement, furthermore, maybe play a very important role in the mechanism of brain damage induced by soman intoxication under hypoxia condition.