Antidepressant Effects Of Abscisic Acid Mediated By The Downregulation Of CRH Gene Expression

Corticotrophin-releasing hormone (CRH) is considered to be the central driving force of the hypothalamic-pituitary-adrenal (HPA) axis, which plays a key role in the stress response and depression. Clinical reports have suggested that excess retinoic acid (RA) is associated with depression. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share a similar molecular structure. Here, we proposed that ABA also plays a role in the regulation of CRH activity sharing with RA signaling pathway. This report is the first to demonstrate that the hypothalamus of rats shows the highest concentration of ABA compared with the cortex and the hippocampus under basal conditions. Under acute stress, ABA concentrations increased in the serum, but decreased in the hypothalamus and were accompanied by increased corticosterone in the serum and c-fos expression in the hypothalamus. Moreover, chronic ABA administration increased sucrose intake and decreased the mRNA expression of CRH and retinoic acid receptor alpha (RARa) in the hypothalamus of rats. Furthermore, ABA improved the symptom of chronic unpredictable mild stress (CUMS) model rats, as indicated by increased sucrose intake, increased swimming in the forced swim test, and reduced mRNA expression of CRH and RARa in the rat hypothalamus. In vitro, CRH expression decreased after ABA treatment across different neural cells.In BE(2)-C cells, ABA inhibited a series of retinoid receptor expression, including RARa, a receptor that could facilitate CRH expression directly. These results suggest that ABA may play a role in the pathogenesis of depression by downregulating CRH mRNA expression shared with the RA signaling pathway.In the present study, we found that ABA and CRH had a negative correlation in normal human serum and the correlation was disappeared in depression patients, who had higher CRH concentrations. This negative correlation was also confirmed in ABA-treated BE (2)-C cells. ABA also inhibited the expression of retinoic acid receptor alpha (RARa) which could regulate CRH gene expression by its recruitment to the CRH promoter. In addition, RARa overexpressing and silencing studies showed that RARa was necessary for CRH expression. When knocking down lanthionine synthetase component C-like protein LANCL2, the membrane receptor of ABA in mammals, ABA-reduced CRH mRNA expression was abrogated. Interestingly, silencing LANCL2resulted in the decreased RARa expression both at mRNA and protein levels accompanied with the reduced CRH mRNA expression, while knocking down RARa had no effect on the expression of LANCL2. These results suggest that ABA negative regulates CRH mRNA expression was through LANCL2-RARa pathway.To explore the potential effect of ABA on spatial learning and memory,20mg/kg ABA was administrated in young rats for six weeks, and the behavior performance was evaluated using a series of behavioral tests. ABA pharmacokinetic study demonstrated that the exogenous ABA distributed widely in the rat brain, characterizing with quick absorption and slow elimination. Results of behavioral tests showed that ABA increased the duration and frequency in the target quadrant in the probe test of Morris water maze, and decreased the latency to find the target quadrant. Moreover, ABA decreased the latency to entry the novel arm in the Y-maze test, accompanying with the increased total entries and distance moved in the three arms. However, there were no significant differences between the ABA-treated and control rats in the open field and elevated plus maze. These results indicated that ABA improves the long-term spatial memory and exploratory activity in young rats.