Effect Of Cinnarizine On The Models Of Dysmnesia Induced By Excitotoxicity In Rats

OBJECTIVE:With the population aging in the world, the incidence rate of senile dementia is increasingly. More than half of the senile dementia is Alzheimer's disease(AD). AD is one of the commonest chronic degeneration of neurons in the older, which disturbs seriously the lives of the aged. So it will be an important task to seek for effctive drugs.Because the pathogenesis of AD is very complex and it's etiology is unknown, there hasn't an ideal animal model. Since the excitotoxicity was suggested, many experiments confirmed that the pathogenesis of AD was related to excitotoxicity. So it was presumed that excitotoxicity was the primary pathogenesis of AD. Animal models were made by injecting quinolinic acid(QA) into both CA1 districts of hippocampuses with microinjector, but there hasn't study about it's pathogenesis from the lesion of hippocampus neurons induced by QA. Investigations further indicated that excitotoxicity resulted the neurodeg- eneration through two steps. Firstly, it resulted the excessivly inflow of Na+, which damage the brain reversibly, then it resulted in excessively inflow of Ca2+, which resulted in a series of damage. So blocking of the inflow of Ca2+, so as to diminished the overload of Ca2+ and their related damage is hope to relieve the neurodegeneration. Cinnarizine(Cin) is a Ca2+ channel antagonist. Our previous experiments and other's studies indicated that Cin could block the accumulation of rat brain cells. But there hasn't study about it's protection from the lesion of hippocampus neurons induced by excitotoxicity.In the present study, to more fully explore the pathogenesis of dysmnesia induced by QA and to study whether Cin can protect the hippocampus neurons from QA, we observed the effects of neurochemistry, neurohistopathology and behavior of animal models, so as to find a new protect agent for senile dementia and other neurodegeneration diseases.METHODS:Animal models were made by injecting QA into both CA1 districts of hippocampuses with microinjector. The distribution of positive cells of tyrosine hydroxylase (TH), choline acetylase (ChAT), tryptophan hydroxy- lase(TPH) and glutamic acid(Glu) in the CA1 districts of hippoc- ampuses were observed. The contents of dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT) in hippocampuses were determined to study the pathogenesis of dysmnesia induced by QA. Fortheremore, there praxiology and pathology were observed to study the protection effect of Cin.RESULTS AND CONCLUSIONS:(1) The distribution of positive cells of TH, ChAT, TPH and Glu in the CA1 distrits of models from the excitotoxicity were decreased obviously, and the contents of DA, NA and 5-HT in hippocampuses also decreased., which indicated that the excitotoxicity of QA is related with these factors.(2) Cin(20 mg/kg and 60 mg/kg)could in a dose-dependent manner, ameliorate the ability of spatial learning and conditional learning of dysmnesia models, improved pathological morphology of their brains,and the differences were significant compared to model. It is indicated that Cin(20 mg/kg and 60 mg/kg)could protecte the neurons of models from the excitotoxicity. But the effct of Cin (7 mg/kg) is not obviously.(3) Cin(20 mg/kg and 60 mg/kg)could in a dose dependent manner, increased the number of TH, TPH, Glu, ChAT positive cells and Nissl body in the CA1 distrits of hippocampuses, and significantly prevented the decrease of the contents of DA, NA and 5-HT in hippocampuses. So we presumed that the protection of Cin(20 mg/kg and 60 mg/kg)from excitotoxicity may be related with these factors.