Medical researchers have made considerable efforts to establish a genetic linkage between Crohn's disease and the NOD2 protein associated with programmed cell death and activation of NF- B, a transcription factor involved in the production of cytokines and chemokines necessary for inflammation.
Regulation of NF- B function has been documented by several agents used in the management of IBD, such as corticosteroids, sulfasalazine, and 5-aminosalicylates (5-ASA). Furthermore, antisense oligonucleotides directed against the p65 subunit (a polypeptide contributing to the activation of NF- B) have been shown to diminish disease activity in an animal model of colitis. Recent work has shown that dietary constituents such as curcumin may also potently inhibit NF- B and diminish attenuate proinflammatory molecule expression. Curcumin is a component of the spice turmeric (Curcuma longa) used in curries and mustard, whose anti-inflammatory properties have been recognized for years. These effects are related, in part, to inhibition of the activities of the cyclooxygenase, lipoxygenase, and NF- B in several cell systems. Furthermore, its role in the attenuation of colonic cancer in animal models has also been established.
Management of IBD involves the use of 5-ASA and immunosuppressives such as corticosteroids and 6-mercaptopurine as well as its precursor azathioprine. Novel agents such as monoclonal antibodies against TNF- have been developed and demonstrate clinical efficacy. However, these agents are expensive and not without side effects. Consequently, there is a need for alternative agents that may be equally or more effective as well as being cheaper. Both curcumin and sulfasalazine target IKK molecules; the importance of inhibition of I?B Kinase complex by curcumin has never been tested in IBD. Here researchers show that this compound has beneficial effects in a rat model of IBD, opening the door to possible future human studies.
A New Study
The new study now provides the first evaluation of curcumin and its effects on NF- B in an experimental model of IBD. The authors of "Curcumin Attenuates DNB-Induced Murine Colitis" are B. Salh, K. Assi, K. Parhar, D. Owen, and A. Gómez-Muñoz, at the Jack Bell Research Centre at the Vancouver General Hospital, and V. Templeman and K. Jacobson of the Department of Pediatric Gastroenterology, Children and Women's Hospital, all in Vancouver, British Columbia, Canada. Their findings appear in the July 2003 edition of the American Journal of Physiology––Gastrointestinal and Liver Physiology. The journal is one of 14 published each month by the American Physiological Society (APS) (www.the-aps.org).
Methodology
The researches used the dinitrobenzene sulfuric acid (DNB) murine model of colitis, which has been previously validated. Seven-week-old C3H mice had inflammation induced with instillation of 100 µl of DNB (60 mg/ml) in 50% ethanol with control animals receiving 100 µl of 50% ethanol alone. After this, they were kept in position for 30 seconds before being returned to their cages. On day 5, post-induction was conducted for evaluation of the colitis. Test groups of five mice had curcumin added to their diet at a concentration of 0.25% beginning five days before the DNB instillation.
Several parameters were determined in the inflamed mucosa. These comprised evaluation of macroscopic damage scores, histological evaluation of inflammation by hematoxylin and eosin staining, processing of tissue for Western analysis, and extraction of RNA for RT-PCR analysis.
Results This animal study produced several key findings:
- Curcumin attenuates macroscopic damage in murine colitis. Animals were weighed daily after induction of colitis and the data shown are representative of all experiments. There was a clear reduction in the amount of weight loss in the animals pretreated with curcumin.
- Curcumin improves intestinal cell function in DNB-induced colitis. After treatment of animals, colons were harvested and histological evaluation was carried out after staining with hematoxylin and eosin. There was mucosal ulceration, thickening of the wall, and significant infiltration with inflammatory cells in the DNB-treated animals that is reduced in those animals pretreated with curcumin.
- When animals were pretreated with curcumin, there was a clear reduction in DNA binding, thus verifying that curcumin does indeed inhibit NF- B activation in the colon in vivo. These findings indicate for the first time that curcumin is able to impact on an important transcriptional mechanism in the gastrointestinal tract.
- Curcumin attenuates activation of p38 MAPK antibodies.
Conclusions
This research is the first evaluation of curcumin and its effects on the MAPKs and NF- B in an experimental model of IBD. In addition to the demonstration that it is able to diminish inflammatory activity in IBD, the Canadian team demonstrated it can reduce NF- B DNA binding activity as well as inhibiting the activation of p38 MAPK antibodies and that the anti-inflammatory effects of curcumin involve a reduction in myeloperoxidase activity, a reduction in the number of infiltrating neutrophils, as well as a reduced expression of the message for IL-1.
Precisely how curcumin achieves its effects is not clear. It has been shown to possess free radical scavenging (antioxidant) properties in addition to its known effects on the activation of NF- B. Its in vivo effects may well rely on a complementation of these two and other activities.
Although curcumin has been shown to be safe up to levels as high as 10 percent (100,000 ppm), the researchers showed effectiveness at a concentration as low as 0.25 percent. This dose was well tolerated with no reduction in dietary intake. Further work will help to clarify the optimal dose for this and other models of IBD.
This research proves that curcumin may prove to be a cheap, well-tolerated, and effective therapy for inflammatory bowel disease. This food ingredient has for generations been regarded as a potent anti-inflammatory within many eastern civilizations. It is equally intriguing that the same agent is a potent antineoplastic agent. It may hold promise for the treatment of IBD in humans.
Source: July 2003 edition of the American Journal of Physiology––Gastrointestinal and Liver Physiology.
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.