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The Orally Active Noncompetitive AMPAR Antagonist Perampanel Attenuates Focal Cerebral Ischemia Injury in Rats

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Abstract

Inhibition of ionotropic glutamate receptors (iGluRs) is a potential target of therapy for ischemic stroke. Perampanel is a potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist with good oral bioavailability and favorable pharmacokinetic properties. Here, we investigated the potential protective effects of perampanel against focal cerebral ischemia in a middle cerebral artery occlusion (MCAO) model in rats. Oral administration with perampanel significantly reduced MCAO-induced brain edema, brain infarct volume, and neuronal apoptosis. These protective effects were associated with improved functional outcomes, as measured by foot-fault test, adhesive removal test, and modified neurological severity score (mNSS) test. Importantly, perampanel was effective even when the administration was delayed to 1 h after reperfusion. The results of enzyme-linked immunosorbent assay (ELISA) showed that perampanel significantly decreased the expression of pro-inflammatory cytokines IL-1β and TNF-α, whereas it increased the levels of anti-inflammatory cytokines IL-10 and TGF-β1 after MCAO. In addition, perampanel treatment markedly decreased the expression of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS), and also inhibited nitric oxide (NO) generation in MCAO-injured rats at 24 and 72 h after reperfusion. In conclusion, this study demonstrated that the orally active AMPAR antagonist perampanel protects against experimental ischemic stroke via regulating inflammatory cytokines and NOS pathways.

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Author notes

  1. Hong-Xia Niu and Jun-Zhe Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Peking University People’s Hospital, Beijing, 100044, China

    Dong-Liang Wang, Jun-Jie Miao & Jing-Ru Zhou

  2. Emergency Department, Beijing Electric Power Hospital, Beijing, 100071, China

    Hong-Xia Niu

  3. Basic Medical Sciences Research Center, Shaanxi Fourth People’s Hospital, Xi’an, 710043, Shaanxi, China

    Jun-Zhe Wang & Wei Liu

  4. Department of Neurosurgery, Shaanxi Fourth People’s Hospital, Xi’an, 710043, Shaanxi, China

    Hua Li, Zhi-Gang Liu, Xing Yuan & Wei Liu

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  1. Hong-Xia Niu
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  2. Jun-Zhe Wang
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  3. Dong-Liang Wang
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  4. Jun-Jie Miao
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Correspondence to Wei Liu or Jing-Ru Zhou.

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Niu, HX., Wang, JZ., Wang, DL. et al. The Orally Active Noncompetitive AMPAR Antagonist Perampanel Attenuates Focal Cerebral Ischemia Injury in Rats. Cell Mol Neurobiol 38, 459–466 (2018). https://doi.org/10.1007/s10571-017-0489-x

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