保护素D1在神经系统疾病中的神经保护与炎症消退机制研究进展综述
A Review of Research Progress on Neuroprotective and Inflammation-Resolving Mechanisms of Protectin D1 in Neurological Disorders
DOI: 10.12677/acm.2026.1651798, PDF,   
作者: 吕忠明：内蒙古自治区鄂尔多斯市乌审旗河南中心卫生院，内蒙古 鄂尔多斯；梁洪宾, 刘希金*：内蒙古自治区鄂尔多斯市中心医院神经科，内蒙古 鄂尔多斯；许艳梅：内蒙古自治区鄂尔多斯市中心医院心血管内科，内蒙古 鄂尔多斯
关键词: 保护素D1；神经保护素D1；神经炎症；炎症消退；神经病理性疼痛；神经保护；特异性促炎症消退介质；Protectin D1； Neuroprotectin D1； Neuroinflammation； Inflammation Resolution； Neuropathic Pain； Neuroprotection； Specialized Pro-Resolving Mediators
摘要: 神经炎症是多种神经系统疾病发生发展的核心病理环节，其有效调控是神经保护与修复的关键。保护素D1 (Protectin D1, PD1)及其在神经系统中的异构体神经保护素D1 (Neuroprotectin D1, NPD1)作为来源于二十二碳六烯酸的特异性促炎症消退介质，在主动终止炎症反应、促进组织稳态方面展现出独特潜力。本文旨在系统综述PD1/NPD1在缺血性脑卒中、阿尔茨海默病、神经病理性疼痛及创伤性脑损伤等疾病中的神经保护作用与机制研究进展。当前研究表明，PD1/NPD1不仅通过促进炎症消退、抑制细胞凋亡与调节自噬等途径发挥保护效应，还涉及对Wnt/β-catenin、SIRT1/CGRP及GSK-3β等关键信号通路的精细调控。本综述通过整合现有研究成果，揭示了PD1/NPD1在神经炎症调控网络中的核心地位，并探讨了以其为靶点开发新型神经保护与修复策略的潜在价值与未来方向。
Abstract: Neuroinflammation serves as a core pathological process in the occurrence and progression of multiple neurological disorders, and its effective regulation is critical for neuroprotection and neural repair. Protectin D1 (PD1) and its isomer neuroprotectin D1 (NPD1), which are specialized pro-resolving lipid mediators derived from docosahexaenoic acid, exhibit unique potential in actively terminating inflammatory responses and restoring tissue homeostasis. This review systematically summarizes recent advances in the neuroprotective effects and underlying mechanisms of PD1/NPD1 in ischemic stroke, Alzheimer’s disease, neuropathic pain, traumatic brain injury, and other neurological diseases. Current studies demonstrate that PD1/NPD1 exert neuroprotective effects not only by promoting inflammation resolution, inhibiting apoptosis, and regulating autophagy, but also by finely modulating key signaling pathways including Wnt/β-catenin, SIRT1/CGRP, and GSK-3β. By integrating existing findings, this review highlights the central role of PD1/NPD1 in the regulatory network of neuroinflammation and discusses the potential value and future directions of developing novel neuroprotective and repair strategies targeting PD1/NPD1.
文章引用：吕忠明, 梁洪宾, 许艳梅, 刘希金. 保护素D1在神经系统疾病中的神经保护与炎症消退机制研究进展综述[J]. 临床医学进展, 2026, 16(5): 131-142. https://doi.org/10.12677/acm.2026.1651798

参考文献

[1] Zia, B., Elmeky, M., Azimullah, S., Jha, N.K., Nagoor Meeran, M.F. and Ojha, S.K. (2025) The Multifaceted Role of Neuroprotectin D1: Physiological, Pathophysiological, and Pharmacological Insights in Neurodegenerative Diseases. Current Neuropharmacology, 23, 1215-1231. [Google Scholar] [CrossRef] [PubMed]
[2] Ebright, B., Assante, I., Poblete, R.A., Wang, S., Duro, M.V., Bennett, D.A., et al. (2022) Eicosanoid Lipidome Activation in Post-Mortem Brain Tissues of Individuals with APOE4 and Alzheimer’s Dementia. Alzheimer’s Research & Therapy, 14, Article No. 152. [Google Scholar] [CrossRef] [PubMed]
[3] Zirpoli, H., Sosunov, S.A., Niatsetskaya, Z.V., Mayurasakorn, K., Manual Kollareth, D.J., Serhan, C.N., et al. (2021) NPD1 Rapidly Targets Mitochondria-Mediated Apoptosis after Acute Injection Protecting Brain against Ischemic Injury. Experimental Neurology, 335, Article ID: 113495. [Google Scholar] [CrossRef] [PubMed]
[4] Reid, M.M., Kautzmann, M.I., Andrew, G., Obenaus, A., Mukherjee, P.K., Khoutorova, L., et al. (2023) NPD1 plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-Homeostatic Microglial and Astrocyte Genes. Cellular and Molecular Neurobiology, 43, 3555-3573. [Google Scholar] [CrossRef] [PubMed]
[5] Belayev, L., Reid, M. and Bazan, N. (2023) Novel Lipid Mediators as a Promising Therapeutic Strategy for Ischemic Stroke. Medical Research Archives, 11, 3333. [Google Scholar] [CrossRef] [PubMed]
[6] Zhu, Y., Zhang, Y., Gao, X., Li, L., Tang, Y. and Wang, Y. (2024) Protectin D1 Ameliorates Non-Compressive Lumbar Disc Herniation through SIRT1-Mediated CGRP Signaling. Molecular Pain, 20, 1-12. [Google Scholar] [CrossRef] [PubMed]
[7] Tian, Y., Liu, Y., Liu, C. and Huang, S. (2024) NPD1 Relieves Neuropathic Pain and Accelerates the Recovery of Motor Function after Peripheral Nerve Injury. Pain Research and Management, 2024, Article ID: 1109287. [Google Scholar] [CrossRef] [PubMed]
[8] Xu, J., Bang, S., Chen, O., Li, Y., McGinnis, A., Zhang, Q., et al. (2025) Neuroprotectin D1 and GPR37 Protect against Chemotherapy-Induced Peripheral Neuropathy and the Transition from Acute to Chronic Pain. Pharmacological Research, 216, Article ID: 107746. [Google Scholar] [CrossRef] [PubMed]
[9] Furutani, K., Chen, O., McGinnis, A., Wang, Y., Serhan, C.N., Hansen, T.V., et al. (2023) Novel Proresolving Lipid Mediator Mimetic 3-oxa-PD1n-3 Docosapentaenoic Acid Reduces Acute and Chronic Itch by Modulating Excitatory and Inhibitory Synaptic Transmission and Astroglial Secretion of Lipocalin-2 in Mice. Pain, 164, 1340-1354. [Google Scholar] [CrossRef] [PubMed]
[10] Zhao, J., Li, R., Wang, Y., Chandra, S., Zhang, V., Wang, H., et al. (2026) NPD1/GPR37 Signaling Protects against Painful Traumatic Brain Injury and Comorbidities by Regulating Demyelination, Glial Responses, and Neuroinflammation in the Mouse Brain. Brain, Behavior, and Immunity, 132, Article ID: 106219. [Google Scholar] [CrossRef] 
[11] Mikroulis, A., Ledri, M., Ruffolo, G., Palma, E., Sperk, G., Dalli, J., et al. (2022) Lipid Mediator N‐3 Docosapentaenoic Acid‐Derived Protectin D1 Enhances Synaptic Inhibition of Hippocampal Principal Neurons by Interaction with a G‐Protein‐Coupled Receptor. The FASEB Journal, 36, e22203. [Google Scholar] [CrossRef] [PubMed]
[12] Zhou, Y., Wang, J., Li, X., Li, K., Chen, L., Zhang, Z., et al. (2020) Neuroprotectin D1 Protects against Postoperative Delirium-Like Behavior in Aged Mice. Frontiers in Aging Neuroscience, 12, Article ID: 582674. [Google Scholar] [CrossRef] [PubMed]
[13] Markworth, J.F., Brown, L.A., Lim, E., Castor‐Macias, J.A., Larouche, J., Macpherson, P.C.D., et al. (2021) Metabolipidomic Profiling Reveals an Age‐related Deficiency of Skeletal Muscle Pro‐Resolving Mediators That Contributes to Maladaptive Tissue Remodeling. Aging Cell, 20, e13393. [Google Scholar] [CrossRef] [PubMed]
[14] Tsai, W., Kalyanaraman, C., Yamaguchi, A., Holinstat, M., Jacobson, M.P. and Holman, T.R. (2021) In Vitro Biosynthetic Pathway Investigations of Neuroprotectin D1 (NPD1) and Protectin DX (PDX) by Human 12-Lipoxygenase, 15-Lipoxygenase-1, and 15-Lipoxygenase-2. Biochemistry, 60, 1741-1754. [Google Scholar] [CrossRef] [PubMed]
[15] Stenvik Haatveit, Å. and Hansen, T.V. (2023) The Biosynthetic Pathways of the Protectins. Prostaglandins & Other Lipid Mediators, 169, Article ID: 106787. [Google Scholar] [CrossRef] [PubMed]
[16] Jin, J., Boeglin, W.E. and Brash, A.R. (2021) Analysis of 12/15-Lipoxygenase Metabolism of EPA and DHA with Special Attention to Authentication of Docosatrienes. Journal of Lipid Research, 62, Article ID: 100088. [Google Scholar] [CrossRef] [PubMed]
[17] Markworth, J.F., Sugg, K.B., Sarver, D.C., Maddipati, K.R. and Brooks, S.V. (2021) Local Shifts in Inflammatory and Resolving Lipid Mediators in Response to Tendon Overuse. The FASEB Journal, 35, e21655. [Google Scholar] [CrossRef] [PubMed]
[18] Halade, G.V., Kain, V., Dillion, C., Beasley, M., Dudenbostel, T., Oparil, S., et al. (2020) Race-Based and Sex-Based Differences in Bioactive Lipid Mediators after Myocardial Infarction. ESC Heart Failure, 7, 1700-1710. [Google Scholar] [CrossRef] [PubMed]
[19] Kain, V., Grilo, G.A., Upadhyay, G., Nadler, J.L., Serhan, C.N. and Halade, G.V. (2024) Macrophage-Specific Lipoxygenase Deletion Amplify Cardiac Repair Activating Treg Cells in Chronic Heart Failure. Journal of Leukocyte Biology, 116, 864-875. [Google Scholar] [CrossRef] [PubMed]
[20] Abma, W., Dahlén, S., Wheelock, C.E., Adner, M., Al‐Amerie, M., Sachs, E., et al. (2025) Protectin D1 and Maresin 1 Attenuate Airway Hyperreactivity Induced by IL‐13 in Human Isolated Small Bronchi. British Journal of Pharmacology, 183, 2049-2060. [Google Scholar] [CrossRef] 
[21] Vidar Hansen, T. and Serhan, C.N. (2022) Protectins: Their Biosynthesis, Metabolism and Structure-Functions. Biochemical Pharmacology, 206, Article ID: 115330. [Google Scholar] [CrossRef] [PubMed]
[22] Chen, J. (2020) Resolvin D1 Alleviates Cerebral Ischemia/Reperfusion Injury in Rats by Inhibiting NLRP3 Signaling Pathway. Journal of Biological Regulators and Homeostatic Agents, 34, 1179-1186.
[23] Li, L., Cheng, S., Sun, Y., Yu, J., Huang, X., Dong, Y., et al. (2023) Resolvin D1 Reprograms Energy Metabolism to Promote Microglia to Phagocytize Neutrophils after Ischemic Stroke. Cell Reports, 42, Article ID: 112617. [Google Scholar] [CrossRef] [PubMed]
[24] Chen, E., Zhou, D. and Deng, R. (2024) Serum Resolvin D1 Potentially Predicts Neurofunctional Recovery, the Risk of Recurrence and Death in Patients with Acute Ischemic Stroke. Biomedical Reports, 20, Article No. 10. [Google Scholar] [CrossRef] [PubMed]
[25] Hao, J., Feng, Y., Xu, X., Li, L., Yang, K., Dai, G., et al. (2022) Plasma Lipid Mediators Associate with Clinical Outcome after Successful Endovascular Thrombectomy in Patients with Acute Ischemic Stroke. Frontiers in Immunology, 13, Article ID: 917974. [Google Scholar] [CrossRef] [PubMed]
[26] Chen, W., Wang, H., Wang, Z., Zhao, C., Xu, J. and Chen, Q. (2020) Resolvin D1 Improves Post-Resuscitation Cardiac and Cerebral Outcomes in a Porcine Model of Cardiac Arrest. Shock, 54, 548-554. [Google Scholar] [CrossRef] [PubMed]
[27] Kotlega, D., Zembron-Lacny, A., Golab-Janowska, M., Nowacki, P. and Szczuko, M. (2020) The Association of Free Fatty Acids and Eicosanoids with the Severity of Depressive Symptoms in Stroke Patients. International Journal of Molecular Sciences, 21, Article No. 5220. [Google Scholar] [CrossRef] [PubMed]
[28] Wang, Y., Liu, S., Zhu, M., Zhang, Q., Sun, H., Liu, K., et al. (2025) Diagnostic and Therapeutic Potential of Resolvin D1 in Guillain-Barré Syndrome. Journal of Advanced Research. [Google Scholar] [CrossRef] 
[29] Dai, S., Zhou, F., Sun, J. and Li, Y. (2021) NPD1 Enhances Autophagy and Reduces Hyperphosphorylated Tau and Amyloid-β42 by Inhibiting GSK3β Activation in N2a/APP695swe Cells. Journal of Alzheimer’s Disease, 84, 869-881. [Google Scholar] [CrossRef] [PubMed]
[30] Miyazawa, K., Fukunaga, H., Tatewaki, Y., Takano, Y., Yamamoto, S., Mutoh, T., et al. (2020) Alzheimer’s Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment? International Journal of Molecular Sciences, 21, Article No. 5783. [Google Scholar] [CrossRef] [PubMed]
[31] Nesman, J.I., Chen, O., Luo, X., Ji, R., Serhan, C.N. and Hansen, T.V. (2021) A New Synthetic Protectin D1 Analog 3-oxa-PD1 n-3 DPA Reduces Neuropathic Pain and Chronic Itch in Mice. Organic & Biomolecular Chemistry, 19, 2744-2752. [Google Scholar] [CrossRef] [PubMed]
[32] Li, Y., Bang, S., Ji, J., Xu, J., Lee, M., Chandra, S., et al. (2026) Protectin DX Resolves Fracture-Induced Postoperative Pain in Mice via Neuronal Signaling and GPR37-Activated Macrophage Efferocytosis. Journal of Clinical Investigation, 136, e190754. [Google Scholar] [CrossRef] 
[33] Zhang, Q., Bang, S., Chandra, S. and Ji, R. (2022) Inflammation and Infection in Pain and the Role of GPR37. International Journal of Molecular Sciences, 23, Article No. 14426. [Google Scholar] [CrossRef] [PubMed]
[34] Wang, K., Zhang, Y., Shu, R., Yuan, L., Tu, H., Wang, S., et al. (2025) GPR37 Activation Alleviates Bone Cancer Pain via the Inhibition of Osteoclastogenesis and Neuronal Hyperexcitability. Advanced Science, 12, e2417367. [Google Scholar] [CrossRef] [PubMed]
[35] Liu, S., Bai, T., Liu, X., Zhao, W., Li, X., Sui, Y., et al. (2025) Role and Regulatory Mechanism of GPR37 in Neurological Diseases. Frontiers in Cellular Neuroscience, 19, Article ID: 1617682. [Google Scholar] [CrossRef] [PubMed]
[36] Adithan, A., Fassler, M., Lu, G., et al. (2025) Protectin D1/GPR37 Signaling Enhances Macrophage-Dependent Efferocytosis to Attenuate Experimental Abdominal Aortic Aneurysm Formation.
[37] Park, J., Langmead, C.J. and Riddy, D.M. (2020) New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery. ACS Pharmacology & Translational Science, 3, 88-106. [Google Scholar] [CrossRef] [PubMed]
[38] Hammond, R.M., Wang, J., Pariyar, R., et al. (2025) GPR37 Activation Erases Spinal Pain Memory and Resolves Increased Nociception in Murine Models.
[39] Bang, S., Donnelly, C.R., Luo, X., Toro-Moreno, M., Tao, X., Wang, Z., et al. (2021) Activation of GPR37 in Macrophages Confers Protection against Infection-Induced Sepsis and Pain-Like Behaviour in Mice. Nature Communications, 12, Article No. 1704. [Google Scholar] [CrossRef] [PubMed]

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