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Neuroprotective effects of a novel poly ( ADP ‐ribose) polymerase‐1 inhibitor, JPI ‐289, in hypoxic rat cortical neurons
Author(s) -
Kim Youngchul,
Kim Young S.,
Noh MinYoung,
Lee Hanchang,
Joe Boyoung,
Kim Hyun Y.,
Kim Jeongmin,
Kim Seung H.,
Park Jiseon
Publication year - 2017
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12757
Subject(s) - neuroprotection , chemistry , poly adp ribose polymerase , cortical neurons , pharmacology , polymerase , microbiology and biotechnology , biochemistry , biology , enzyme
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 ( IC 50 =18.5 nmol/L) and cellular PAR formation ( IC 50 =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.