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Diabetes 52:1683-1688, 2003
© 2003 by the American Diabetes Association, Inc.

Poly (ADP-Ribose) Polymerase Inhibition Prevents Spontaneous and Recurrent Autoimmune Diabetes in NOD Mice by Inducing Apoptosis of Islet-Infiltrating Leukocytes

Wilma L. Suarez-Pinzon1, Jon G. Mabley2, Robert Power3, Csaba Szabó2, and Alex Rabinovitch1

1 Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
2 Inotek Pharmaceuticals Corporation, Beverly, Massachusetts
3 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada

Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. The PARP inhibitor nicotinamide prevents NAD consumption and protects islet ß-cells from chemically induced necrosis but not cytokine-induced apoptosis. Therefore, it is unclear how nicotinamide protects NOD mice from autoimmune diabetes in which apoptosis is the mode of ß-cell death. To investigate the mechanism of diabetes prevention by PARP inhibition, we studied the effects of a novel, potent PARP inhibitor, PJ34, a phenanthridinone derivative, on diabetes development in NOD mice and on diabetes recurrence in diabetic NOD mice transplanted with syngeneic islets. PJ34 administration from age 5 or 15 weeks significantly decreased insulitis, ß-cell destruction and diabetes incidence, and protection from diabetes continued for 12 weeks after PJ34 therapy was stopped. Similarly, syngeneic islet graft survival was prolonged and outlasted therapy in PJ34-treated mice. Immunohistochemical studies revealed significantly fewer leukocytes in islet grafts of PJ34-treated mice, together with increased apoptosis of these cells and decreased expression of the T helper 1-type cytokine interferon (IFN)-{gamma}. These results suggest that PARP inhibition protects against autoimmune ß-cell destruction in NOD mice by inducing apoptosis of islet-infiltrating leukocytes and decreasing IFN-{gamma} expression in the islets.

Address correspondence and reprint requests to Alex Rabinovitch, 430 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2. E-mail: alex.rabinovitch{at}ualberta.ca


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Copyright © 2003 by the American Diabetes Association.