Poly (ADP-ribose) polymerase inhibition prevents spontaneous and recurrent autoimmune diabetes in NOD mice by inducing apoptosis of islet-infiltrating leukocytes.
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 beta-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 beta-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, beta-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 beta-cell destruction in NOD mice by inducing apoptosis of islet-infiltrating leukocytes and decreasing IFN-gamma expression in the islets.
Suarez-Pinzon
Wilma L
WL
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Mabley
Jon G
JG
Power
Robert
R
Szabó
Csaba
C
Rabinovitch
Alex
A
D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D009536:Niacinamide / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger / Q000235:genetics; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014185:Transplantation, Isogeneic
D004791:Enzyme Inhibitors; D007378:Interleukins; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D009536:Niacinamide; D007371:Interferon-gamma