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Anti-Apoptotic Effects of AMPA Receptor Antagonist Perampanel in Early Brain Injury After Subarachnoid Hemorrhage in Mice

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Abstract

This study was aimed to investigate if acute neuronal apoptosis is induced by activation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors (AMPARs) and inhibited by a clinically available selective AMPAR antagonist and antiepileptic drug perampanel (PER) in subarachnoid hemorrhage (SAH), and if the mechanisms include upregulation of an inflammation-related matricellular protein periostin. Sham-operated and endovascular perforation SAH mice randomly received an administration of 3 mg/kg PER or the vehicle intraperitoneally. Post-SAH neurological impairments and increased caspase-dependent neuronal apoptosis were associated with activation of AMPAR subunits GluA1 and GluA2, and upregulation of periostin and proinflammatory cytokines interleukins-1β and -6, all of which were suppressed by PER. PER also inhibited post-SAH convulsion-unrelated increases in the total spectral power on video electroencephalogram (EEG) monitoring. Intracerebroventricularly injected recombinant periostin blocked PER’s anti-apoptotic effects on neurons. An intracerebroventricular injection of a selective agonist for GluA1 and GluA2 aggravated neurological impairment, neuronal apoptosis as well as periostin upregulation, but did not increase the EEG total spectral power after SAH. A higher dosage (10 mg/kg) of PER had even more anti-apoptotic effects compared with 3 mg/kg PER. Thus, this study first showed that AMPAR activation causes post-SAH neuronal apoptosis at least partly via periostin upregulation. A clinically available AMPAR antagonist PER appears to be neuroprotective against post-SAH early brain injury through the anti-inflammatory and anti-apoptotic effects, independent of the antiepileptic action, and deserves further study.

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Data Availability

Data from this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Ms. Chiduru Yamamoto-Nakamura (Department of Neurosurgery, Mie University Graduate School of Medicine) for her technical assistance.

Funding

This work was funded by JSPS KAKENHI Grant Number JP20K17963 and Sanikai Foundation (Grant Number, N/A) to Dr. Kawakita, and Taiju Life Social Welfare Foundation (Grant Number, N/A) to Dr. Suzuki.

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  1. Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Mie , 514-8507, Tsu, Japan

    Fumihiro Kawakita, Fumi Nakano, Hideki Kanamaru, Reona Asada & Hidenori Suzuki

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  1. Fumihiro Kawakita
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  3. Hideki Kanamaru
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Contributions

Conceptualization and design, F.K. and H.S.; methodology, material preparation, data collection and analyses, F.K., F.N., H.K., R.A. and H.S.; writing—original draft preparation, F.K.; writing—review and editing, F.N., H.K., R.A., and H.S. All authors approved the final version.

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Correspondence to Hidenori Suzuki.

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All experiments in the present study were approved by the Animal Ethics Review Committee of Mie University.

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Dr. Suzuki is one of the Editorial Board Members in this journal, and reported personal fees from Eisai and Kowa, and a research fund from Japan Blood Products Organization outside the submitted work. The other authors declare that they have no conflict of interest.

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Kawakita, F., Nakano, F., Kanamaru, H. et al. Anti-Apoptotic Effects of AMPA Receptor Antagonist Perampanel in Early Brain Injury After Subarachnoid Hemorrhage in Mice. Transl. Stroke Res. 15, 462–475 (2024). https://doi.org/10.1007/s12975-023-01138-4

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