School of Medicine, Yunnan University, Kunming 650091, China.
School of Medicine, Yunnan University, Kunming 650091, China.
Biochem Pharmacol. 2021 Jun;188:114561. doi: 10.1016/j.bcp.2021.114561. Epub 2021 Apr 20.
Major depressive disorder (MDD) is a common, chronic, recurrent disease. The existing drugs are ineffective for approximately half of patients, so the development of antidepressant drugs with novel mechanisms is urgent. Cumulative evidence has shown neuro-inflammation plays a key role in the etiology of major depressive disorder. Clinical studies implicated that bile acids, an important component of gut-brain axis, inhibit neuro-inflammation and mediate the pathophysiology of the MDD. Here, we found that ganoderic acid A (GAA) modulated bile acid receptor FXR (farnesoid X receptor), inhibited brain inflammatory activity, and showed antidepressant effects in the chronic social defeat stress depression model, tail suspension, forced swimming, and sucrose preference tests. GAA directly inhibited the activity of the NLRP3 inflammasome, and activated the phosphorylation and expression of the AMPA receptor by modulating FXR in the prefrontal cortex of mice. If we knocked out FXR or injected the FXR-specific inhibitor z-gugglesterone (GS), the antidepressant effects induced by GAA were completely abolished. These results suggest that GAA modulates the bile acid receptor FXR and subsequently regulates neuroimmune and antidepressant behaviors. GAA and its receptor FXR have potential as targets for the treatment of MDD.
重度抑郁症（MDD）是一种常见的、慢性的、复发性疾病。现有的药物对大约一半的患者无效，因此迫切需要开发具有新机制的抗抑郁药物。越来越多的证据表明，神经炎症在重度抑郁症的发病机制中起着关键作用。临床研究表明，胆汁酸作为肠脑轴的重要组成部分，可抑制神经炎症，并调节 MDD 的病理生理学。在这里，我们发现灵芝酸 A（GAA）调节胆汁酸受体 FXR（法尼醇 X 受体），抑制大脑炎症活动，并在慢性社交挫败应激抑郁模型、悬尾、强迫游泳和蔗糖偏好测试中显示出抗抑郁作用。GAA 通过调节 FXR 直接抑制 NLRP3 炎性小体的活性，并激活 AMPA 受体的磷酸化和表达。如果敲除 FXR 或注射 FXR 特异性抑制剂 Z-鹅去氧胆酸（GS），则 GAA 诱导的抗抑郁作用完全被消除。这些结果表明，GAA 调节胆汁酸受体 FXR，进而调节神经免疫和抗抑郁行为。GAA 和其受体 FXR 可能成为治疗 MDD 的靶点。
