mGluR5介导的缺血性脑卒中病理调控： 细胞类型特异性机制与靶向干预策略
mGluR5-Mediated Pathological Regulation in Ischemic Stroke: Cell Type-Specific Mechanisms and Targeted Intervention Strategies
DOI: 10.12677/acm.2026.1641650, PDF,   
作者: 朱俊杰*, 曾凌华, 张聪慧, 蔡青青：赣南医科大学第一临床医学院，江西 赣州；梁伟东#：赣南医科大学第一附属医院麻醉手术中心，江西 赣州
关键词: 缺血性脑卒中；mGluR5；神经炎症；兴奋毒性；治疗靶点；Ischemic Stroke； mGluR5； Neuroinflammation； Excitotoxicity； Therapeutic Target
摘要: 缺血性脑卒中(ischemic stroke, IS)是全球范围内导致死亡和长期残疾的主要神经系统疾病之一。其发病机制复杂，涉及兴奋毒性、氧化应激、炎症反应及血脑屏障破坏等多种病理过程。在卒中急性期，谷氨酸异常释放及其受体过度激活是神经元损伤的重要分子基础。代谢型谷氨酸受体5 (metabotropic glutamate receptor 5, mGluR5)为1组代谢型谷氨酸受体家族(mGluR)成员，广泛表达于神经元及胶质细胞，激活后可通过Gq/PLC/IP3-DAG等通路调控胞内Ca2+稳态，并与NMDA-R等受体/离子通道形成信号耦联，从而在脑缺血损伤中呈现“损伤促进–修复支持”并存的双相效应。本文围绕mGluR5的生物学特性，系统梳理其在兴奋毒性、炎症反应、水肿形成与神经修复中的作用机制，总结其作为潜在治疗靶点的研究进展及转化挑战，以期为卒中精准干预提供理论依据。
Abstract: Ischemic stroke (IS) is one of the leading neurological diseases causing death and long-term disability worldwide. Its pathogenesis is complex, involving excitotoxicity, oxidative stress, inflammatory responses, and blood-brain barrier disruption, among other pathological processes. During the acute phase of stroke, abnormal glutamate release and overstimulation of its receptors are important molecular bases for neuronal injury. Metabotropic glutamate receptor 5 (mGluR5), a Group I member of the metabotropic glutamate receptor family (mGluR), is widely expressed in neurons and glial cells. Upon activation, it can regulate intracellular Ca2+ homeostasis through pathways such as Gq/PLC/IP3-DAG and form signal coupling with receptors/ion channels like NMDA-R, thereby exhibiting a biphasic effect of both “damage promotion-repair support” in cerebral ischemic injury. This article, focusing on the biological characteristics of mGluR5, systematically reviews its mechanisms in excitotoxicity, inflammatory responses, edema formation, and neural repair, summarizes research progress and translational challenges as a potential therapeutic target, aiming to provide a theoretical basis for precise stroke interventions.
文章引用：朱俊杰, 曾凌华, 张聪慧, 蔡青青, 梁伟东. mGluR5介导的缺血性脑卒中病理调控： 细胞类型特异性机制与靶向干预策略[J]. 临床医学进展, 2026, 16(4): 3825-3832. https://doi.org/10.12677/acm.2026.1641650

参考文献

[1] Saini, V., Guada, L. and Yavagal, D.R. (2021) Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions. Neurology, 97, S6-S16. [Google Scholar] [CrossRef] [PubMed]
[2] Eren, F. and Yilmaz, S.E. (2022) Neuroprotective Approach in Acute Ischemic Stroke: A Systematic Review of Clinical and Experimental Studies. Brain Circulation, 8, 172-179. [Google Scholar] [CrossRef] [PubMed]
[3] Jia, J., Jin, H., Nan, D., Yu, W. and Huang, Y. (2021) New Insights into Targeting Mitochondria in Ischemic Injury. Apoptosis, 26, 163-183. [Google Scholar] [CrossRef] [PubMed]
[4] Iadecola, C., Buckwalter, M.S. and Anrather, J. (2020) Immune Responses to Stroke: Mechanisms, Modulation, and Therapeutic Potential. Journal of Clinical Investigation, 130, 2777-2788. [Google Scholar] [CrossRef] [PubMed]
[5] Xu, N., Jiang, X., Zhang, W., Shi, Y., Leak, R.K., Keep, R.F., et al. (2024) Endothelial Peroxiredoxin-4 Is Indispensable for Blood-Brain Barrier Integrity and Long-Term Functional Recovery after Ischemic Stroke. Proceedings of the National Academy of Sciences of the United States of America, 121, e2400272121. [Google Scholar] [CrossRef] [PubMed]
[6] Neha, Salman, M. and Parvez, S. (2023) Animal Toxins: As an Alternative Therapeutic Target Following Ischemic Stroke Condition. Life Sciences, 317, Article ID: 121365. [Google Scholar] [CrossRef] [PubMed]
[7] Gonzalez-Lozano, M.A., Wortel, J., van der Loo, R.J., van Weering, J.R.T., Smit, A.B. and Li, K.W. (2021) Reduced mGluR5 Activity Modulates Mitochondrial Function. Cells, 10, Article 1375. [Google Scholar] [CrossRef] [PubMed]
[8] Lai, Y., Han, J., Qiu, D., Liu, X., Sun, K., Fan, Y., et al. (2024) The Protective Effects of Methylene Blue on Astrocytic Swelling after Cerebral Ischemia-Reperfusion Injuries Are Mediated by Aquaporin-4 and Metabotropic Glutamate Receptor 5 Activation. Heliyon, 10, e29483. [Google Scholar] [CrossRef] [PubMed]
[9] 何存宝, 杨绍杰, 朱国旗. 4-(芳基乙炔基)-吡咯并[2, 3-d]嘧啶通过抑制mGluR5调控ERK1/2-SGK1信号通路改善小鼠创伤后应激障碍[J]. 南方医科大学学报, 2025, 45(4): 765-773.
[10] AL-Nasser, M.N., Mellor, I.R. and Carter, W.G. (2022) Is L-Glutamate Toxic to Neurons and Thereby Contributes to Neuronal Loss and Neurodegeneration? a Systematic Review. Brain Sciences, 12, Article 577. [Google Scholar] [CrossRef] [PubMed]
[11] Chen, T., Li, Y., Ren, X. and Wang, Y. (2024) The mGluR5‐Mediated Arc Activation Protects against Experimental Traumatic Brain Injury in Rats. CNS Neuroscience & Therapeutics, 30, e14695. [Google Scholar] [CrossRef] [PubMed]
[12] Wang, Q., Yang, F., Duo, K., Liu, Y., Yu, J., Wu, Q., et al. (2024) The Role of Necroptosis in Cerebral Ischemic Stroke. Molecular Neurobiology, 61, 3882-3898. [Google Scholar] [CrossRef] [PubMed]
[13] Kumari, S., Dhapola, R., Sharma, P., Nagar, P., Medhi, B. and HariKrishnaReddy, D. (2024) The Impact of Cytokines in Neuroinflammation-Mediated Stroke. Cytokine & Growth Factor Reviews, 78, 105-119. [Google Scholar] [CrossRef] [PubMed]
[14] Azam, S., Jakaria, M., Kim, J., Ahn, J., Kim, I. and Choi, D. (2022) Group I mGluRs in Therapy and Diagnosis of Parkinson’s Disease: Focus on mGluR5 Subtype. Biomedicines, 10, Article 864. [Google Scholar] [CrossRef] [PubMed]
[15] Acher, F.C., Cabayé, A., Eshak, F., Goupil-Lamy, A. and Pin, J. (2022) Metabotropic Glutamate Receptor Orthosteric Ligands and Their Binding Sites. Neuropharmacology, 204, Article ID: 108886. [Google Scholar] [CrossRef] [PubMed]
[16] Li, Y., Zhang, Y., Lin, J., Liu, Y., Li, Y., Feng, Y., et al. (2023) Metabotropic Glutamate Receptor 5‐Mediated Inhibition of Inward‐Rectifying K+ Channel 4.1 Contributes to Orofacial Ectopic Mechanical Allodynia Following Inferior Alveolar Nerve Transection in Male Mice. Journal of Neuroscience Research, 101, 1170-1187. [Google Scholar] [CrossRef] [PubMed]
[17] Pandey, S., Ramsakha, N., Sharma, R., Gulia, R., Ojha, P., Lu, W., et al. (2020) The Post-Synaptic Scaffolding Protein Tamalin Regulates Ligand-Mediated Trafficking of Metabotropic Glutamate Receptors. Journal of Biological Chemistry, 295, 8575-8588. [Google Scholar] [CrossRef] [PubMed]
[18] Lutzu, S., Alviña, K., Puente, N., Grandes, P. and Castillo, P.E. (2023) Target Cell-Specific Plasticity Rules of NMDA Receptor-Mediated Synaptic Transmission in the Hippocampus. Frontiers in Cellular Neuroscience, 17, Article 1068472. [Google Scholar] [CrossRef] [PubMed]
[19] Lee, S., Kim, J., Ryu, H., Jang, H., Lee, D., Lee, S., et al. (2024) SHP2 Regulates Glua2 Tyrosine Phosphorylation Required for AMPA Receptor Endocytosis and mGluR-LTD. Proceedings of the National Academy of Sciences of the United States of America, 121, e2316819121. [Google Scholar] [CrossRef] [PubMed]
[20] Chen, Y., Zhang, Y., Chen, Q., Liu, Y., Wei, X., Wu, M., et al. (2023) Inhibition of mGluR5/PI3K-AKT Pathway Alleviates Alzheimer’s Disease-Like Pathology through the Activation of Autophagy in 5XFAD Mice. Journal of Alzheimer’s Disease, 91, 1197-1214. [Google Scholar] [CrossRef] [PubMed]
[21] McCarthy, C.I., Zack Ma, Z., Monteggia, L.M. and Kavalali, E.T. (2025) Spontaneous Glutamate Release Activates mGluR Signaling to Drive Rapid Antidepressant Responses. Proceedings of the National Academy of Sciences of the United States of America, 122, e2510642122. [Google Scholar] [CrossRef] 
[22] Harbers, M., Nakao, H., Watanabe, T., Matsuyama, K., Tohyama, S., Nakao, K., et al. (2022) mGluR5 Is Substitutable for mGluR1 in Cerebellar Purkinje Cells for Motor Coordination, Developmental Synapse Elimination, and Motor Learning. Cells, 11, Article 2004. [Google Scholar] [CrossRef] [PubMed]
[23] Kim, J., Lee, J., Song, H., Koo, J.W. and Kang, S. (2025) mGluR5 as a Potential Orchestrator of Astrocyte Interactions in Neurological Disorders. Neural Plasticity, 2025, Article ID: 7259018. [Google Scholar] [CrossRef] 
[24] Rahman, M.S., Yang, J., Luan, Y., Qiu, Z., Zhang, J., Lu, H., et al. (2020) Attenuation of Acute Intracerebral Hemorrhage-Induced Microglial Activation and Neuronal Death Mediated by the Blockade of Metabotropic Glutamate Receptor 5 in Vivo. Neurochemical Research, 45, 1230-1243. [Google Scholar] [CrossRef] [PubMed]
[25] Yang, T., Zhang, D., Huang, H., Liu, F., Wu, J., Ma, X., et al. (2025) Astrocytic mGluR5-Dependent Calcium Hyperactivity Promotes Amyloid-Β Pathology and Cognitive Impairment. Brain, 149, 134-149. [Google Scholar] [CrossRef] [PubMed]
[26] Reed, M.M. and Blazer-Yost, B. (2022) Channels and Transporters in Astrocyte Volume Regulation in Health and Disease. Cellular Physiology and Biochemistry, 56, 12-30. [Google Scholar] [CrossRef] [PubMed]
[27] Planas-Fontánez, T.M., Dreyfus, C.F. and Saitta, K.S. (2020) Reactive Astrocytes as Therapeutic Targets for Brain Degenerative Diseases: Roles Played by Metabotropic Glutamate Receptors. Neurochemical Research, 45, 541-550. [Google Scholar] [CrossRef] [PubMed]
[28] Shrivastava, A.N., Kowalewski, J.M., Renner, M., Bousset, L., Koulakoff, A., Melki, R., et al. (2013) β-Amyloid and ATP-Induced Diffusional Trapping of Astrocyte and Neuronal Metabotropic Glutamate Type-5 Receptors. Glia, 61, 1673-1686. [Google Scholar] [CrossRef] [PubMed]
[29] Grolla, A.A., Fakhfouri, G., Balzaretti, G., Marcello, E., Gardoni, F., Canonico, P.L., et al. (2013) Aβ Leads to Ca2+ Signaling Alterations and Transcriptional Changes in Glial Cells. Neurobiology of Aging, 34, 511-522. [Google Scholar] [CrossRef] [PubMed]
[30] MacKay, K.B., Patel, T.R., Galbraith, S.L., Woodruff, G.N. and McCulloch, J. (1996) The Relationship between Glutamate Release and Cerebral Blood Flow after Focal Cerebral Ischaemia in the Cat: Effect of Pretreatment with Enadoline (a κ Receptor Agonist). Brain Research, 712, 329-334. [Google Scholar] [CrossRef] [PubMed]
[31] Yang, J.S., Jeon, S., Jang, H. and Yoon, S.H. (2022) Group 1 Metabotropic Glutamate Receptor 5 Is Involved in Synaptically-Induced Ca2+-Spikes and Cell Death in Cultured Rat Hippocampal Neurons. The Korean Journal of Physiology & Pharmacology, 26, 531-540. [Google Scholar] [CrossRef] [PubMed]
[32] Neves, D., Salazar, I.L., Almeida, R.D. and Silva, R.M. (2023) Molecular Mechanisms of Ischemia and Glutamate Excitotoxicity. Life Sciences, 328, Article ID: 121814. [Google Scholar] [CrossRef] [PubMed]
[33] Cavallo, D., Landucci, E., Gerace, E., Lana, D., Ugolini, F., Henley, J.M., et al. (2020) Neuroprotective Effects of mGluR5 Activation through the PI3K/Akt Pathway and the Molecular Switch of AMPA Receptors. Neuropharmacology, 162, Article ID: 107810. [Google Scholar] [CrossRef] [PubMed]
[34] Qian, X., Wu, Y., Che, Y., Zhao, W., Shu, L., Zhu, J., et al. (2021) IP3R-Mediated Activation of BK Channels Contributes to mGluR5-Induced Protection against Spinal Cord Ischemia-Reperfusion Injury. Neurochemistry International, 150, Article ID: 105191. [Google Scholar] [CrossRef] [PubMed]
[35] Bhat, S.A., Henry, R.J., Blanchard, A.C., Stoica, B.A., Loane, D.J. and Faden, A.I. (2021) Enhanced Akt/GSK-3β/CREB Signaling Mediates the Anti‐Inflammatory Actions of mGluR5 Positive Allosteric Modulators in Microglia and Following Traumatic Brain Injury in Male Mice. Journal of Neurochemistry, 156, 225-248. [Google Scholar] [CrossRef] [PubMed]
[36] Yan, A., Song, L., Zhang, Y., Wang, X. and Liu, Z. (2021) Systemic Inflammation Increases the Susceptibility to Levodopa-Induced Dyskinesia in 6-OHDA Lesioned Rats by Targeting the NR2B-Medicated PKC/MEK/ERK Pathway. Frontiers in Aging Neuroscience, 12, Article 625166. [Google Scholar] [CrossRef] [PubMed]
[37] Dahl, V., Helmbrecht, H., Rios Sigler, A., Hildahl, K., Sullivan, H., Janakiraman, S., et al. (2022) Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome. Life, 12, Article 1308. [Google Scholar] [CrossRef] [PubMed]
[38] Gurgone, A., Pizzo, R., Raspanti, A., Chiantia, G., Devi, S., Comai, D., et al. (2023) mGluR5 PAMs Rescue Cortical and Behavioural Defects in a Mouse Model of CDKL5 Deficiency Disorder. Neuropsychopharmacology, 48, 877-886. [Google Scholar] [CrossRef] [PubMed]
[39] Zhang, Y., Fan, J., Gu, L., Yang, H., Zhan, S. and Zhang, H. (2021) Metabotropic Glutamate Receptor 5 Inhibits α-Synuclein-Induced Microglia Inflammation to Protect from Neurotoxicity in Parkinson’s Disease. Journal of Neuroinflammation, 18, Article No. 23. [Google Scholar] [CrossRef] [PubMed]
[40] Lei, S., Oraegbuna, C.S., Boyle, C.A. and Mastrud, M.R. (2025) Ionic and Signaling Mechanisms Involved in the Excitation of Entorhinal Neurons by Group I mGluRs. Neuropharmacology, 280, Article ID: 110683. [Google Scholar] [CrossRef] 
[41] Gu, L., Luo, W., Xia, N., Zhang, J., Fan, J., Yang, H., et al. (2022) Upregulated mGluR5 Induces ER Stress and DNA Damage by Regulating the NMDA Receptor Subunit NR2B. The Journal of Biochemistry, 171, 349-359. [Google Scholar] [CrossRef] [PubMed]
[42] Hakon, J., Quattromani, M.J., Sjölund, C., Talhada, D., Kim, B., Moyanova, S., et al. (2023) Inhibiting Metabotropic Glutamate Receptor 5 after Stroke Restores Brain Function and Connectivity. Brain, 147, 186-200. [Google Scholar] [CrossRef] [PubMed]

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