期刊
BIOCHEMICAL PHARMACOLOGY
卷 188, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114561
关键词
Ganoderic acid A; Farnesoid X receptor; NLRP3 inflammasome; AMPA receptor; Major depressive disorder
资金
- National Natural Science Foundation of China [31860267, 81760651, 31650005]
- Science and Technology Project of Yunnan Province [202001BB050003, 2019FD136]
Major depressive disorder (MDD) is a common, chronic, recurrent disease, with approximately half of patients being ineffective to existing drugs, highlighting the urgent need for novel antidepressant drugs. Neuro-inflammation plays a key role in the etiology of MDD, with bile acids inhibiting neuroinflammation and mediating the pathophysiology of the disorder. Ganoderic acid A (GAA) was found to modulate bile acid receptor FXR, inhibit brain inflammatory activity, and exhibit antidepressant effects, offering potential as a target for MDD treatment.
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 neuroinflammation 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.
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