Nitric oxide as a target for dietary intervention in colitis

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DESCRIPTION (provided by applicant): Current medical interventions for colitis consist of application of anti-inflammatory and/or immunosuppressive agents, each complicated by the development of undesirable side effects. Despite treatment options, for many patients disease remains refractory with episodic periods of remission. Clearly, novel therapeutic strategies are needed to lessen the impact and sequelae of colitis. Use of alternative medicine is common in the United States and 40% of colitis suffers currently use dietary supplements. However, the scientific evidence for the use of alternative medicines is often lacking or weak, and potentially beneficial mechanisms of action have not rigorously been assessed. Overproduction of nitric oxide by inducible nitric oxide synthase (iNOS) has been proposed as a pathogenic factor in colitis. Here, we postulate that two antioxidant herbal supplements, Ginkgo biloba and American ginseng (Panax quinquefolis), will inhibit colitis through the inhibition of nitric oxide synthase, inhibiting subsequent nitric oxide production, and thus modulate nitric oxide-induced DNA damage. Although published studies have shown ginkgo and ginseng both inhibit nitric oxide production in various cell types, their effects in human colorectal cells have not been studied. An objective of this project is to determine the effects and mechanisms by which ginkgo and ginseng modulate nitric oxide production and nitric oxide induced DNA damage in human colon cancer cells. We will also determine whether ginkgo or ginseng reduce colitis and examine whether this is a nitric oxide- mediated event by using iNOS-/- and iNOS+/+ mice with induced colitis. In addition to pathology to examine the extent of colitis, we will extend in vitro findings by examining the effects of ginkgo and ginseng on inflammation-driven DNA damage. Because pRb hyperphosphorylation is associated with carcinogenesis and it is hyperphosphorylated in colitis, we will examine the effects of ginkgo and ginseng on pRb hyperphosphorylation. These studies should provide strong pre-clinical evidence for the potential use of ginkgo and ginseng in the amelioration of experimental colitis through defined molecular pathways. The overall goal of this application is to provide the public some assurance that the dietary supplements gingko and ginseng, have the capacity to alleviate colitis.