Selective activation of mGlu4 metabotropic glutamate receptors is protective against excitotoxic neuronal death
Selective activation of mGlu4 metabotropic glutamate receptors is protective against excitotoxic neuronal death
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DOI：
10.1523/jneurosci.20-17-06413.2000
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发表时间：
2000-09-01
影响因子：
5.3
通讯作者：
Flor, PJ
中科院分区：
文献类型：
--
作者：
Bruno, V;Battaglia, G;Flor, PJ
已确定III组代谢型谷氨酸受体（mGluR 4、mGluR 6、mGluR 7和mGluR 8）的激活在体外和体内具有神经保护作用。为了公开发挥保护作用的受体亚型的身份，我们使用了III组激动剂与mGluR 4亚型缺陷型小鼠（-/-）的组合。在从野生型（+/+）小鼠制备并暴露于NMDA毒性脉冲的皮质培养物中，选择性III组激动剂（+）-4-膦酰基苯基甘氨酸[（+）-PPG]逆转兴奋性毒性，EC 50值为4.9 μ M，而其对映体（-）-PPG无活性。这与（+）-PPG激活重组mGluR 4a的效力密切相关。在-/-小鼠的皮质神经元中，（+）-PPG在高达300 μ M的浓度下对NMDA损伤没有保护作用，而I/II组mGluR配体仍保留其保护活性。经典的III组激动剂（L-2-氨基-4-膦酰基丁酸和L-丝氨酸-O-磷酸）在+/+和杂合（+/-）培养物中也对NMDA毒性具有显著的神经保护作用，但在-/-培养物中无活性。有趣的是，-/-文化更容易受到低浓度的NMDA，并表现出更高的细胞外谷氨酸水平相比，+/+文化。我们还研究了野生型或mGluR 4缺陷小鼠纹状体内注入NMDA诱导的神经变性。低剂量（R，S）-PPG（10 nmol/0.5 μ l）显著降低+/+小鼠的NMDA毒性，但对-/-小鼠无效。较高剂量的（R，S）-PPG在两种动物品系中均具有神经保护作用。最后，微透析研究表明，纹状体内注入NMDA增加细胞外谷氨酸水平在更大程度上在-/-比在+/+小鼠，支持的假设mGluR 4亚型是必要的维持细胞外谷氨酸水平的稳态。
Activation of group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, and mGluR8) has been established to be neuroprotective in vitro and in vivo. To disclose the identity of the receptor subtype(s) that exert(s) the protective effect, we have used group III agonists in combination with mGluR4 subtype-deficient mice (-/-). In cortical cultures prepared from wild-type (+/+) mice and exposed to a toxic pulse of NMDA, the selective group III agonist (+)-4-phosphonophenylglycine [(+)-PPG] reversed excitotoxicity with an EC50 value of 4.9 mu M, whereas its enantiomer (-)-PPG was inactive. This correlated closely with the potency of (+)-PPG in activating recombinant mGluR4a. In cortical neurons from -/- mice, (+)-PPG showed no protection against the NMDA insult up to 300 mu M, whereas group I/II mGluR ligands still retained their protective activity. Classical group III agonists (L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate) were also substantially neuroprotective against NMDA toxicity in +/+ and heterozygous (+/-) cultures but were inactive in -/- cultures. Interestingly, -/- cultures were more vulnerable to low concentrations of NMDA and showed higher extracellular glutamate levels compared with +/+ cultures. We have also examined neurodegeneration induced by intrastriatal infusion of NMDA in wild-type or mGluR4-deficient mice. Low doses of (R,S)-PPG (10 nmol/0.5 mu l) substantially reduced NMDA toxicity in +/+ mice but were ineffective in -/- mice. Higher doses of (R,S)-PPG were neuroprotective in both strains of animals. Finally, microdialysis studies showed that intrastriatal infusion of NMDA increased extracellular glutamate levels to a greater extent in -/- than in +/+ mice, supporting the hypothesis that the mGluR4 subtype is necessary for the maintenance of the homeostasis of extracellular glutamate levels.