Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective
Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective
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DOI：
10.1124/mol.110.067488
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发表时间：
2011-03-01
影响因子：
3.6
通讯作者：
Nicoletti, Ferdinando
中科院分区：
文献类型：
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作者：
Caraci, Filippo;Molinaro, Gemma;Nicoletti, Ferdinando
代谢型谷氨酸2(MGlu2)和mGlu3受体的双正构体激动剂正在被开发为没有传统抗精神病药物不良反应的新型抗精神病药物。因此，这些药物可能有助于治疗与阿尔茨海默病(AD)相关的精神症状。在实验动物中，mGlu2/3受体激动剂的抗精神病活性在很大程度上是由mGlu2受体的激活介导的，并被mGlu2受体的选择性正变构调节剂(PAM)模拟。我们研究了人工合成β-淀粉样蛋白(Aβ)对混合和纯神经元培养中mGlu2和mGlu3受体的不同影响，以建立AD神经变性的模型。MGlu2受体PAM，N-4‘-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide盐酸盐(LY566332)本身无毒性，可增强Aβ诱导的神经变性，这种作用可被mGlu2/3受体拮抗剂(2S，1’S，2‘S)-2-(9-xanthylmethyl)-2-(2’-carboxycyclopropyl)glycine(LY341495))所阻断。LY566332增强Aβ毒性，无论是否存在胶质细胞mGlu3受体，但当神经元缺乏mGlu2受体时，LY566332增强Aβ毒性。双重mGlu2/3受体激动剂(-)-2-oxa-4-aminobicyclo[3.1.0]exhane-4，6-dicarboxylic酸(LY379268)在混合培养中通过转化生长因子-β1介导的旁分泌机制发挥神经保护作用。LY379268对缺乏mGlu3受体的星形胶质细胞生长的神经元失去保护作用，表明对Aβ神经毒性的保护完全是由胶质细胞mGlu3受体介导的。选择性非竞争性mGlu3受体拮抗剂(3S)-1-(5-bromopyrimidin-2-yl)-N-(2，4-dichlorobenzyl)pyrrolidin-3-amine甲烷磺酸盐(LY2389575)能单独放大Aβ毒性，有趣的是，LY379268具有神经毒性作用，这可能是通过激活mGlu2受体介导的。这些数据表明，mGlu2受体的选择性增强增强了神经元对Aβ的易感性，而mGlu2和mGlu3受体的双重激活对Aβ诱导的毒性具有保护作用。
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 beta-amyloid protein (A beta) 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 A beta-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 A beta 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-beta 1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against A beta 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 A beta 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 A beta, whereas dual activation of mGlu2 and mGlu3 receptors is protective against A beta-induced toxicity.