ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS COUPLED TO INOSITOL PHOSPHOLIPID HYDROLYSIS AMPLIFIES NMDA-INDUCED NEURONAL DEGENERATION IN CULTURED CORTICAL-CELLS
ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS COUPLED TO INOSITOL PHOSPHOLIPID HYDROLYSIS AMPLIFIES NMDA-INDUCED NEURONAL DEGENERATION IN CULTURED CORTICAL-CELLS
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DOI：
10.1016/0028-3908(95)00077-j
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发表时间：
1995-08-01
影响因子：
4.7
通讯作者：
NICOLETTI, F
中科院分区：
文献类型：
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作者：
BRUNO, V;COPANI, A;NICOLETTI, F
我们研究了一类代谢性谷氨酸受体（mGluRs）对星形胶质细胞单层培养的小鼠皮质神经元兴奋性毒性神经元变性的影响。这些培养物表达了高水平的mGluRS mRNA，这与从大脑皮层中提取的RNA相当。混合培养的皮质神经元被mGluRS抗体大量染色，也被mGluR1a抗体染色（尽管程度要低得多），但不被mGluR1b或c抗体染色。一类mGluR的优先激动剂，如半qualate， 3,5-二羟基苯基甘氨酸（DHPG），反式氮杂丁-2,4-二羧酸（t-ADA），以及混合的mGluR激动剂，1(S),3(R)-1-氨基环戊烷- 1,3 -二羧酸(1(S),3(R)-ACPD)，都刺激了培养皮质细胞中PPI的水解。n -甲基- d -天冬氨酸（NMDA）诱导神经元退行性变的效力显著增强，当该药物与准质酸、DHPG或t-ADA共孵育10分钟（“快速”毒性模式）。mGluR激动剂本身不影响神经元活力。通过一系列蛋白激酶C （PKC）抑制剂，准质酸或DHPG对NMDA毒性的扩增被减弱，这表明I类mGluRs至少在一定程度上通过激活PKC起作用。准质酸，特别是DHPG，即使在NMDA毒性脉冲后应用，也能增强兴奋性毒性神经元变性。这种作用可能发生在兴奋毒性损伤成熟的早期，因为在NMDA脉冲后2或3小时，I类mGluRs的功能活性大幅降低。这些结果表明，I类mGluRs的激活增强了nmda受体介导的神经元毒性，并鼓励寻找选择性拮抗剂用于急性或慢性神经退行性疾病的实验性治疗。
We have studied the influence of class I metabotropic glutamate receptors (mGluRs) on excitotoxic neuronal degeneration in cultured murine cortical neurons grown on a monolayer of astrocytes. These cultures expressed high levels of mGluRS mRNA, which were comparable to those found in RNA extracts from cerebral cortex. Cortical neurons in mixed cultures were heavily stained with antibodies raised against mGluRS and were also stained-albeit to a much lower extent-with mGluR1a but not with mGluR1b or c antibodies. Preferential agonists of class I mGluRs, such as quisqualate, 3,5-dihydroxyphenylglycine (DHPG), and trans-azetidine-2,4-dicarboxylic acid (t-ADA), as well as the mixed mGluR agonist, 1(S),3(R)-1-aminocyclopentane-1 ,3-dicarboxylic acid (1(S),3(R)-ACPD) all stimulated PPI hydrolysis in cultured cortical cells.The potency of N-methyl-D-aspartate (NMDA) in inducing neuronal degeneration was substantially enhanced when the drug was coincubated with quisqualate, DHPG or t-ADA during a 10-min pulse (paradigm of ''fast'' toxicity). None of the mGluR agonists influenced neuronal viability by itself. The amplification of NMDA toxicity by quisqualate or DHPG was attenuated by a series of protein kinase C (PKC) inhibitors, suggesting that class I mGluRs operate, at least in part, through activation of PKC.Quisqualate and, in particular, DHPG enhanced excitotoxic neuronal degeneration even when applied after the toxic pulse with NMDA. This action is likely to occur early in the maturation of excitotoxic damage, because the functional activity of class I mGluRs was substantially reduced at 2 or 3 hr after the NMDA pulse.These results suggest that activation of class I mGluRs enhances NMDA-receptor mediated neuronal toxicity and encourage the search for selective antagonists for the experimental therapy of acute or chronic neurodegenerative diseases.