Department of Formative Processes, University of Catania, Catania, Italy.
Neurochem Int. 2012 Sep;61(4):559-65. doi: 10.1016/j.neuint.2012.01.017. Epub 2012 Jan 25.
Moving from early studies, we here review the most recent evidence linking metabotropic glutamate (mGlu) receptors to processes of neurodegeneration/neuroprotection. The use of knockout mice and subtype-selective drugs has increased our knowledge of the precise role played by individual mGlu receptor subtypes in these processes. Activation of mGlu1 and mGlu5 receptors may either amplify or reduce neuronal damage depending on the context and the nature of the toxic insults. In contrast, mGlu1 and mGlu5 receptors antagonists are consistently protective in in vitro and in vivo models of neuronal death. A series of studies suggest that mGlu1 receptor antagonists or negative allosteric modulators (NAMs) are promising candidates for the treatment of ischemic brain damage, whereas mGlu5 receptor NAMs, which have been clinically developed for the treatment of Parkinson's disease (PD) and l-DOPA-induced dyskinesias, protect nigro-striatal dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice and monkeys. Activation of glial mGlu3 receptors promotes the formation of various neurotrophic factors, such as transforming growth factor-β (TGF-β), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). Hence, selective mGlu3 receptor agonists or positive allosteric modulators (PAMs) (not yet available) are potentially helpful in the treatment of chronic neurodegenerative disorders such as PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis. Selective mGlu2 receptor PAMs should be used with caution in AD patients because these drugs are shown to amplify β-amyloid neurotoxicity. Finally, mGlu4 receptor agonists/PAMs share with mGlu5 receptor NAMs the ability to improve motor symptoms associated with PD and attenuate nigro-striatal degeneration at the same time. No data are yet available on the role of mGlu7 and mGlu8 receptors in neurodegeneration/neuroprotection.
从早期研究开始，我们在这里回顾了最近将代谢型谷氨酸(mGlu)受体与神经退行性变/神经保护过程联系起来的证据。使用基因敲除小鼠和亚型选择性药物增加了我们对单个 mGlu 受体亚型在这些过程中所起的确切作用的了解。mGlu1 和 mGlu5 受体的激活可能会根据上下文和毒性刺激的性质放大或减少神经元损伤。相比之下，mGlu1 和 mGlu5 受体拮抗剂在体外和体内神经元死亡模型中始终具有保护作用。一系列研究表明，mGlu1 受体拮抗剂或负变构调节剂(NAMs)是治疗缺血性脑损伤的有前途的候选药物，而已经为治疗帕金森病(PD)和 l-多巴诱导的运动障碍而开发的 mGlu5 受体 NAMs 可保护黑质纹状体多巴胺能神经元免受 1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)在小鼠和猴子中的毒性。胶质细胞 mGlu3 受体的激活促进了各种神经营养因子的形成，如转化生长因子-β(TGF-β)、胶质衍生神经营养因子(GDNF)、神经生长因子(NGF)和脑源性神经营养因子(BDNF)。因此，选择性 mGlu3 受体激动剂或正变构调节剂(PAMs)(尚未上市)可能有助于治疗慢性神经退行性疾病，如 PD、阿尔茨海默病(AD)和肌萎缩侧索硬化症。由于这些药物显示出放大β-淀粉样蛋白神经毒性的作用，因此在 AD 患者中应谨慎使用选择性 mGlu2 受体 PAMs。最后，mGlu4 受体激动剂/PAMs 与 mGlu5 受体 NAMs 具有相同的能力，可改善 PD 相关的运动症状并同时减轻黑质纹状体变性。目前尚无关于 mGlu7 和 mGlu8 受体在神经退行性变/神经保护中的作用的数据。
