| Anxiety disorder is a common mental illness. With the growing social pressure, incidence of this disease has been rising gradually. Anxiety is characteristed by momentary or persistent anxiety and tension, the pathology of which is still not completely clear. Traditional Chinese Medicine (TCM) contribute the pathogenesis of anxiety to emotional disease.Compound Ma Ti Xiang (CMTX) is originated from a clinical experiential prescription, which consists of Valerianae Jatamansi Rhizoma et Radix, Albizia Cortex, Ziziphi Spinosae Semen Tostum and Junci Medulla.lt can regulating qi and relieving depression, nourishing blood for tranquillization.To endeavor to obtain a new drug candidate of Chinese medicine with low toxicity and anxiolytic effects and provide basic data for eventual clinical trials, an intensive research on CMTX, including preliminary pharmacodynamics study neural mechanisms and primary evaluation of safety was carried out. The archieved results are as follow:1 Pharmacological and toxicological researches1.1 Pharmacological researchAccording to the results of the elevate plus maze test (EPM) in rat, CMTX III groups (3 g/kg/d) could significantly increase the open entries percent and open time percent, the result of EPM in rats verified that CMTX had a stable anxiolytic effect without increasing the activity of the animals. The results of the Vogel's conflict test suggested that CMTX I-III groups (0.75g/kg/d,1.5g/kg/d,3g/kg/d) significantly increased the number of licks during the punished period comparing with the control group (P<0.05). In pentylenetetrazol (PTZ) discrimination test, CMTX II, III groups could significantly decrease the right PTZ discrimination rate, and the anxiolytic effect was dose and time dependent. Results obtained in the open-field test showed that CMTX, chronically administered, did not promote any distance or emotional (rearing, grooming and defecation) changes of the rat. Animals subjected to restraint showed an excessive anxiety in the EPM, since they exhibited a reduction in the percentage of time spent and entries on open arms. However, CMTX could prevent the emergence of stress-induced excessive anxiety.1.2 Acute toxicity studyPreliminary experiment showed that the maximally tolerated dose of CMTX was 44g/kg, which was 100 times as of the clinical dose. The result suggested that CMTX capsule is safe.2 Mechanism studies2.1 Effects of CMTX on the GABA pathway by stress exposureIn the GABAA-BZD binding assay, CMTX was able to displace 3H-Ro 15-1788 to brain synaptosomal membranes, denoting that CMTX showed an effective concentration-dependent binding activity, suggesting a central BDZ-like activity.RT-PCR was used to analyze the effects of CMTX on al-GABAA,a2-GABAA and a3-GABAA receptor mRNA expression in hippocampus of after 3 days acute stress. The result indicated that a2-GABAA andα3-GABAA receptor mRNA expression level could be increased by CMTX.2.2 Effects of CMTX on the Cdk5/p35 pathway by stress exposureOur results revealed that the development of anxiety-like behaviors were associated with increased Cdk5 activity. Moreover, treatment with CMTX not only prevented the excessive anxiety but also attenuated the Cdk5 and p35 in the hippocampus of stressed rats. Yet CMTX had little effect on the p39. Thus, Cdk5 could be a novel target for therapeutic treatment of anxiety. Besides, enhanced Cdk5/p35 activity can activate glutamic acid and reduce GAB A expression. In agreement, our results showed that CMTX influenced both the GABA expression and activity of Cdk5/p35 in the hippocampus of stressed rats. Hence, the anxiolytic effect of CMTX may also be due to the interaction with Cdk5/p35 and GABA. Future experiments are necessary to evaluate this possibility.2.3 Effects of CMTX on the monoamines by stress exposureThe enzyme-linked immunosorbent assay (ELISA) method was used to analyze the effects on the monoamines. CMTX had the obvious effect in decreasing the content of 5-HT and NA in hippocampus and cortex, however there was no significant difference regarding to the content of DA between groups.2.4 Effects of CMTX on the immune factors by stress exposureIn the present study, previously restrained animals increased the levels of IL-ip> TNF-cu IL-6.CMTX can adjust immune function under anxiety state via decreasing the plasma content of IL-1βTNF-α,IL-6 by using ELISA method.Conclusions:These results suggest that CMTX treatment stable anxiolytic effect, possibly via increasingα2-GABAA andα3-GABAA receptor mRNA expression level; influencing Cdk5/p35 activity; reducing the content of 5-HT or NE and adjusting immune function. |
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