| Depression is a chronic, recurring and potentially life-threatening illness that affects up to 20% of the population in the world. Depressed patients generally display co-morbid symptoms, and depression frequently accompanies other serious disorders. According to the survey by the World Health Organization, depression is one of the top ten causes of morbidity and mortality worldwide, and it will be the most leading cause of disability in the world by the year 2020. Significant progress has been made in the development of therapeutic agents, such as the serotonin and norepinephrine selective reuptake inhibitors, which function in the same manner as the prototypical tricyclic antidepressants (ADs), with fewer side effects. Unfortunately for patients and clinicians, the mood improvement starts only after 3-6 weeks of AD treatment. In addition, approximately 30% of patients are resistant to current drug therapies. Moreover, economic considerations need to be taken into account because of worse cost-effectiveness in depression treatment. Given this background, there is a pressing need to develop conceptually novel drugs or methods to obtain a therapeutic effect in a faster response, less side-effects, better quality of remission and cost-effectiveness. Recent advances in neuroscience are rapidly promoting our understanding of the pathophysiology of mood states. In a novel theory, a failure of adult hippocampal neurogenesis has been proposed to provide the biological and cellular basis of major depression and stimulating hippocampal neurogenesis could provide novel avenues for the treatment of anxiety and depressive disorders. Thus, in the present study, we first assessed the neurogenic potential of the screening drugs by using BrdU labeling in adult mice. All the drug candidates were monomer or compound which were extracted from traditional Chinese herbal medicine in our laboratory or other’s. Thereafter, we would examine whether they have antidepressant effects by using various animal models, such as forced swimming test (FST), novelty-suppressed feeding (NSF) test, open field test, chronic social defeat stress, chronic mild stress (CMS).if so, what may be the underlying mechanism would be explored.The first part of our research is drug screening base on promoting of adult hippocampal neurogenesis. To evaluate the effect of screening drugs on cell proliferation, we employ BrdU, a thymidine analogue that is incorporated into DNA during the S phase of mitosis, to label dividing cells in the dentate gyrus. In this study, we found that fuzi polysaccharide-1 (FPS), paeoniflorin (PF), huperzine A and actein administration significantly increased BrdU labeling cells in the subgranular zone (SGZ) of adult C57BL/6 mice, suggesting that they four may have neurogenic effect in adult hippocampus.The second part of our research is that FPS produces rapid onset of antidepressant-like effects in mice. FPS is a new water-soluble polysaccharide isolated from Fuzi which has been used to treat mood disorders in traditional Chinese medicine for ages. Our results showed that FPS increased the number of new born cells in the dentate gyrus in adult mice, and most of these cells subsequently differentiate into new neurons. We also found that FPS administration reduces immobility in the FST, and the latency in NSF test. Moreover, a 14-day regimen with FPS reverses avoidance behavior and inhibition of hippocampal neurogenesis induced by chronic defeat stress; by contrast, imipramine, a well known antidepressant, reverses this avoidance behavior only after 4 weeks of continuous administration. Finally, acute treatment with FPS has no effect on brain monoamine levels in frontal cortex but significantly increases BDNF in the hippocampus, and the antidepressant effect and enhancement of cell proliferation induced by FPS administration were totally blocked by K252a, an inhibitor of trkB in chronic social defeat depression model, suggesting that the neurogenic and antidepressant effects of FPS may involve BDNF signaling.The third part is antidepressant effects of PF in behavioral models of depression. PF is the major bioactive constituent of peony root, which has been used to treat depressive patients in Traditional Chinese Medicine. The main goal of the present work was to evaluate the antidepressant effects of PF (i.p.) in various rodent animal models of depression, including the FST, the NSF test and the CMS paradigm, and its possible mechanisms underlying the behavioral changes. Acute PF treatment significantly decreased the total time of immobility in the FST, and the latency in the NSF test is also decreased after 7-day PF injection in adult mice. These effects were observed 7 days after PF administration and lasted up to 1 month. Importantly, the 2-week administration of PF,1.0 mg/kg/day, reversed the anhedonia in rats exposed to a 7-week chronic mild stress protocol. In this respect, the effect of PF was similar to that obtained after the administration of imipramine,20 mg/kg/day. In addition, PF treatment group showed more rapid onset of action than imipramine treatment’s. Our findings also indicated that there were more newborn neurons in the hippocampus in PF-treated animals and most of them were differentiated into mature neuron. Moreover, we found that BDNF and VEGF were significantly increased in the hippocampus after PF administration. Together, these results suggest that PF is able to produce antidepressant effects in several models of depression and the effect is probably mediated by increased neurogenesis which may associated with BDNF or/and VEGF signaling.In conclusion, our findings provide a promising strategy that increasing adult hippocampal neurogenesis might be a new avenue for the development of antidepressants. In addition, our finding suggest that FPS could be developed as a putative antidepressant with a rapid onset of action, PF could be as a potential therapeutic tool for depression with fast action and long lasting effects. |
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