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目的:观察代谢型谷氨酸受体部分激动剂/拮抗剂L-(+)-2-氨基-3-磷酸基丙酸(L-AP_3)脑内注射引起的神经毒性作用,并探讨其机制。方法:大鼠尾状核内微量注射药物后,观察动物意识状态和活动情况,测定脑组织含水量、Na~+、K~+、Ca~(2+)含量及血脑屏障(BBB)通透性变化,并进行组织学研究。结果:L-AP_3 600nmol脑内注射后动物出现嗜睡,并引起脑组织含水量、Na~+和Ca~(2+)含量增加,K~+含量减少,同时BBB通透性增加P<0.01,L-AP_3 60nmol未产生上述变化。电镜检查发现L-AP_3引起星形胶质细胞高度肿胀,神经元变性坏死。D-(+)-2-氨基-3-磷酸基丙酸和L-(+)2-氨基-4-磷酸丁酸不能模拟L-AP_3引起的变化,DL-2-氨基-5-磷酸基戊酸可以减轻L-AP_3的作用,(±)-α-甲基-(4-羧基苯基)甘氨酸不能减轻L-AP_3的作用。结论:脑内注射高剂量的L-AP_3引起神经毒性作用,以血管源性脑水肿、神经元损伤及脑组织高Ca~(2+)含量为特征,此作用是立体构型特异的,可能与磷脂酶C激活有关,部分通过NMDA受体介导。
AIM: To observe the neurotoxicity induced by intracerebral injection of L-glutamate receptor partial agonist / antagonist L-(+) - 2-amino-3-phosphonopropionic acid (L-AP_3) . Methods: After consciously injected into the caudate nucleus, the animals were observed for the state of consciousness and activity. The contents of water, Na ~ +, K ~ +, Ca ~ (2+) and BBB Permeability changes, and histological studies. RESULTS: After intratracheal instillation of 600nmol L-AP_3, the rats appeared lethargy and caused the water content of brain tissue. The content of Na ~ + and Ca ~ (2+) increased and the content of K ~ + decreased, while the permeability of BBB increased P < L-AP_3 60nmol did not produce the above changes. Electron microscopy revealed that L-AP_3 caused a high degree of astrocyte swelling and degeneration and necrosis of neurons. D - (+) - 2-amino-3-phosphonopropionic acid and L - (+) 2-amino-4 -phosphate butyric acid did not mimic the changes caused by L-AP_3. Valeric acid can reduce the effect of L-AP_3, while (±) -α-methyl- (4-carboxyphenyl) glycine can not alleviate the effect of L-AP_3. Conclusion: The intracerebral injection of high doses of L-AP_3 caused neurotoxicity characterized by vasogenic brain edema, neuronal damage and high Ca 2+ content in brain tissue. The effect is stereospecific and may be Associated with phospholipase C activation, partly mediated by NMDA receptors.