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6.28.8.2.5 Poly(ADP-ribose) polymerase inhibitors

Poly(ADP-ribose) polymerase (PARP-1 and PARP-2) plays an essential role in the cellular response to genotoxic stress, facilitating DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Under conditions of oxidative stress and inflammation, PARP becomes overactivated and consumes NAD+ and ATP, culminating in cell dysfunction and necrosis. The potential contribution of the PARP family to IBD is emphasized by a number of observations. When administered to the IL10_'_ mouse, ISIS 110251 (25mgkg_ 1 subcutaneously), a modified 2'-O-(2-methoxy) ethyl antisense oligonucleotide inhibitor of PARP-2 (CTT-TTG-CTTTGT-TGA-GGT-CA) normalized colonic epithelial barrier and transport function, reduced pro-inflammatory cytokine secretion and inducible nitrous oxide synthase (iNOS) activity, and attenuated inflammation.74 In contrast, PARP-1 _'_ mice exhibit a reduced tendency to inflammation and colon damage in the TNBS-induced model of colitis. GP-1650 (25) (Ki = 60 nM), one of the founding members and most extensively studied of the isoquinoline series of nicotinamide mimetic PARP-1 inhibitors, significantly reduced the inflammatory response to rectal 4,6-dinitrobenzene sulfonic (DNBS) acid (40 mgkg_ 1 day _ 1, intraperitoneally).76 Several other classes of PARP inhibitors have emerged with improved potency and solubility, among them AG14361 (26) (Ki<5nM) that is effective at sensitizing cancer cells to cytotoxicity induced by chemotherapeutics,77 but few studies have investigated the wider utility of these chemotypes in inflammatory models.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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