State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, China; College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China.
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Brain Res Bull. 2018 Oct;143:19-26. doi: 10.1016/j.brainresbull.2018.08.015. Epub 2018 Aug 24.
Anxiety disorders are chronic, disabling conditions across the world, and bring a great burden to individuals and society. Although advances have been made in understanding of the pathophysiology of these diseases, no mechanistically new drugs for anxiety disorders have reached the market in the past two decades. Some evidence indicates that stress increases neuroinflammatory signaling, which is related to the development of anxiety and depression. Minocycline, a broad-spectrum tetracycline-antibiotic, has been reported to suppress microglia activation-mediated brain endogenous inflammation. However, it is still unknown whether minocycline can be developed to treat stress-induced anxiety disorders and what is the underlying mechanisms. We chose the anxiety model induced by repeated stress consisting of 2 h of restraint on each of 7 consecutive days. The behavioral test results showed that chronic minocycline treatment, not acute minocycline treatment, increased the time spent in the center area in the open field test and the number of open arm entries and time spent in open arms in the elevated plus maze test, which were comparable with the effect of buspirone. Further mechanism studies demonstrated that chronic minocycline treatment inhibited the microglia activation and decreased the levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). In addition, peroxisome proliferator-activated receptor gamma/ nuclear factor kappa B (PPAR-γ/NF-κB) signaling pathway was also modulated by chronic minocycline treatment. In conclusion, our findings support the hypothesis that immune dysregulation plays an important role in stress-induced anxiety disorders, and minocycline can be developed to be used in these diseases.
焦虑障碍是全球范围内慢性且致残的疾病，给个人和社会带来了巨大负担。尽管人们在这些疾病的病理生理学理解方面取得了进展，但在过去的二十年中，没有一种机制新颖的焦虑障碍治疗药物进入市场。一些证据表明，压力会增加神经炎症信号，这与焦虑和抑郁的发展有关。米诺环素是一种广谱四环素类抗生素，已被报道可抑制小胶质细胞激活介导的脑内源性炎症。然而，目前尚不清楚米诺环素是否可以开发用于治疗应激引起的焦虑障碍，以及其潜在机制是什么。我们选择了由连续 7 天每天 2 小时束缚引起的焦虑模型。行为测试结果表明，慢性米诺环素治疗而非急性米诺环素治疗增加了旷场试验中处于中央区域的时间和高架十字迷宫试验中进入开放臂的次数和时间，这与丁螺环酮的效果相当。进一步的机制研究表明，慢性米诺环素治疗抑制了小胶质细胞激活，并降低了白细胞介素 6（IL-6）和肿瘤坏死因子 alpha（TNF-α）的水平。此外，过氧化物酶体增殖物激活受体 γ/核因子 kappa B（PPAR-γ/NF-κB）信号通路也被慢性米诺环素治疗所调节。总之，我们的研究结果支持免疫失调在应激引起的焦虑障碍中起重要作用的假说，并且米诺环素可以开发用于治疗这些疾病。
