Neuroprotective effects of memantine via enhancement of autophagy

Kazuoki Hirano, Motoki Fujimaki, Yukiko Sasazawa, Akihiro Yamaguchi, Kei Ichi Ishikawa, Kengo Miyamoto, Sanae Souma, Norihiko Furuya, Yoko Imamichi, Daisuke Yamada, Hideyuki Saya, Wado Akamatsu, Shinji Saiki, Nobutaka Hattori

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Introduction: Chemical intervention of autophagy has been investigated in clinical trials for various age-related conditions such as sarcopenia and neurodegeneration. However, at present, no autophagy inducer has been established as a disease-modifying agent against neurodegenerative diseases. Methods: We screened a library consisting of 796 medicines clinically approved (in Japan) for autophagy enhancers as potential neurodegeneration therapeutics using HeLa cells stably expressing green fluorescent protein-microtubule-associated protein light chain 3 (GFP-LC3) followed by an analysis of the molecular mechanisms using various neuronal models. Results: The primary screening identified 152 hits in a static cellular state. A widely available Alzheimer's disease drug, memantine, which antagonizes N-Methyl-D-aspartate receptor (NMDAR), was one of the hits. Memantine increased the levels of LC3-II in a dose-dependent and time-dependent manner, and upregulated autophagic flux. In addition, the pharmacological effects of memantine on autophagy were independent of mTORC1 activity and NMDAR activation. Furthermore, a VPS34 inhibitor suppressed the memantine-induced LC3-II upregulation, suggesting that memantine may affect VPS34 complex activity. Notably, intracellular Huntington's disease-specific aggregates of elongated huntingtin, a well-established autophagy substrate, were significantly decreased by memantine. In addition, memantine enhanced elimination of degraded mitochondrial in neurons derived from induced pluripotent stem cells of PARK2 or PARK6 patients, who exhibited defective PINK1/parkin-mediated mitophagy, suggests that memantine accelerated the clearance of damaged mitochondria. Conclusion: These findings indicate that memantine may be beneficial for the treatment of neurodegeneration characterized by the abnormal accumulation of autophagy or mitophagy substrates.

元の言語English
ページ(範囲)161-170
ページ数10
ジャーナルBiochemical and Biophysical Research Communications
518
発行部数1
DOI
出版物ステータスPublished - 2019 10 8

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ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

Hirano, K., Fujimaki, M., Sasazawa, Y., Yamaguchi, A., Ishikawa, K. I., Miyamoto, K., Souma, S., Furuya, N., Imamichi, Y., Yamada, D., Saya, H., Akamatsu, W., Saiki, S., & Hattori, N. (2019). Neuroprotective effects of memantine via enhancement of autophagy. Biochemical and Biophysical Research Communications, 518(1), 161-170. https://doi.org/10.1016/j.bbrc.2019.08.025