Update to Medicinal Chemistry of Nicotinamide in the Treatment of Ischemia and Reperfusion

Abstract

Nicotinamide and its analogs are currently being used or investigated for the treatment of ischemia reperfusion conditions. Nicorandil has been investigated for use in cardiac ischemia and reperfusion and is approved for use in Europe and Japan in angina. Nicotinamide has been extensively investigated in animal models of stroke, including middle cerebral artery occlusion and spontaneously hypertensive rats. Dose response curves and time response curves have been produced for nicotinamide in these models. Nicotinamide spares ATP by increasing NAD levels and protecting DNA from fragmentation. Inhibitors of poly(ADP-ribo se) polymerase, including nicotinamide, have been investigated in ischemia reperfusion conditions in other organs such as the testicles and liver. New evidence suggests that nicotinamide may have other mechanisms of action involving the regulation of cellular processes. allergic encephalomyelitis (4). PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor kappa B-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Therefore, PARP inhibitors, such as nicotinamide may prove useful for the therapy of these diseases. Most of its effects have been shown in preclinical animal disease models.