MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, ameliorates ischemic brain damage in a non-human primate model
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Published on: December 9, 2013
Shigeru Matsuura1, Yasuhiro Egi, Satoshi Yuki
1Pharmacology Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Japan. matsuura.shigeru@mx.mt-pharma.co.jp
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.
Insights
MP-124, a novel poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor, significantly reduced brain infarcts and neurological deficits in monkey models of ischemic stroke. This neuroprotective effect was observed across various doses and within a broad therapeutic time window, suggesting potential benefits for acute ischemic stroke treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Medicine
Background:
- Poly (ADP-ribose) polymerase-1 (PARP-1) overactivation contributes to neuronal injury after ischemic stroke.
- Developing effective treatments for ischemic stroke remains a critical medical challenge.
Purpose of the Study:
- To evaluate the neuroprotective effects of MP-124, a novel PARP-1 inhibitor, in non-human primate models of ischemic stroke.
- To assess the impact of MP-124 on neurological deficits and cerebral infarct volume following middle cerebral artery occlusion (MCAO).
Main Methods:
- MP-124 efficacy was tested in permanent (pMCAO) and transient (tMCAO) MCAO models in monkeys.
- Dose-dependency and therapeutic time window (TTW) studies were conducted to assess infarct volume and neurological deficits.
- Neurological deficits and infarct volumes were measured at various time points post-MCAO.
Main Results:
- MP-124 significantly reduced cerebral infarct volume in a dose-dependent manner (22-64% reduction).
- All tested doses of MP-124 significantly improved neurological deficits in both male and female monkeys.
- Treatment with MP-124 within 3-6 hours after MCAO demonstrated significant neuroprotection, reducing both deficits and infarct size.
Conclusions:
- MP-124 exhibits significant neuroprotective effects in MCAO models, reducing infarct volume and neurological deficits.
- The drug demonstrates a broad therapeutic time window and efficacy regardless of sex.
- These findings suggest MP-124 holds promise as a potential therapeutic agent for acute ischemic stroke.
