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.
| Original language | English |
|---|---|
| Pages (from-to) | 161-170 |
| Number of pages | 10 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 518 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2019 Oct 8 |
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Keywords
- Autophagy
- Chemical screening
- Memantine
- Mitophagy
- Neurodegenerative diseases
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Neuroprotective effects of memantine via enhancement of autophagy. / Hirano, Kazuoki; Fujimaki, Motoki; Sasazawa, Yukiko; Yamaguchi, Akihiro; Ishikawa, Kei Ichi; Miyamoto, Kengo; Souma, Sanae; Furuya, Norihiko; Imamichi, Yoko; Yamada, Daisuke; Saya, Hideyuki; Akamatsu, Wado; Saiki, Shinji; Hattori, Nobutaka.
In: Biochemical and Biophysical Research Communications, Vol. 518, No. 1, 08.10.2019, p. 161-170.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Neuroprotective effects of memantine via enhancement of autophagy
AU - Hirano, Kazuoki
AU - Fujimaki, Motoki
AU - Sasazawa, Yukiko
AU - Yamaguchi, Akihiro
AU - Ishikawa, Kei Ichi
AU - Miyamoto, Kengo
AU - Souma, Sanae
AU - Furuya, Norihiko
AU - Imamichi, Yoko
AU - Yamada, Daisuke
AU - Saya, Hideyuki
AU - Akamatsu, Wado
AU - Saiki, Shinji
AU - Hattori, Nobutaka
PY - 2019/10/8
Y1 - 2019/10/8
N2 - 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.
AB - 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.
KW - Autophagy
KW - Chemical screening
KW - Memantine
KW - Mitophagy
KW - Neurodegenerative diseases
UR - http://www.scopus.com/inward/record.url?scp=85070720182&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070720182&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2019.08.025
DO - 10.1016/j.bbrc.2019.08.025
M3 - Article
VL - 518
SP - 161
EP - 170
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -