Therapeutic effects of a novel PARP-1 inhibitor, JPI-289, in models of acute ischemic stroke

Abstract

Excessive activation of Poly (ADP-ribose) polymerase-1 (PARP-1) after ischemic stroke is known to develop neuronal apoptosis, necrosis and inflammation. The present study investigated in vitro and in vivo neuroprotective effects of a novel PARP-1 inhibitor, JPI-289. The inhibitor strongly inhibited PARP-1 activity (IC50 = 18.5 nM) and cellular PAR level (IC50 = 10.7 nM). In rat cortical neuronal cells, JPI-289 did not affect cell viability up to 1 mM as shown in trypan blue staining (TBS) and lactate dehydrogenase (LDH) assays. In oxygen glucose deprived (OGD) rat cortical neuron, treatment of JPI-289 attenuated PARP activity and restored ATP and NAD+ levels. JPI-289 treatment in the OGD model showed decrement of apoptosis-associated molecules including apoptosis-inducing factor (AIF), cytochrome-C and cleaved caspase-3. After the evaluation of JPI-289 in vitro model, we investigated the neuroprotective effects of JPI-289 in rat permanent and transient stroke models. In transient middle cerebral artery occlusion (MCAO) model in rats, JPI-289 treatment showed significant reduction of infarcted area of brain, which was maximal at the dose of 10 mg/kg up to 36% reduction. The therapeutic time window was 8 hours for reduction of ischemic volume up to 29%. Moreover, number of apoptotic cells decreased by 56% compared to control. When model was twitched to permanent MCAO model in rats, JPI-289 treatment significantly reduced infarcted volume up to 20% at the dose of 40 mg/kg, and improved behavioral socre. Along with stable and safe data of novel PARP-1 inhibitor, JPI-289 on pharmacokinetics and toxicology, its effectiveness on ischemic stroke models and modes of action mechanisms suggest that JPI-289 could be a potential therapeutic agent for the treatment of acute ischemic stroke.