AMPA Receptor Antagonist Perampanel Ameliorates Post-Stroke Functional and Cognitive Impairments

Masataka Nakajima; Satoshi Suda; Kota Sowa; Yuki Sakamoto; Chikako Nito; Yasuhiro Nishiyama; Junya Aoki; Masayuki Ueda; Shoji Yokobori; Marina Yamada; Hiroyuki Yokota; Takashi Okada; Kazumi Kimura

doi:10.1016/j.neuroscience.2018.06.043

AMPA Receptor Antagonist Perampanel Ameliorates Post-Stroke Functional and Cognitive Impairments

Neuroscience. 2018 Aug 21:386:256-264. doi: 10.1016/j.neuroscience.2018.06.043. Epub 2018 Jul 5.

Authors

Masataka Nakajima¹, Satoshi Suda², Kota Sowa³, Yuki Sakamoto⁴, Chikako Nito⁵, Yasuhiro Nishiyama⁶, Junya Aoki⁷, Masayuki Ueda⁸, Shoji Yokobori⁹, Marina Yamada¹⁰, Hiroyuki Yokota¹¹, Takashi Okada¹², Kazumi Kimura¹³

Affiliations

¹ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan; Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: masa-nakajima@nms.ac.jp.
² Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: suda-sa@nms.ac.jp.
³ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan; Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: 5058-ksowa@nms.ac.jp.
⁴ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan; Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: yuki-sakamoto@nms.ac.jp.
⁵ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: cnito@nms.ac.jp.
⁶ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: nomo16@nms.ac.jp.
⁷ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: j-aoki@nms.ac.jp.
⁸ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: ueda@nms.ac.jp.
⁹ Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: shoji@nms.ac.jp.
¹⁰ Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: myamada58@nms.ac.jp.
¹¹ Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: yokota@nms.ac.jp.
¹² Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: t-okada@nms.ac.jp.
¹³ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: k-kimura@nms.ac.jp.

PMID: 29981363
DOI: 10.1016/j.neuroscience.2018.06.043

Abstract

Perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist, clinically used for seizure control, has been reported to exert neuroprotective effects in experimental models of neurodegenerative diseases. However, few studies have investigated the therapeutic effects of PER in brain injury including stroke. Our aim was to investigate the neuroprotective potential of PER using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90-min MCAO followed by intraperitoneal PER administration at a dose of 1.5 mg/kg. Infarct volumes, neurological deficits, and immunological analyses were performed at 7 days after MCAO. PER significantly reduced infarct volumes (p < 0.05) and improved motor function (p < 0.05) compared with vehicle. Immunological analysis showed that PER significantly inhibited microglial activation, pro-inflammatory cytokine expression, and oxidative stress compared with vehicle. Moreover, PER suppressed neurodegeneration in the cortical ischemic boundary zone, via downregulation of Bcl-2-associated x and upregulation of Bcl-extra-large with Akt activation. In addition, post-stroke secondary neuronal damage and cognitive impairments, using the Y-maze test, were assessed 30 days after MCAO. PER significantly improved spatial working memory, which was accompanied by hippocampal CA1 neuronal loss and cortical thinning, compared with vehicle. These results indicate that PER attenuates infarct volumes and motor function deficits possibly through its anti-inflammatory, antioxidant, and anti-apoptotic activities, mediated via activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathways in the acute ischemic phase, and further ameliorates post-stroke cognitive impairments via the suppression of secondary neuronal damage in the chronic ischemic phase.

Keywords: AMPA receptor; focal cerebral ischemia; neuroprotection; perampanel; post-stroke cognitive impairment.

MeSH terms

Animals
Cognitive Dysfunction / drug therapy*
Cognitive Dysfunction / physiopathology
Cognitive Dysfunction / psychology
Excitatory Amino Acid Antagonists / pharmacology
Excitatory Amino Acid Antagonists / therapeutic use
Infarction, Middle Cerebral Artery / drug therapy*
Infarction, Middle Cerebral Artery / physiopathology
Infarction, Middle Cerebral Artery / psychology
Male
Maze Learning / drug effects
Maze Learning / physiology
Nitriles
Pyridones / pharmacology
Pyridones / therapeutic use*
Rats
Rats, Sprague-Dawley
Receptors, AMPA / antagonists & inhibitors*
Receptors, AMPA / physiology
Recovery of Function / drug effects*
Recovery of Function / physiology
Stroke / drug therapy*
Stroke / physiopathology
Stroke / psychology

Substances

Excitatory Amino Acid Antagonists
Nitriles
Pyridones
Receptors, AMPA
perampanel