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Early Treatment with Poly(ADP-Ribose) Polymerase-1 Inhibitor (JPI-289) Reduces Infarct Volume and Improves Long-Term Behavior in an Animal Model of Ischemic Stroke

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Abstract

In patients with stroke and neurodegenerative diseases, overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) causes harmful effects by inducing apoptosis, necrosis, neuroinflammation, and immune dysregulation. The current study investigated the neuroprotective effect of a novel PARP-1 inhibitor, JPI-289, in an animal model of ischemic stroke. A transient middle cerebral artery occlusion (tMCAO, 2 h) model was used to determine the therapeutic effect and the most effective dose and time window of administration of JPI-289. We also investigated the long-term outcomes of treatment with JPI-289 by diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI and by measuring neurological function at 24 h, 7 days, and 28 days after MCAO. The most effective dose and time window of administration of JPI-289 was 10 mg/kg administered 2 h after MCAO with reperfusion. Twenty-four hours after MCAO, infarct volume was reduced by 53% and the number of apoptotic cells was reduced by 56% compared with control. JPI-289 also reduced infarct volume by 16% in the permanent MCAO model. In an MRI-based study, initial infarct volume, as measured using DWI, was similar in the control and JPI-289-treated groups. However, infarct volume and brain swelling were significantly reduced in the group treated with JPI-289 (2 h) at 24 h and 7 days after MCAO. Neurological functions also improved in the group treated with JPI-289 (2 h) until 28 days after MCAO. Inhibition of PARP-1 has neuroprotective effects (reduction of infarct volume and brain swelling) in both tMCAO and pMCAO models of ischemic stroke.

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Funding

This study was funded by grant of the Korea Drug Development Fund (KDDF-201410-08) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (A100453) for the clinical development of JPI-289.

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Author notes

  1. Youngchul Kim, Young Seo Kim and Hyun Young Kim contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Pharmacology & Toxicology, R&D Center, Jeil Pharmaceutical Co., Ltd., 7, Cheongganggachang-Ro, Baekam-Myun, Cheoin-Gu, Yongin City, Kyunggi-Do, 17172, Republic of Korea

    Youngchul Kim, Jeongmin Kim & Jiseon Park

  2. Department of Neurology, College of Medicine, Hanyang University, 222-1 Wangsimniro, Seongdong-gu, Seoul, 04763, Republic of Korea

    Youngchul Kim, Young Seo Kim, Hyun Young Kim, Min-Young Noh & Seung Hyun Kim

  3. Department of Nuclear Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea

    Ji Young Kim

  4. Department of Radiology, College of Medicine, Hanyang University, Seoul, Republic of Korea

    Young-Jun Lee

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  1. Youngchul Kim
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Correspondence to Jiseon Park or Seung Hyun Kim.

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Kim, Y., Kim, Y.S., Kim, H.Y. et al. Early Treatment with Poly(ADP-Ribose) Polymerase-1 Inhibitor (JPI-289) Reduces Infarct Volume and Improves Long-Term Behavior in an Animal Model of Ischemic Stroke. Mol Neurobiol 55, 7153–7163 (2018). https://doi.org/10.1007/s12035-018-0910-6

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