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
N1 - Funding Information:
Dr. Hattori received personal fees outside of this work from Hisamitsu Pharmaceutical , Dainippon Sumitomo Pharma , Otsuka Pharmaceutical , Novartis Pharma , GlaxoSmithKline , Nippon Boehringer Ingelheim , FP Pharmaceutical , Eisai , Kissei Pharmaceutical , Janssen Pharmaceutical , Nihon Medi-Physics and Kyowa Hakko Kirin , and received research grants from the Japan Agency for Medical Research and Development [CREST, program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) ] and the JSPS ( 15H04842 , 18H04043 ).
Funding Information:
Ms. Imamichi a received research grant from the JSPS ( 16H00625 ).
Funding Information:
Dr. Furuya a received research grant from Japan Society for the Promotion of Science ( 15K09325 ).
Funding Information:
Dr. Akamatsu received research grants from the Japan Agency for Medical Research and Development ( JP19ak0101066 ).
Funding Information:
Dr. Sasazawa a received research grant from the Ministry of Education, Culture, Sports, Science and Technology ( 18K15464 ).
Funding Information:
Dr. Saiki received research grants from the Ministry of Education, Culture, Sports, Science and Technology ( 25111007 , 25111001 ), the JSPS ( 15H04843 , 18H02744 , 18KT0027 ).
Funding Information:
Dr. Ishikawa a received research grant from the Ministry of Education, Culture, Sports, Science and Technology ( 18K15463 ).
Funding Information:
Dr. Saya received research grants from the Japan Society for the JSPS ( 17H01401 ).
Publisher Copyright:
© 2019 Elsevier Inc.
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
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U2 - 10.1016/j.bbrc.2019.08.025
DO - 10.1016/j.bbrc.2019.08.025
M3 - Article
C2 - 31431260
AN - SCOPUS:85070720182
VL - 518
SP - 161
EP - 170
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -