Inflammation is an essential component of host defense, however seriously debilitating situations can occur when this process is inappropriately activated. Inflammatory bowel disease (IBD) and rheumatoid arthritis are both examples of debilitating inflammatory disease. IBD, an umbrella term for the two distinct and chronic conditions ulcerative colitis and Crohn’s disease, afflicts over 1.5 million individuals in the major pharmaceutical markets. Currently in excess of $0.5 billion, IBD related sales have been forcasted to increase by 3-10% each year between now and 2008 as more effective anti-inflammatories are identified. When the inflammatory process is excessively activated the consequences can be life threatening. This is well exemplified by sepsis, which occurs in 1-2% of hospital admissions and is secondary to the systemic appearance of bacterial toxins including lipopolysaccaride (LPS). The frequent progression of sepsis to septic shock results in hypotension and inadequate tissue perfusion. Septic shock carries a 45% risk of mortality making it the most common cause of death in intensive care units. Consequently over 30 pharmaceutical products are in development for this condition although Lilly's drotrecogin, is the only one to have reached the market. Since the discovery of the vanilloid VR1 receptor, pharmaceutical interest in the well-recognized analgesic properties of capsaicin and other VR1 receptor ligands has growth dramatically. A less well investigated aspect of capsaicin is its anti-inflammatory activity. Capsiate and its dihydroderivatives are new capsaicinoids distinct from capsaicin both with respect to structure and their inability to activate the VR1 receptor. The two families do however share some biological activities mediated in a VR1-independent fashion. Spanish researchers have now shown that capsiate and nordihydrocapsiate inhibit early and late events in T cell activation, including CD69, CD25 and ICAM-1 cell surface expression, progression to the S phase of the cell cycle and proliferation in response to TCR and CD28 co-engagement. Moreover, both capsiate and nordihydrocapsiate inhibit NF-kappaB activation in response to different agents including TNF-alpha. Capsiate itself does not affect the DNA-binding ability of NF-kappaB but it prevents IkappaB kinase activation and IkappaBalpha degradation in a dose-dependent manner, without inhibiting the activation of the mitogen-activated protein kinases, p38, extracellular regulated kinase and c-Jun N-terminal protein kinase. Moreover, intraperitoneal pretreatment with capsiate prevented mice from lethal septic shock induced by lipopolysaccharide. Capsiate pretreatment also reduced inflammation in mice with experimental IBD. Taken together, these results suggest that capsiate and related synthetic analogues target specific pathways involved in inflammation, and may offer leads for pharmaceutical development.

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