Development of fast acting antidepressants based on nuclear receptor mechanism

Title : Development of fast acting antidepressants based on nuclear receptor mechanism

Abstract:

Major depressive disorder is a common, chronic and recurrent disease. Existing drugs are ineffective to one third of patients, so it is urgent to develop novel and  rapid antidepressants. Accumulative evidence has shown that immune inflammation, particularly inflammasome activity, plays an important role in the pathophysiology of MDD. We summarize the evidence on nuclear receptors (NRs), such as glucocorticoid receptor, vitamin D receptor, estrogen receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor(PPARs), in modulating the inflammasome activity and depression-associated behaviors. Chronic Social Defeat Stress (CSDS) depressed mice reduced the expression level in prefrontal cortex (PFC) of farnesoid X receptor(FXR), which is a nuclear receptor activated by CDCA. We found that CDCA treatment restored the level of FXR in the CSDS mice, decreased the activity of the NLRP3 inflammasome and caspase-1 and subsequently showed antidepressant effects in the tests of sucrose preference, tail suspension, and forced swimming in CSDS mouse model of depression. Moreover, we also found that ganoderic acid A (GAA) modulated CDCA receptor FXR, 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 synaptic AMPA by regulating FXR in the PFC 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. In another independent study, we found that oridonin significantly enhanced the expression of nuclear receptor PPAR-γ, GluA1 (Ser845) phosphorylation, GluA1 in the total protein extract of the prefrontal cortex (PFC), and showed antidepressant efficacy.  Blocking nuclear receptor PPAR-γ was able to block antidepressant effects of oridonin. These studies demonstrate that nuclear receptor signaling regulates neuroimmune and antidepressant behaviors and are potential targets for the treatment of MDD.

What will audience learn from your presentation?

• Nuclear receptors (NRs), modulating the inflammasome activity, could be the key mechanism for novel antidepressant drug development.
• Ganoderic acid A (GAA) activated nuclear receptor FXR , inhibited the activity of the NLRP3 inflammasome, and showed the antidepressant effects.
• Oridonin mediated through nuclear receptor PPAR-γ also showed antidepressant efficacy.

Biography:

Jing Du is a professor in Beijing Anding Hospital affiliated to Capital Medical University in Beijing, China. In Beijing Anding Hospital, she is mainly engaged in the research of cellular and molecular pathophysiology and neuropsychopharmacology of mental diseases such as depression, anxiety, autism and Alzheimer's disease. She was formerly a staff scientist at the National Institute of Mental Health of the National Institutes of Health(NIH) in USA. She has won many awards, such as the Award for Special Achievement issued by the National Institutes of Health of the United States. Full member of the American College of Neuropsychopharmacology (ACNP). In 2001, she began to work as a staff scientist at NIMH, NIH, leading a team to perform research on the treatment of depression, mania and stress-related mental diseases. She was invited to serve as the editorial board of "BMC neuroscience". She has published 62 SCI articles. She is recognized nationally and internationally for her research contributions and achievements in psychopharmacology.