The Preventive And Therapeutic Effects Of Curcumin On Inflammation And Visceral Hyperalgesia In Rat Model Of Ulcerative Colitis

Background: The clinical symptoms such as abdominal discomfort and pain are usually present in patients with inflammatory bowel disease(IBD)and limit the quality of life.IBD are not medically curable,however,the inhibition of inflammation and blockage of pain signaling transduction may be required for the treatment of IBD-associated pain.It is well known that the interactions between inflammation and transient receptor potential vanilloid 1(TRPV1)plays an important role in the development of chronic visceral pain,and also 5-hydroxytryptamine(5-HT)plays a key role in gastrointestinal inflammation.Curcumin is polyphenols which has multiple target effects including anti-inflammatory and anti-nociceptive effects.The current study investigated the preventive and therapeutic effects of curcumin on inflammation and visceral hyperalgesia induced by ulcerative colitis,and further explored the roles of 5-HT and TRPV1 in the effects induced by curcumin.Method: Ulcerative colitis(UC)was induced by 5% dextran sulfate sodium(DSS)in drinking water provided to Sprague-Dawly(SD)rats for continuous 7 days.The oral administrations of curcumin(60mg/kg)were started at 1 day and at 4 day since the establishment of UC model(once a day for 10 days)for preventive and therapeutic treatments,respectively.The anti-inflammatory effects of curcumin were assessed by disease activities index(DAI)score and colonic pathological score.The analgesic effects of curcumin was assessed by abdominal withdrawal reflex(AWR)score.The effects of curcumin on expression of tryptophan hydroxylase(TPH),the rate-limiting enzyme for 5-HTsynthesis,TRPV1 and phosphorylated TRPV1(pTRPV1)were examined by western blot.The effect of curcumin on TRPV1 function was examined by patch clamp technique in HEK293 cells steadily transfected with human TRPV1.The effects of curcumin with or without protein kinase c activator PMA on the expression of membrane TRPV1(mTRPV1)was detected by western blotting in hTRPV1-transfected HEK293 cells.Results: We found that 1)DSS-induced histopathological change in colon defined as UC and increase in DAI score,AWR score,the number of 5-HT-immunoreactive cells,the protein level of either TRPV1 or TPH of colon tissue;2)compared with control group,preventive treatments with curcumin significantly inhibited pathological score,DAI score,AWR score and pTRPV1 protein level of inflamed colon tissue,while curcumin did not altered the protein level in TRPV1 and TPH;3)compared with control group,therapeutic treatments with curcumin obviously attenuated AWR score,protein level of either TRPV1,pTRPV1 or TPH of inflamed colon tissue,while curcumin did not affect the DAI and pathological scores;4)in HEK293 cells steadily transfected with hTRPV1,curcumin dose-dependently inhibited capsaicin-induced inward currents.Curcumin(10mm)significantly reduced the expression of mTRPV1 and curcumin(1,3 mm)also inhibited PMA-induced up-regulation of mTRPV1 in HEK293 cells.Conclusion: Both preventive and therapeutic treatments with curcumin alleviate visceral hyperalgesia and reduce the expression of pTRPV1 of inflamed colon tissue.In addition,curcumin inhibited membrane translocation of TRPV1 promoted by phosphorylation of TRPV1.These findings suggest that the inhibition of pTRPV1 by curcumin contributes to the analgesic effect of curcumin in rat model of UC.Furthermore,preventive instead of therapeutic treatment with curcumin suppresses the inflammatory responses.On the contrary,therapeutic rather than preventive treatment with curcumin reduces the expression of TPH.These findings indicate that anti-inflammatory effect of curcumin is independent of inhibition of 5-HT synthesis.This study may provide potential strategy for inflammatory bowel disease.