Glucagon-like Peptide 1 Receptor Activation Inhibits Microglial Pyroptosis via Promoting Mitophagy to Alleviate Depression-like Behaviors in Diabetic Mice.
Glucagon-like Peptide 1 Receptor Activation Inhibits Microglial Pyroptosis via Promoting Mitophagy to Alleviate Depression-like Behaviors in Diabetic Mice.
复制标题
胰高血糖素样肽1受体激活通过促进线粒体自噬抑制小胶质细胞凋亡减轻糖尿病小鼠抑郁样行为
作者：
抑郁症是糖尿病常见的严重并发症，对患者的预后和生活质量有不良影响。胰高血糖素样肽-1受体（GLP-1 R）激动剂广泛用于治疗糖尿病，据报道在中枢神经系统中发挥神经保护作用。因此，我们的目的是评估GLP-1 R激动剂exendin-4（EX-4）是否可以减轻糖尿病小鼠的抑郁样行为，并探讨其潜在的机制。EX-4的抗抑郁作用使用db/db小鼠中的行为测试来评估。在N9小胶质细胞中评估EX-4对小胶质细胞焦亡和神经炎症的影响。EX-4给药减轻了糖尿病db/db小鼠的抑郁样行为。在糖尿病小鼠和脂多糖（LPS）致敏的N9小胶质细胞中，EX-4激活GLP-1 R可通过下调gasdermin D（GSDMD）和白细胞介素（IL）-1β显著抑制小胶质细胞焦亡和神经炎症。从机制上讲，GLP-1 R活化通过减少线粒体活性氧（mtROS）蓄积和细胞内ROS产生，改善线粒体功能并促进线粒体自噬。EX-4在糖尿病小鼠中对糖尿病相关抑郁症表现出抗抑郁作用，这可能是通过促进线粒体自噬抑制小胶质细胞裂解而介导的。GLP-1 R激动剂有望成为治疗糖尿病相关抑郁症的有效药物。
Depression is a frequent and serious comorbidity associated with diabetes which adversely affects prognosis and quality of life. Glucagon-like peptide-1 receptor (GLP-1R) agonists, widely used in the treatment of diabetes, are reported to exert neuroprotective effects in the central nervous system. Thus, we aim to evaluate whether GLP-1R agonist exendin-4 (EX-4) could alleviate depression-like behaviors in diabetic mice and to explore its underlying mechanism. The antidepressant effects of EX-4 were evaluated using behavioral tests in db/db mice. The effects of EX-4 on microglial pyroptosis and neuroinflammation were assessed in N9 microglial cells. EX-4 administration alleviated depression-like behaviors in diabetic db/db mice. GLP-1R activation by EX-4 significantly suppressed microglial pyroptosis and neuroinflammation by downregulation of gasdermin D (GSDMD) and interleukin (IL)-1β in diabetic mice and lipopolysaccharide (LPS)-primed N9 microglia. Mechanistically, GLP-1R activation improved mitochondrial function and promoted mitophagy by decreasing the accumulation of mitochondrial reactive oxygen species (mtROS) and intracellular ROS production. EX-4 exhibits antidepressant effects in depression associated with diabetes in diabetic mice, which may be mediated by inhibiting microglial pyroptisis via promoting mitophagy. It is supposed that GLP-1R agonists may be a promising therapy in depression associated with diabetes.