Studies On The Antidepressant Effect And Underlying Mechanism Of Wuling Powder

Depression (also known as depressive disorders) is a common mental disorder, with essential features are depressed mood, thought slowness, thinking volitional activity drops give priority to, cognitive dysfunction and physical impairment, including sleep disorders, fatigue, loss of appetite, weight loss and so on. The prevalence exhibited a gradually rising tendency. The treatment of depression has recently gained considerable interest not only for psychiatry, but also for other disciplines.The pathogenesis of depression remains incompletely understood. Antidepressants are the main drugs for the treatment of depressive symptoms. The traditional antidepressants were mainly developed from "monoamine hypothesis". Although great progress has been made in the development of antidepressants, there is still lack of ideal therapeutic drugs. Aside lower toxicity and few side effects, the long-term use may still cause potential adverse reactions with the novel antidepressants. Thus, further investigation into the pathogenesis of depressive disorder remains to be done, and the development of the next generation of novel antidepressants is urgent.Xylariasp is the fungus sclerotia which grow in termite nests, and its medicinal properties include diuresis, filling the mind, to treat insomnia, vomiting blood and postpartum bleeding treatment. Wuling powder is a light brown to brown powder, which is made by cultivating Xylariasp mycelium using submerged fermentation technology. The capsule preparation of Wuling powder is mainly used to soothe nerves and anti-insomnia in clinic. The antidepressant and anti-anxiety effect of Wuling powder has been confirmed in clinic, which indicated the unique advantage of Chinese medicine. In order to further establish this advantage, it’s still need to in-depth research the mechanism of action. This research adopted two animal models of depression in mice, learned helplessness and social defeat stress, to observe the antidepressant effect of Wuling powder. We explored the underlying mechanism of Wuling powder by analyzing the difference of gene expression using the gene expression profile chip technology, and provided theoretical basis for the clinical application of Wuling powder.Part I:Studies on the antidepressant effect of Wuling powder1. In the learned helplessness animal model, mice were subjected to the shuttle box text to assess the helpless behavior. Results showed that the number of escape failures was significantly increased in model group (P<0.01). Meanwhile, the average escape latency to crossing shuttle box of model group was observably longer than that of the control group (P<0.01). While treatment with Wuling powder significantly decreased both the number of escape failures (P<0.05) and the average escape latency (P<0.05) in a dose-dependent pattern. In the novelty suppressed feeding test, the latency to chew the pellet is defined as feeding latency. Results showed that mice in model group spent significantly more time to initiate feeding (P<0.05). Treatment with Wuling powder shortened the latency to feed (P<0.05). In the forced swimming test, model mice displayed an obvious increase in immobility time (P<0.01). On the contrary, the immobility time was shortened in Wuling powder administrated mice (P<0.0l) with a dose-dependent pattern.2. In the social interaction test in social defeat stress animal model, the ratio of time model mice spent in the interaction zone in the presence of a target CD-1 compared with the absence of a target CD-1 was obviously decreased (P<0.01). After treatment with Wuling powder, the ratio was ameliorated observably (P<0.01). In addition, the ratio of time model mice spent in the corner zone in the presence of a target CD-1 compared with the absence of a target CD-1 was significantly increased (P<0.01), and treatment with Wuling powder dramaticlly decreased this ratio (P<0.01).Part Ⅱ:Studies on the antidepressant mechanisms of Wuling powder1. In the learned helplessness animal model, the results of whole genomic expression profile analysis showed that 18kDa translocator protein (TSPO) differentially expressed by inescapable e-shock exposure, which plays an important role in regulating mitochondrial function.2. We investigated the TSPO/VDAC1-mediated mitochondrial autophagy related pathway to study the antidepressant mechanisms of Wuling powder in the learned helplessness animal model. The down-regulation of TSPO、VDAC1 and PINK1 were observed in LH model mice (P<0.05), while Wuling powder enhanced their expression level dramatically (P<0.05). The expression of Parkin was upregulated in LH model mice (P<0.01), Wuling powder markedly reverse this change induced by inescapable e-shock exposure (P<0.01). Meanwhile, results showed that model mice experienced reduced level of Beclinl expression (P<0.01), and Wuling powder was capable of alleviating this impact (Wuling-L/M P<0.05; Wuling-H P<0.01). KIFC2, a kinesin family member C2, may play a role in retrograde axonal transport. In this study, we observed a decrease in the expression level of KIFC2 (P<0.05), and Wuling powder increased its expression level (P<0.05).3. Immunohistochemistry analysis indicated that the IOD of Synaptogyrin-3-positive nerve fibers in the ventral striatum in LH model group decreased obviously (P<0.01), and treatment of Wuling powder (0.5 g/kg and 1.0 g/kg) significantly elevated the relative IOD of Synaptogyrin-3-positive nerve fibers (P<0.01), which indicated the improvement of synaptogenesis by Wuling powder.4. Our results suggested that Wuling powder exhibited an obvious antidepressant effect, which could be due to the improvement of TSPO-mediated mitophagy signaling pathway.