Abstract

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD+) by poly(ADP-ribose) polymerase (PARP) and mainly degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD+/ATP, which leads to cell death. We showed before that PARP inhibitors such as GPI 6150, which was insoluble in water and administered i.p, provided beneficial effects in numerous animal models of diseases. Now we synthesized water-soluble PARP inhibitors, which were not only more potent but also achieved high concentrations in brain, heart and plasma after i.v. administration. We found that iv dosing of the water-soluble PARP inhibitors, e.g. GPI 15427, were efficacious in rodent models of cerebral ischemia, heart ischemia, chemotherapy of tumors, liver transplantation and cardiac arrest. In addition, we investigated whether PARG inhibition could achieve similar protection as an alternative target for the poly(ADP-ribose) cycle. We identified a novel PARG inhibitor, GPI 16552, and demonstrated that either pre- or post-ischemia treatment with the compound significantly reduced brain infarct volumes in a rat model of focal cerebral ischemia. Our result provided the first evidence that PARG inhibitors could ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.

Keywords: Cell Death, Ischemia, neuroprotection, cardioprotection, chemotherapy