Ji Ming, Gong Wenliang, Wang Siman, Zhang Dianjun, Chen Binjie, Li Xinyu, Wu Xiafang, Cui Lulu, Feng Yuliang, Verkhratsky Alexei, Li Baoman
Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China.
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
Neurochem Res. 2023 Apr;48(4):1180-1190. doi: 10.1007/s11064-022-03655-4. Epub 2022 Jun 24.
Accumulating evidence suggests that the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Astrocytes, the homeostatic cells of the central nervous system are intimately involved into pathophysiology of various mental disorders including PTSD. We demonstrated previously that leptin exerts neuroprotection and ameliorates chronic sleep deprivation-induced depressive-like behaviours. Here, we extended the study of therapeutic effects of leptin to PTSD model mice. We discovered that PTSD is associated with significant activation of NLRP3 inflammasome in astrocytes sorted from GFAP-GFP transgenic mice, while administration of leptin markedly suppressed the activation of astrocytic NLRP3 inflammasome. Leptin effectively improved PTSD-associated behavioural alterations including fear memory, cognitive impairments, and depressive-like behaviours. Therapeutic effects of leptin were mediated by the signal transducer and activator of transcription 3 (STAT3) in astrocytes. In addition, the PTSD-related activation of NLRP3 inflammasome impairs astrocytic mitochondria suppressing ATP synthesis and leading to an increased ROS production. Leptin reversed mitochondrial inhibition by stimulating STAT3 in astrocytes. We propose leptin as a novel candidate for the pharmacological treatment of PTSD.
越来越多的证据表明，核苷酸结合结构域富含亮氨酸重复蛋白3（NLRP3）炎性小体的激活参与了创伤后应激障碍（PTSD）的病理生理过程。星形胶质细胞作为中枢神经系统的稳态细胞，密切参与包括PTSD在内的各种精神障碍的病理生理过程。我们之前证明，瘦素具有神经保护作用，并能改善慢性睡眠剥夺诱导的抑郁样行为。在此，我们将瘦素治疗作用的研究扩展至PTSD模型小鼠。我们发现，从GFAP-GFP转基因小鼠分选的星形胶质细胞中，PTSD与NLRP3炎性小体的显著激活相关，而给予瘦素可显著抑制星形胶质细胞NLRP3炎性小体的激活。瘦素有效改善了与PTSD相关的行为改变，包括恐惧记忆、认知障碍和抑郁样行为。瘦素的治疗作用由星形胶质细胞中的信号转导子和转录激活子3（STAT3）介导。此外，PTSD相关的NLRP3炎性小体激活损害星形胶质细胞线粒体，抑制ATP合成并导致活性氧生成增加。瘦素通过刺激星形胶质细胞中的STAT3逆转线粒体抑制。我们提出瘦素作为PTSD药物治疗的新候选物。
