Antidepressant Effects Of Xiaochaihutang And Its Regulation Of Neurotransmitters, Neurotrophic Factors And Female Hormones

Xiaochaihutang (XCHT) was described in a manuscript entitled "Shang Han za bing Lun", which has been used in China for thousands of years to treat Shaoyang syndrome. Shaoyang syndrome involves depressive-like symptoms including "poor appetite and upset", suggesting XCHT may have antidepressant effect. Clinical practise reported that XCHT was an effective TCM prescriptionin the treatment of depressive disorders and our previous study had found that it could upregulate the contents of monoamine neurotransmitters in the rat brain. However, no studies were conducted to systematically demonstrate its antidepressant effect and mechanism. In the present study, the antidepressant effect of XCHT was studied using variety of animal depressive models, the pharmacology mechanisms were explored focusing on the neurotransmitters, neurotrophic factor and female hormones, and variety of pharmacological methods were used for detecting the neural biochemical, protein and receptor levels.Firstly, the behavioral despair models in mice were carried out to determine the antidepressant effect, and a time and dose dependent of XCHT were obtained at the same time. Results showed that, clinical equivalent dose of XCHT (7g/kg mice) significantly reduced the immobility time in mouse tail suspension test and forced swimming test. One third of clinical equivalent dose (2.3g/kg in mouse and1.7g/kg in rat) significantly reduced the immobility time both in mouse forced swimming test and rat forced swimming test. Meanwhile, XCHT had no effect on general activity, assessed as locomotor activity in mice and open field behavior in rats. Thus, these results support an antidepressant-like effect of XCHT in the behavioral despair models in rodents. To further confirm the antidepressant effects of XCHT, drug induced model in mice were carried out in the current study. It was found that XCHT antagonized reserpine-induced hypothermia and ptosis in mice, and increased the frequency of5-HTP-induced head twitches, suggesting that XCHT possess antidepressant effect and restoration of monoaminergic function, especially enhancing5-HT levels, may underlie the anti-depressant effects of XCHT. To validate the neurotransmitter mechanisms of XCHT, the levels of5-hydroxytryptamine (5-HT), dopamine (DA),5-hydroxyindoleacetic acid (5-HIAA) and 3,4-Dihydroxyphenylacetic Acid (DOPAC) in animal depression related brain regions in behavioral despair test were measured using HPLC-ECD. Moreover, the extracellular Y-aminobutyric acid (GABA) and glutamic acid (Glu) in rat hippocampus were assessed by using microdialysis coupled to HPLC-FLD. Results showed that XCHT increased5-HT and DA levels in prefrontal cortex, hippocampus and striatum in mice and rats, decreased Glu level in rat hippocampus and decreased5-HT/5-HIAA and DA/DOPAC in these regions, indicating that the antidepressant effect of XCHT in the behavioral despair models is related to maintaining the brain neurotransmitter homeostasis.In the present study we investigated the antidepressant-like effect of XCHT in a CUMS model in rats, and evaluated the neurotrophic mechanism of action of XCHT by examining the expression of BDNF、NGF and their receptors TrkB and TrkA in the hippocampus. Results showed that XCHT significantly suppressed the CUMS induced reductions of sucrose preference, general activity and food consumption, suggesting that XCHT has a therapeutic effect on the depression behavior in the rat model. Moreover, we found tha CUMS exposure reduces NeuN,BDNF,HGF and their receptors expression in the hippocampus, while XCHT significantly reverses the CUMS-induced changes in these protein, and XCHT activated the downstream PI3K/Akt/CREB pathway of TrkB and TrkA. These results suggest that the antidepressant effect of XCHT is related to the regulation of neurotrophic factor, activation of neurotrophic factor receptor downstream pathways and protection of neuronal function.Finally, C57BL/6mice were isolated immediately after weaning to establish a social isolation model in the present study, and the antidepressant effect of XCHT and its regulation effects on estradiol and progesterone were investigated. The results found that XCHT can significantly reversed isolation induced despair and aggressive behaviors, and also significantly decreased the isolation induced upregulation of spontaneous activity of mice. XCHT significantly increased the levels of estradiol and progesterone in isolated mouse brain and significantly activated ERK and CREB proteins in the downstream pathways of estradiol and progesterone receptors, indicating that the antidepressant effect of XCHT in the isolation induced depression model in mice may be associated with the regulation of estradiol and progesterone levels and there downstream pathways in brain.In conclusion, the present study found that XCHT had protective effect in depression models caused by a variety of factors. The mechanism may be associated to maintenance of neurotransmitter homeostasis, enhancing the neurotrophy, regulating of female hormones and their downstream signaling pathways, and neuroprotection. The present paper revealed the antidepressant mechanism of XCHT, laid a foundation for further studies to clarify the target of its antidepressant effect and supplied a scientific basis for development of new TCM prescriptions based on XCHT for antidepressant.