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目的:研究缺氧时纹状体多巴胺能神经毒性的机制。方法:采用大鼠纹状体脑片体外培养模型,以底物磷酸化~(32)P-掺入法测定Ca~(2+)-钙调蛋白依赖性蛋白激酶Ⅱ(CCDPKⅡ)的活性。结果:缺氧30min,纹状体脑片CCDPKⅡ活性降低75％,慢性利血平化使得缺氧诱导的酶活性降低程度减轻,与对照组相比大约降低40％。外源性多巴胺显著降低纹状体脑片CCDPKⅡ活性。去除胞外Ca~(2+)后,多巴胺诱导的酶活性降低作用被削弱。阿扑吗啡(非特异性多巴胺受体激动剂)、SKF38393(特异性D_1样受体激动剂)和喹吡罗(特异性D_2样受体激动剂)均可显著降低CCDPKⅡ的活性。Sch-23390(特异性D_1样受体拮抗剂)和吗丁啉(特异性D_2样受体拮抗剂)均可拮抗多巴胺所诱导的酶活性的抑制作用。结论:多巴胺参与缺氧诱导的纹状体CCDPKⅡ活性抑制,其作用机制与D_1样和D_2样受体的激活以及胞外Ca~(2+)的内流有关,从而导致多巴胺介导的纹状体神经损伤。
Aims: To investigate the mechanism of dopaminergic neurotoxicity in striatum during hypoxia. Methods: Rat brain slices of striatum were cultured in vitro and the activity of Ca2 + - calmodulin - dependent protein kinase Ⅱ (CCDPK Ⅱ) was measured by phosphorylated ~ (32) P - incorporation method. RESULTS: After hypoxia for 30 min, CCDPKⅡ activity in striatum slices decreased by 75%. Chronic reserpine treatment reduced hypoxia-induced decrease in enzyme activity by about 40% compared with control group. Exogenous dopamine significantly reduced CCDPKII activity in striatum slices. Removal of extracellular Ca2 +, dopamine-induced decrease in enzyme activity was weakened. Apomorphine (a non-specific dopamine receptor agonist), SKF38393 (a specific D-like receptor agonist), and quinpirole (a specific D 2 -like receptor agonist) all significantly reduced CCDPKII activity. Both Sch-23390 (a specific D 1 -like receptor antagonist) and domperidone (a specific D 2 -like receptor antagonist) antagonized the inhibitory effect of dopamine-induced enzyme activity. CONCLUSION: Dopamine is involved in the inhibition of CCDPKⅡ activity induced by hypoxia, and its mechanism is related to the activation of D_1-like and D_2-like receptors and the influx of extracellular Ca ~ (2+), leading to dopamine-mediated striatum Body nerve injury.