Studies On The Antidepressant Effect And Mechanisms Of Total Timosaponin And Sarsasapogenin

Depression is an affective disorder associated with high rates of chronicity, relapse and recurrence; psychosocial and physical impairment; and a high suicide rate, which has mufti-negative to individuals, families and society. The incidence of depression is rapidly increasing during these years. Nonetheless, many currently available antidepressants have low rates of response and remission. Moreover, contemporary antidepressants can produce many unwanted side effects. Therefore, research for new antidepressants with greater effectiveness from herbs is desirable.Total timosaponin （TT） is a mixture of total saponins extracted from the rhizome of Anemarrhena asphodeloides Bunge, containing a high level of steroid saponins such as timosaponin A-I, A-III, B and E, which exhibits a variety of pharmacological effects such as the promotion of neurogenesis activity, antioxidative action, antistress action and improving cognitive impairment. Sarsasapogenin is a major bioactive group of total timosaponin. Our dissertation studied the antidepressant effects of TT and sarsasapogenin with various animal models and their possible mechanisms in celluar and molecular levels.TT can distinctly antagonized the syndrome induced by reserpine, increase the head-twitch response induced by 5-HTP, and enhanced the toxicity induced by yohimbine. The research results indicated the mechanisms of its antidepressant effects may be related with the reinforcement of NE and 5-HT nerves system.Our results showed that TT treatment at 12.5 to 50 mg/kg （p.o.） for 14 days significantly reduced the duration of immobility in the forced swimming test and tail suspension test, and produced no overt locomotor activity change in the open-field test, indicating an antidepressant activity. TT siginificantly decreased the number of escape deficits in the LH test. After a three-week treatment, TT markedly enhanced the locomotor activity and increased consumption of sucrose solution in chronic mild stressed （CMS） mice. The research results indicated TT had antidepressant effects in depression mouse models.Abnormally high corticosteroid levels have been associated with both psychiatric problems and neuronal damage. The research results demonstrated that CMS activied the hypothalamic-pituitary-adrenal （HPA） axis and induced hippocampal neuronal damage. After a three-week treatment, TT markedly decreased the enhanced plasma corticosterone and adrenocorticotrophic hormone levels, and decreased the hyperplasy of adrenal gland. TT can also improve hippocampal neuronal density and morphologic changes induced by CMS. Furthermore, TT ameliorated the decreacing of anti-oxidative stress capability and brain-derived neurotrophic factor （BDNF） levels. The research results of corticosterone induced PC12 cells damage model demonstrated TT （0.05, 0.5, 5 mg/L） could improve the morphological change induced by corticosterone, markedly increase the survival rate and decrease the LDH activity. In the fura-2/AM labeling assay, TT attenuated Cort-induced intracellular Ca²⁺ overloading in PC12 cells. Furthermore, TT improved the decreaced of anti-oxidative stress capability. In summary, the mechanisms of its antidepressant effects may be related with the protection of neuronal damage induced by stress. At least a couple of factors seem to be involved in the neuronal protecting effects of TT. Firstly, TT can inhibit stress-induced the activation of the HPA axis and decrease the adrenal cortex hormone levels. Secondly, TT can increase BDNF levels and improve Cort-induced intracellular Ca²⁺ overloading and superoxide dismutase activity breakdown.To search the antidepressant active component of TT, we extracted sarsasapogenin form Anernarrhema asphodeloides Bunge by acid-degradation analysis, extraction, gel silica collumn separation, and re-crystallization methods. The extracted production is white needl crystal, and the purity of sarsasapogenin is more than 98%. Our results showed that sarsasapogenin treatment at 12.5 to 50 mg/kg （p.o.） for 14 days significantly reduced the duration of immobility in the forced swimming test, and produced no overt locomotor activity change in the open-field test, indicating an antidepressant activity. The results indicated sarsasapogenin is a major active component of TT. If some monosaccharides side chains were introduced at its 3rd position, we can possibly fine the new derivate of sarsasapogenin with more potent antidepressant activity. Furthermore, in the monoamine assay, chronic sarsasapogenin administration significantly elevated the NE and 5-HT level in hypothalamus and hippocampus. According to the present results, it is possible that the MAO inhibition contributes, at least in part, to the enhancement of NE and 5-HT levels in mouse brain. In conclusion, our study indicated that TT and sarsasapogenin have distinctive antidepressant effects in several of animal models. The mechanisms of its antidepressant effects may be related with the adjustment of neurobiochemist function, neuroendocrine function and improvation of neuronal damage. This study could be of interest in the study of the potential therapeutic of TT and sarsasapogenin on depression treatment.