Department of Pharmaceutical Sciences, University of Catania, Catania, Italy.
Mol Pharmacol. 2011 Mar;79(3):618-26. doi: 10.1124/mol.110.067488. Epub 2010 Dec 15.
Dual orthosteric agonists of metabotropic glutamate 2 (mGlu2) and mGlu3 receptors are being developed as novel antipsychotic agents devoid of the adverse effects of conventional antipsychotics. Therefore, these drugs could be helpful for the treatment of psychotic symptoms associated with Alzheimer's disease (AD). In experimental animals, the antipsychotic activity of mGlu2/3 receptor agonists is largely mediated by the activation of mGlu2 receptors and is mimicked by selective positive allosteric modulators (PAMs) of mGlu2 receptors. We investigated the distinct influence of mGlu2 and mGlu3 receptors in mixed and pure neuronal cultures exposed to synthetic β-amyloid protein (Aβ) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified Aβ-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl)glycine (LY341495). LY566332 potentiated Aβ toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]exhane-4,6-dicarboxylic acid (LY379268), was neuroprotective in mixed cultures via a paracrine mechanism mediated by transforming growth factor-β1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Aβ neurotoxicity was mediated entirely by glial mGlu3 receptors. The selective noncompetitive mGlu3 receptor antagonist, (3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl)pyrrolidin-3-amine methanesulfonate hydrate (LY2389575), amplified Aβ toxicity on its own, and, interestingly, unmasked a neurotoxic activity of LY379268, which probably was mediated by the activation of mGlu2 receptors. These data indicate that selective potentiation of mGlu2 receptors enhances neuronal vulnerability to Aβ, whereas dual activation of mGlu2 and mGlu3 receptors is protective against Aβ-induced toxicity.
代谢型谷氨酸 2（mGlu2）和 mGlu3 受体的双重变构激动剂被开发为新型抗精神病药物，没有传统抗精神病药物的不良反应。因此，这些药物可能有助于治疗与阿尔茨海默病（AD）相关的精神病症状。在实验动物中，mGlu2/3 受体激动剂的抗精神病活性主要由 mGlu2 受体的激活介导，并被 mGlu2 受体的选择性正变构调节剂（PAMs）模拟。我们研究了 mGlu2 和 mGlu3 受体在混合和纯神经元培养物中对合成β-淀粉样蛋白（Aβ）的不同影响，以模拟 AD 中发生的神经退行性变。mGlu2 受体 PAM，N-4'-氰基联苯-3-基）-N-（3-吡啶基甲基）-乙磺酰胺盐酸盐（LY566332）本身无毒，放大了 Aβ 诱导的神经退行性变，而这种作用被 mGlu2/3 受体拮抗剂（2S，1'S，2'S）-2-（9-黄嘌呤基甲基）-2-（2'-羧基环丙基）甘氨酸（LY341495）所阻止。LY566332 增强了 Aβ 毒性，无论是否存在神经胶质 mGlu3 受体，但当神经元缺乏 mGlu2 受体时，它则没有活性。双重 mGlu2/3 受体激动剂，（-）-2-氧代-4-氨基双环[3.1.0]己烷-4,6-二羧酸（LY379268）通过转化生长因子-β1 介导的旁分泌机制在混合培养物中具有神经保护作用。LY379268 在与缺乏 mGlu3 受体的星形胶质细胞一起培养的神经元中失去了其保护活性，表明对 Aβ 神经毒性的保护完全由神经胶质 mGlu3 受体介导。选择性非竞争性 mGlu3 受体拮抗剂，（3S）-1-（5-溴嘧啶-2-基）-N-（2,4-二氯苄基）吡咯烷-3-胺甲磺酸盐水合物（LY2389575）单独增强了 Aβ 的毒性，有趣的是，它揭示了 LY379268 的神经毒性活性，这可能是由 mGlu2 受体的激活介导的。这些数据表明，选择性增强 mGlu2 受体可增强神经元对 Aβ 的易感性，而双重激活 mGlu2 和 mGlu3 受体可对抗 Aβ 诱导的毒性。
