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Biochem Biophys Res Commun. 2019 Oct 8;518(1):161-170. doi: 10.1016/j.bbrc.2019.08.025. Epub 2019 Aug 17.

Neuroprotective effects of memantine via enhancement of autophagy.

Author information

1
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan.
2
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo, 113-8421, Japan.
3
Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan.
4
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan; Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan.
5
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan; Department of Research and Therapeutics for Movement Disorders, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan.
6
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
7
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan. Electronic address: ssaiki@juntendo.ac.jp.
8
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, 113-8421, Japan; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo, 113-8421, Japan. Electronic address: nhattori@juntendo.ac.jp.

Abstract

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.

KEYWORDS:

Autophagy; Chemical screening; Memantine; Mitophagy; Neurodegenerative diseases

PMID:
31431260
DOI:
10.1016/j.bbrc.2019.08.025

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