中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (6): 2380-2388.doi: 10.4103/NRR.NRR-D-24-01070

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

褪黑素通过靶向cGAS减轻脑缺血损伤

  

  • 出版日期:2026-06-15 发布日期:2026-04-17

Melatonin alleviates neuroinflammation in ischemic stroke by regulating cyclic GMP-AMP synthase–mediated microglial pyroptosis signaling

Qian Li1, *, Lin Feng1, Yu Tian2, Erliang Guo3, Yiran Li4, Jingyan Niu1, Haodong Pan1, Chun Dang5, Yaoheng Lu6, Lihua Wang1, *   

  1. 1Department of Neurology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; 
    2Department of Geriatrics, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China; 
    3Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China; 
    4State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu Province, China; 
    5Department of Periodical Press, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China; 
    6Department of General Surgery, Chengdu Integrated Traditional Chinese Medicine and Western Medicine Hospital, Chengdu, Sichuan Province, China
  • Online:2026-06-15 Published:2026-04-17
  • Contact: Qian Li, MD, PhD, drliqianhmu@sina.com; Lihua Wang, MD, PhD, wanglh211@163.com.
  • Supported by:
    This work was supported by the Natural Science Foundation of Heilongjiang Province, No. YQ2021H011 (to QL); China Postdoctoral Science Foundation, Nos. 2020M670925, 2022T150172 (to QL); Postdoctoral Foundation of Heilongjiang Province, Nos. LBH‐Z19027, LBH‐TZ2019 (to QL); Institute Cultivation Fund, No. PYMS2023-1 (to QL); and Natural Science Foundation of Jiangsu Province, No. BK20241233 (to YL).

PDF

1

摘要：

炎症是加重缺血性脑卒中（IS）继发性脑损伤的关键因素。褪黑素是一种内源性神经内分泌激素，具有调节线粒体平衡的特性。然而，褪黑素通过双链DNA（dsDNA）传感环GMP-AMP合成酶（cGAS）信号传导调节小胶质细胞炎症性细胞死亡（焦亡）和炎症级联反应的作用和机制仍有待进一步研究。实验利用大脑中动脉阻塞（MCAO）小鼠研究了褪黑素对cGAS介导的细胞焦亡和神经炎症的影响。结果发现，MCAO后，DNA损伤和dsDNA释放（通过γH2AX反映）显著增加，cGAS-STING通路活化加剧，但褪黑素治疗明显抑制了这些影响。褪黑素还能减轻IS后小胶质细胞中NLRP3炎性体的激活和NF-κB/GSDMD介导的细胞焦亡。褪黑素能减轻小鼠对缺血的免疫反应，从而减少缺血脑中外周嗜中性粒细胞和单核细胞/巨噬细胞的浸润。此外，褪黑素还能减少 Iba1+细胞的数量，并抑制小胶质细胞产生白细胞介素6 和肿瘤坏死因子α。褪黑素能明显缩小脑梗死体积，改善小鼠神经功能。值得注意的是，褪黑素的保护作用与 cGAS 活性的抑制相关。该研究还创新性地开发了与ROS（活性氧）响应性纳米颗粒结合的巨噬细胞膜仿生褪黑素递送系统（Mф-MLT@FNGs）。这种纳米颗粒通过靶向脑缺血区域，增强了褪黑素的药效，显现出显著的神经保护优势，为缺血性脑卒中的治疗提供了全新策略。这些结果表明，褪黑素可抑制神经炎症，通过调节cGAS-STING-NF-κB信号通路重塑免疫微环境，从而挽救受损大脑，保护神经功能，提示褪黑素可能是缺血性脑卒中的一种潜在神经保护治疗方法。


https://orcid.org/0000-0002-2900-2494 (Qian Li)

关键词: cGAS, 免疫损伤, 炎症, 缺血性脑卒中, 褪黑激素, 热蛋白沉积, STING, 小胶质细胞

Abstract: Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke. Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis. However, the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA (dsDNA)-sensing cyclic GMP-AMP synthase (cGAS) signaling warrant further study. Using middle cerebral artery occlusion mice, we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation. Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release, as reflected by γH2AX staining, as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway, both of which were notably suppressed by melatonin treatment. Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activation and nuclear factor (NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke, while exhibiting the capacity to attenuate the immune response to ischemia in mice. This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain. Specifically, melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-α by microglia. Regarding neurological outcomes, melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice. Notably, the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity. We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles (Mф-MLT@FNGs), which exhibited therapeutic properties in middle cerebral artery occlusion mice. Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway. By doing so, melatonin rescues damaged brain tissue and protects neurological function, highlighting its potential as a neuroprotective treatment for ischemic stroke.

Key words: cGAS, immune injury, inflammation, ischemic stroke, melatonin, pyroptosis, STING, microglia