title: Neuroprotective effects of a novel poly (ADP-ribose) polymerase-1 inhibitor, JPI-289, in hypoxic rat cortical neurons.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology & Toxicology, R&D Center, Jeil Pharmaceutical Co., Yongin-City, Kyunggi-Do, Korea.|Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Young S
authors.identifier: http://orcid.org/0000-0002-7050-3426
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Noh
authors.affiliation: Laboratory of Pharmacology & Toxicology, R&D Center, Jeil Pharmaceutical Co., Yongin-City, Kyunggi-Do, Korea.
authors.forename: Hanchang
authors.initials: H
authors.lastname: Lee
authors.affiliation: Laboratory of Pharmacology & Toxicology, R&D Center, Jeil Pharmaceutical Co., Yongin-City, Kyunggi-Do, Korea.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joe
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Hyun Y
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Laboratory of Pharmacology & Toxicology, R&D Center, Jeil Pharmaceutical Co., Yongin-City, Kyunggi-Do, Korea.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Seung H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Laboratory of Pharmacology & Toxicology, R&D Center, Jeil Pharmaceutical Co., Yongin-City, Kyunggi-Do, Korea.
authors.forename: Jiseon
authors.initials: J
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; C000625768:JPI-289; D009287:Naphthyridines; D018696:Neuroprotective Agents; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: PARP-1 inhibitor; cerebral ischaemia; stroke