| Inflammatory bowel disease (IBD), consisting of ulcerative colitis (UC) andCrohn’s disease (CD), has been classified as refractory disease by the World HealthOrganization. The prevalence and incidence of IBD are increasing at a disturbing rate.The pathogenesis of IBD is not still completely clear. The possible pathogenesisinvolved in infection, heredity, psychology and immunity, of which the disturbance ofimmunomodulation plays a key role. So far, the ideal drug for IBD has not been found.Existing treatment means mainly include resection and relief medication, such as5-aminosalicylic acid, corticosteroids, immunomodulating drugs and biological agents,represented by tumor necrosis factor-alpha (TNF-α) blockers. However, sometimesthere are various adverse effects, drug resistance and drug tolerance existing in theadministration of these drugs. For example, new-type TNF-α blockers are expensiveand not effective to a large propotion of patients who are resistant to traditionalremedities. More innovative and effective drugs are heavily in need.Due to less side effects and good safety, herbal products have been highlyregarded on novel agent research. Hydroxynaphthoquinones extracted from Zicao, atraditional Chinese herbal medicine, have been identified as the main activeanti-inflammation ingredients. It mainly contains alkannin and shikonin as well astheir derivatives. Recent pharmacological studies have demonstrated thathydroxynaphthoquinones possess favourable biological activities such asanti-inflammation, wound healing, anti-ulcer and immunoregulatory activity. Inaddition, they can inhibit the transcriptional activation of TNF-α and reduce theproduction of inflammatory mediators. However, no reports have demonstrated theeffect of hydroxynaphthoquinones on inflammatory intestinal diseases.We isolated a hydroxynaphthoquione mixture (HM) from Zicao, which mainlyconsisted of seven alkannin derivatives. We have confirmed that HM could prevent and cure experimental arthritis, attenuate pathological intestinal changes inTNBS-induced colitis, reduce TNF-α level in serum and colonic tissues of rat modelsof inflammatory disease. Thus, the present study provided more evidences suggestingthe therapeutic effect of HM on IBD mice model induced by dextran sulfate sodium(DSS), and explored its underlying mechanisms.The results revealed that administration of3.5%DSS for6days successfullyinduced colitis, associated with similarities to human UC. Meanwhile, mice wereorally administered HM3.5,7and14mg/kg and mesalazine200mg/kg per day for7days. Administration of HM effectively attenuated the severity of colonic mucosainjury, relieved body weight loss of mice, and reduced DAI score and inhibited thedecrease in colon length. For histopathological analysis, treatment with HM improvedhistological alterations and lowered pathological score as compared with DSS onlygroup. This manifested as a reduction in the extent of colon injury and inflammatorycell infiltrations, as well as the degree of mucosal destruction. In addition, HMmarkedly decreased MPO activity in colonic tissue and serum TNF-α level, thedifferences between HM7-and14mg/kg-treated groups and DSS only group arestatistically significant (P<0.05). Furthermore, HM effectively down-regulated theexpression of TNF-αã€p-IκBα in colonic tissue and NF-κB p65in the nucleus whileup-regulating IκBα protein expression in colonic tissue. These results suggest that thesignificant anti-inflammatory effect of HM may attribute to its inhibition of TNF-αexpression and NF-κB activation.In summary, HM has a favourable therapeutic effect on DSS-inducedexperimental colitis. It effectively helped animals have better clinical signs and lighterhistological damage, decreased MPO activity and cytokine TNF-α level. The resultssuggest that the mechanism of HM protection against colitis could be the inhibition ofTNF-α expression and NF-κB activation. These novel findings provide thepharmacological foundations for the application of HM in the treatment of IBD. |
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