| Objective: To establish rat and mouse models of acute gouty arthritis,to comprehensively evaluate the efficacy and side effects of basic and modified gout prescriptions,and to further evaluate the dose-response relationship of treatment efficacy and analgesic mechanism of the most promising modified gout prescription,in order to provide a new treatment option.Method:(1)The SD rat and KM mouse models of acute gouty arthritis were established using gavaged hypoxanthine,subcutaneously injected potassium oxonate and ankle injected improved sodium urate.(2)After model establishment,the rats were divided into 3 treatment groups: basic prescription of traditional Chinese medicine,improved prescription of traditional Chinese medicine and the combined improved prescription of Chinese and Western medicine.The efficacy of the different treatments were assessed using right ankle joint circumference,gait score,joint pain scores of flexion and extension,daily diet,daily drinking,body weight,stomach pathology,and visceral index.(3)Compared to the 2 other treatments,the improved prescription of traditional Chinese medicine was comparably effective and had fewer side effects.Thus,it was further studied using low-dose,medium-dose and high-dose the mouse model groups.The efficacy of different doses was assessed using right ankle joint circumference,ankle circumference difference,gait score,joint pain scores of flexion and extension,daily diet,daily drinking,body weight,stomach pathology,and visceral index.(4)To explore the therapeutic effects and analgesic mechanisms of the improved prescription of traditional Chinese medicine in the mice,ELISA was used to measure mice serum uric acid(UA),serum substance P(SP),cyclooxygenase-2(COX-2)and heat shock protein 70(HSP70)at different times.Results: 1.Comparison of the efficacy of the 3 treatments in the rat model:(1)At 8h,ankle circumference and joint flexion and extension pain scores were significantly different between each of the 4 model groups and the control group(P < 0.05),suggesting the successful establishment of acute gouty arthritis in the model groups.(2)At administration 1.5d,only the basic and the improved prescription of traditional Chinese medicine relieved joint swelling significantly more than did no treatment(P < 0.05),suggesting that both are more effective treatments for relieving joint swelling than the combined improved prescription of Chinese and Western medicine;At administration 2.5d,only the combined improvement prescription of Chinese and Western medicine relieved gait score significantly more than did no treatment(P < 0.05).At administration 3.5d,only the improved prescription of traditional Chinese medicine relieved gait score significantly more than did no treatment(P < 0.05).This suggests that the combined improvement prescription of Chinese and Western medicine is a more effective treatment for improving joint gait than the improved prescription of traditional Chinese medicine,which is better than the basic prescription of traditional Chinese medicine;At administration 1d,1.5d,2.5d and 3.5d,the improved prescription of traditional Chinese medicine and the combined improved prescription of Chinese and Western medicine relieved joint pain scores of flexion and extension significantly more than did no treatment(P < 0.05),suggesting that both are more effective treatments for relieving joint pain scores of flexion and extension than the basic prescription of traditional Chinese medicine.(3)Regarding side effects,compared to the control group,the combined improved prescription of Chinese and Western medicine significantly reduced the daily diet of rats(P < 0.05)at administration 2.5d and 3.5d and significantly reduced the daily drinking of rats(P < 0.05)at administration 1.5d-7.5d.At experiment 8d,that treatment had a significantly worse side effect on liver index(P < 0.05),And the stomach gross specimen showed vascular dilatation and congestion on the outside and mucosal edema on the inside.This all suggesting that the side effects of the combined improved prescription of Chinese and Western medicine are much more serious than the other 2 treatments.2.Comparison of the efficacy of different doses(low,medium and high)in the mice model of the improved prescription of traditional Chinese medicine,the most promising gout treatment based on the aforementioned results:(1)Joint pain scores of flexion and extension at 12 h and right ankle circumference and gait scores at 24 h were significantly different between each of the 4 model groups and the control group(P < 0.05),suggesting the successful establishment of acute gouty arthritis in the model groups.(2)Only the high-dose group was not significantly different from the control group in terms of articular circumference-difference at administration 24 h,had significantly relieved joint pain scores of flexion and extension than the model group at administration 24h(P < 0.05),and had significantly relieved articular gait score than the model group at admistration 1.5d(P < 0.05),suggesting that the improved prescription of traditional Chinese medicine had a dose effect relationship.(3)The only time a dose group significantly affected daily diet weight compared to the control group was high-dose at experiment 3d(P < 0.05).The only instance of the treatment affecting stomach gross pathology was one mouse in the high-dose group had slight vasodilation.Visceral index did not significant vary within any of the dose groups(P > 0.05).This all suggests that the improved prescription of traditional Chinese medicine had essentially no side effect on the mice.3.Uric acid and the analgesic mechanism of the improved prescription of traditional Chinese medicine: At experiment 1d and 2d,uric acid levels in each of the 4 model group were significantly different compare with the control group(P < 0.05),suggesting the successful establishment of a hyperuricemia mice model.At administration 2.5d,medium-dose and high-dose groups significantly reduced uric acid levels compared to the model group(P < 0.05);At administration 1.5d,each dose group significantly reduced the serum cyclooxygenase-2(COX-2)level compared to the model group(P < 0.05),and the high-dose group continued to do so until experiment 7d,while the medium-dose group continued to do so until experiment 5d;At administration 4.5d,each dose group significantly reduced the serum substance P(SP)level compared to the model group(P < 0.05).This suggests that the improved prescription of traditional Chinese medicine could rapidly reduce the level of uric acid,has an analgesic effect by inhibiting serum substance P(SP)and cyclooxygenase-2(COX-2).Conclusion:(1)Combining gavaged hypoxanthine,subcutaneously injected potassium oxonate and ankle injected improved sodium urate could successfully establish rat and mouse models of acute gouty arthritis.(2)The basic prescription of traditional Chinese medicine,the improved prescription of traditional Chinese medicine and the combined improved prescription of Chinese and Western medicine all alleviated rats' articular circumference,gait score and pain score of flexion and extension.The improved prescription of traditional Chinese medicine and the combined improved prescription of Chinese and Western medicine had comparable effects,and both were superior to the basic prescription of traditional Chinese medicine.Because the combined improved prescription of Chinese and Western medicine had some side effects on rats' daily diet,drinking,liver index and stomach pathologic specimens,the improved prescription of traditional Chinese medicine was better overall.(3)Each dose group of the improved prescription of traditional Chinese medicine was effective at relieving ankle circumference-difference,gait score and joint pain scores of flexion and extension;and its efficacy had a dose-response relationship,and there were no significant injury of side effects.(4)Furthermore,that treatment could alleviate the pain caused by acute gouty arthritis,and its efficacy had a dose-response relationship.Its analgesic mechanism was through reducing the serum uric acid levels to achieve its treatment effects,reducing the release of pain factors such as prostacyclin by inhibiting the synthesis of COX-2 and reducing the nerve impulse conduction of pain by inhibiting serum substance P. |
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