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MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, ameliorates ischemic brain damage in a non-human primate model.

Abstract
Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) in response to DNA damage is considered to play a crucial role in the development of post-ischemic neuronal injury, such as ischemic stroke. The present study was undertaken to clarify the beneficial effects of MP-124, a novel PARP-1 inhibitor, on neurological deficits and cerebral infarcts following middle cerebral artery occlusion (MCAO) in the monkey. The effects of MP-124 on cerebral infarcts and neurological deficits in monkeys were investigated in permanent MCAO (pMCAO) and transient MCAO (tMCAO) models. In a dose-dependency study, the neurological deficits and cerebral infarct volume were assessed at 28h after pMCAO. MP-124 significantly reduced the total infarct volume, including that in the cortex/white matter and striatum, at doses of 0.3, 1 and 3mg/kg/h by 22, 54 and 64%, respectively. In addition, MP-124 at all doses significantly reduced the overall neurological deficits. Such ameliorative effects of MP-124 were observed in female as well as male monkeys. In the therapeutic time window (TTW) study, the neurological deficits and cerebral infarct volume were assessed at several time points after pMCAO or tMCAO. Treatment with MP-124 at 3 and 6h after MCAO significantly ameliorated not only the neurological deficits but also the infarct volume. MP-124 is thought to exhibit neuroprotective effects with a broad TTW regardless of sex in MCAO models. Such findings suggest that MP-124 may be beneficial for the treatment of acute ischemic stroke.
AuthorsShigeru Matsuura, Yasuhiro Egi, Satoshi Yuki, Takashi Horikawa, Hiroyuki Satoh, Toshiaki Akira
JournalBrain research (Brain Res) Vol. 1410 Pg. 122-31 (Sep 2 2011) ISSN: 1872-6240 [Electronic] Netherlands
PMID21741620 (Publication Type: Journal Article)
CopyrightCopyright © 2011 Elsevier B.V. All rights reserved.
Chemical References
  • Enzyme Inhibitors
  • Isoquinolines
  • MP 124
  • Poly(ADP-ribose) Polymerase Inhibitors
Topics
  • Animals
  • Brain (drug effects, pathology)
  • Brain Ischemia (drug therapy, pathology)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (pharmacology, therapeutic use)
  • Female
  • Isoquinolines (pharmacology, therapeutic use)
  • Macaca fascicularis
  • Macaca mulatta
  • Male
  • Neurons (drug effects, pathology)
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Sex Factors
  • Stroke (drug therapy, pathology)

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