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

• Published in: Brain research 2011-09, Vol.1410, p.122-131
• Main Authors: Matsuura, Shigeru, Egi, Yasuhiro, Yuki, Satoshi, Horikawa, Takashi, Satoh, Hiroyuki, Akira, Toshiaki
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; brain; Brain - drug effects; Brain - pathology; brain damage; Brain Ischemia - drug therapy; Brain Ischemia - pathology; cortex; Disease Models, Animal; DNA damage; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; infarction; Isoquinolines - pharmacology; Isoquinolines - therapeutic use; Macaca fascicularis; Macaca mulatta; Male; Medical sciences; Middle cerebral artery occlusion; Monkey; monkeys; Neurology; Neurons - drug effects; Neurons - pathology; Neuroprotectant; neuroprotective effect; Poly (ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors; Primates; Sex difference; Sex Factors; stroke; Stroke - drug therapy; Stroke - pathology; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2011.05.069

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 28 h 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 3 mg/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 6 h 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.