Corti Corrado, Battaglia Giuseppe, Molinaro Gemma, Riozzi Barbara, Pittaluga Anna, Corsi Mauro, Mugnaini Manolo, Nicoletti Ferdinando, Bruno Valeria
Department of Biology, Psychiatry Centre of Excellence in Drug Discovery, GlaxoSmithKline Medicines Research Centre, 37135 Verona, Italy.
J Neurosci. 2007 Aug 1;27(31):8297-308. doi: 10.1523/JNEUROSCI.1889-07.2007.
Dual metabotropic glutamate 2/3 (mGlu2/3) receptor agonists have been examined with success in the clinic with positive proof of efficacy in several tests of anxiety and schizophrenia. Moreover, a large body of evidence has accumulated that these drugs have significant neuroprotective potential. An important discussion in the field deals with dissecting effects on mGlu2 versus effects on mGlu3 receptors, which is relevant for the potential use of subtype-selective agonists or allosteric activators. We addressed this issue using mGlu2 and mGlu3 receptor knock-out mice. We used mixed cultures of cortical cells in which astrocytes and neurons were plated at different times and could therefore originate from different mice. Cultures were challenged with NMDA for the induction of excitotoxic neuronal death. The mGlu2/3 receptor agonist, (-)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), was equally neuroprotective in cultures containing neurons from wild-type, mGlu2-/-, or mGlu3-/- mice. Neuroprotection was instead abolished when astrocytes lacked mGlu3 receptors, unless neuronal mGlu2 receptors were also absent. The latter condition partially restored the protective activity of LY379268. Cultures in which neurons originated from mGlu2-/- mice were also intrinsically resistant to NMDA toxicity. In in vivo experiments, systemic administration of LY379268 protected striatal neurons against NMDA toxicity in wild-type and mGlu2-/- mice but not in mGlu3-/- mice. In addition, LY379268 was protective against nigrostriatal degeneration induced by low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only in mice lacking mGlu2 receptors. We conclude that neuroprotection by mGlu2/3 receptor agonists requires the activation of astrocytic mGlu3 receptors, whereas, unexpectedly, activation of mGlu2 receptors might be harmful to neurons exposed to toxic insults.
双代谢型谷氨酸2/3（mGlu2/3）受体激动剂已在临床上得到验证，在多项焦虑症和精神分裂症测试中显示出积极的疗效证据。此外，大量证据表明这些药物具有显著的神经保护潜力。该领域的一个重要讨论是剖析对mGlu2和mGlu3受体的影响，这与亚型选择性激动剂或变构激活剂的潜在用途相关。我们使用mGlu2和mGlu3受体基因敲除小鼠来解决这个问题。我们采用了皮质细胞的混合培养物，其中星形胶质细胞和神经元在不同时间接种，因此可能来自不同的小鼠。用N-甲基-D-天冬氨酸（NMDA）刺激培养物以诱导兴奋性毒性神经元死亡。mGlu2/3受体激动剂（-）-2-氧杂-4-氨基环[3.1.0]己烷-4,6-二羧酸（LY379268）在含有野生型、mGlu2基因敲除或mGlu3基因敲除小鼠神经元的培养物中具有同等的神经保护作用。相反，当星形胶质细胞缺乏mGlu3受体时，神经保护作用消失，除非神经元mGlu2受体也不存在。后一种情况部分恢复了LY379268的保护活性。神经元来自mGlu2基因敲除小鼠的培养物对NMDA毒性也具有内在抗性。在体内实验中，全身性给予LY379268可保护野生型和mGlu2基因敲除小鼠的纹状体神经元免受NMDA毒性，但对mGlu3基因敲除小鼠无效。此外，LY379268仅在缺乏mGlu2受体的小鼠中对低剂量1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的黑质纹状体变性具有保护作用。我们得出结论，mGlu2/3受体激动剂的神经保护作用需要激活星形胶质细胞的mGlu3受体，而出乎意料的是，mGlu2受体的激活可能对暴露于毒性损伤的神经元有害。
