| Retinoic acid has been reported to participate in the process of depression by many studies. Based on hypothalamic-pituitary-adrenal (HPA) axis over-activation hypothesis and BDNF-TrkB mediated synaptic dyregulation hypothesis, in this study we tried to elucidate the role of retinoic acid in the pathogenesis of depression, which may help to understand and cure depression from a new aspect.1. Regulation of corticotropin-releasing hormome gene expression by CREB via a nonclassical retinoic acid signaling pathwayCorticotropin-releasing hormome (CRH) is considered as the vital factor in the hypothalamic-pituitary-adrenal (HPA) axis and plays an important role in the pathogenesis of depression. Nonclassical action of retinoic acid on the expression of endogenous CRH was investigated in BE(2)C cell line. Endogenous CRH expression was activated by RA and it can be blocked by silencing of CREB or inhibition of CREB phosphorylation. To further assess the role of CREB in RA-induced transcriptional activity of CRH, the mRNA level and phosphorylation state of CREB were detected between RA treatment and control groups. Phosphorylation protein level, not the mRNA level of CREB was significantly changed. The results indicated that CREB is sufficient for RA to regulate the expression of CRH.2. The regulatory effect of retinoic acid receptor a on corticotropin-releasing hormome gene expressionWe previously showed that RARa regulated the expression of CRH by binding to CRH promoter domain. In this study, we further investigated the underlying mechanism of RARa-induced CRH expression. When RARa was overexpressed in CHO cell line, with or without retinoic acid, the activity of CRH promoter was upregulated. When two estrogen response elements half sites (1/2ERE) or the cAMP regulatory element (CRE) in the CRH promoter was depleted, the activation effect of CRH promoter was reduced, which implied that these sites were required for RARa-mediated upregulation of CRH promoter activity. Moreover, we detected the interaction between RARa and estrogen receptor a(ERa) which founctioned in a similar way on the activity of CRH promoter. When ERa was kockdowned in BE(2)C cells, RA-induced upregulation of CRH expression was reduced significantly. In bimolecular fluorescence complementation (BiFC) assay, ERa was found to bind to RARa, implying that the two receptors may cooperate in the regulation of CRH expression.3. Abnormal retinoid and TrkB signaling in the prefrontal cortex in mood disordersIt has been reported that retinoid signaling as well as brain-derived neurotrophic factor (BDNF) and its receptor TrkB were involved in the pathologenesis of depression. In vitro studies, retinoic acid receptor-a was found to bind to the TrkB promoter region via a putative retinoic acid response element within the TrkB promoter and transactivate its expression. Moreover, phosphorylation of TrkB and its downstream Akt, ERK were upregulated by retinoic acid. The mRNA levels of the important elements in the retinoid signaling, brain-derived neurotrophic factor and TrkB isoforms were reduced in the postmortem dorsolateral prefrontal cortex/anterior cingulate cortex. In the chronic unpredictable mild stress animal model for depression, similar results were observed in the prefrontal cortex. Along with neuronal immunopositive for both retinoic acid receptor-a and TrkB, a positive correlation between mRNA levels of the two receptors was found in the anterior cingulate cortex of control subjects but not of depressed patients, suggesting that the interaction between them was affected. In conclusion, regulation of TrkB pathway by retinoic acid receptor-a may provide an alternative therapeutic strategy for depression. |
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