Neuroprotective effects of a novel poly (ADP‐ribose) polymerase‐1 inhibitor, JPI‐289, in hypoxic rat cortical neurons

• Published in: Clinical and experimental pharmacology & physiology Vol. 44; no. 6; pp. 671 - 679
• Main Authors: Kim, Youngchul, Kim, Young S., Noh, Min‐Young, Lee, Hanchang, Joe, Boyoung, Kim, Hyun Y., Kim, Jeongmin, Kim, Seung H., Park, Jiseon
• Format: Journal Article
• Language: English
• Published: Australia Wiley Subscription Services, Inc 01-06-2017
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing factor; Bioavailability; Brain - cytology; Brain - drug effects; Brain injury; Caspase-3; Cell Hypoxia - drug effects; Cell Survival - drug effects; cerebral ischaemia; Cytochrome c; Cytochromes; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Head injuries; Hypoxia; Inhibitors; Intracellular Space - drug effects; Intracellular Space - metabolism; Intravenous administration; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; NAD; Naphthyridines - chemistry; Naphthyridines - pharmacokinetics; Naphthyridines - pharmacology; Necrosis; Neurons - cytology; Neurons - drug effects; Neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Oral administration; PARP‐1 inhibitor; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly(ADP-ribose) polymerase; Rats; Ribose; Rodents; Signal Transduction - drug effects; Solubility; Stroke; cerebral ischaemia; PARP-1 inhibitor; stroke
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/1440-1681.12757

Summary
Excessive activation of poly (ADP‐ribose) polymerase‐1 (PARP‐1) is known to develop neuronal apoptosis, necrosis and inflammation after ischaemic brain injury. Therefore, PARP‐1 inhibition after ischaemic stroke has been attempted in successful animal studies. The purpose of present work was to develop a novel water soluble PARP‐1 inhibitor (JPI‐289) and explore its neuroprotective effect on ischaemic injury in an in vitro model. The half‐life of JPI‐289 after intravenous or oral administration in rats was relatively long (1.4‐1.5 hours) with 65.6% bioavailability. The inhibitor strongly inhibited PARP‐1 activity (IC50=18.5 nmol/L) and cellular PAR formation (IC50=10.7 nmol/L) in the nanomolar range. In rat cortical neuronal cells, JPI‐289 did not affect cell viability up to 1 mmol/L as assayed by Trypan blue staining (TBS) and lactate dehydrogenase (LDH) assay. Treatment of JPI‐289 for 2 hours after 2 hours of oxygen glucose deprived (OGD) rat cortical neuron attenuated PARP activity and restored ATP and NAD+ levels. Apoptosis‐associated molecules such as apoptosis inducing factor (AIF), cytochrome C and cleaved caspase‐3 were reduced after JPI‐289 treatment in the OGD model. The present findings suggest that the novel PARP‐1 inhibitor, JPI‐289, is a potential neuroprotective agent which could be useful as a treatment for acute ischaemic stroke.