Spampinato Simona Federica, Copani Agata, Nicoletti Ferdinando, Sortino Maria Angela, Caraci Filippo
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Department of Drug Sciences, University of Catania, Catania, Italy.
Front Mol Neurosci. 2018 Nov 13;11:414. doi: 10.3389/fnmol.2018.00414. eCollection 2018.
Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders.
神经退行性疾病的特征是兴奋性毒性和神经炎症，最终导致神经元缓慢变性和死亡。虽然神经元是主要靶点，但神经胶质细胞也是重要参与者，因为它们通过加剧或抑制导致神经炎症和神经元损伤的事件来发挥作用。谷氨酸能系统功能障碍是这些疾病病理生理学中的常见现象。代谢型谷氨酸（mGlu）受体属于一大类G蛋白偶联受体，在神经元和神经胶质细胞中大量表达。它们在神经退行性变相关区域常表现为过度表达，在这些区域可调节谷氨酸能传递。值得注意的是，mGlu受体上调可能涉及小胶质细胞，甚至更常见的是星形胶质细胞，其激活会导致可能影响神经元死亡的因子释放。在少突胶质细胞上也有mGlu受体表达的报道，少突胶质细胞是一种与多发性硬化症发展特别相关的神经胶质细胞类型。在此，我们将概述神经胶质细胞上表达的mGlu受体在不同神经退行性疾病发病机制中的可能作用，以及亚型选择性mGlu受体配体作为神经退行性疾病治疗候选药物的潜在用途。mGlu5受体的负变构调节剂（NAM）可能是开发这些疾病新神经保护策略的一种相关药理学工具。最近的证据表明，用mGlu3受体的正变构调节剂（PAM）靶向星形胶质细胞和小胶质细胞，或用mGlu4 PAM靶向少突胶质细胞，可能代表治疗神经退行性疾病的新型药理学方法。
