TY - JOUR
T1 - Therapeutic effect of a novel curcumin derivative GT863 on a mouse model of amyotrophic lateral sclerosis
AU - Kato, Hajime
AU - Sato, Hiroyasu
AU - Okuda, Michiaki
AU - Wu, Jun
AU - Koyama, Shingo
AU - Izumi, Yasuhiko
AU - Waku, Tomonori
AU - Iino, Mitsuyoshi
AU - Aoki, Masashi
AU - Arawaka, Shigeki
AU - Ohta, Yasuyuki
AU - Ishizawa, Kenichi
AU - Kawasaki, Kanan
AU - Urano, Yasuomi
AU - Miyasaka, Tomohiro
AU - Noguchi, Noriko
AU - Kume, Toshiaki
AU - Akaike, Akinori
AU - Sugimoto, Hachiro
AU - Kato, Takeo
N1 - Publisher Copyright:
© 2021 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.
PY - 2022
Y1 - 2022
N2 - The present study investigated the therapeutic effects of the curcumin derivative 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole (GT863) in amyotrophic lateral sclerosis (ALS). The inhibitory effect of GT863 on superoxide dismutase 1 (SOD1) aggregation was evaluated in cell-free assays. GT863 interfered with the conformational changes of the SOD1 protein and later, oligomeric aggregation. Furthermore, its antioxidant, anti-inflammatory, and neuroprotective effects were evaluated in cell-free and cultured cell assays. GT863 inhibited H2O2− and glutamate-induced cytotoxicity and activated an antioxidant responsive element pathway. Additionally, in vivo effects of GT863 in the ALS mice model were evaluated by its oral administration to H46R mutant SOD1 transgenic mice. Rotarod test showed that GT863 administration significantly slowed the progression of motor dysfunction in the mice. In addition, GT863 substantially reduced highly-aggregated SOD1, further preserving large neurons in the spinal cord of GT863-treated mice. Collectively, these results indicated that GT863 could be a viable therapeutic agent with multiple vital actions for the treatment of ALS.
AB - The present study investigated the therapeutic effects of the curcumin derivative 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole (GT863) in amyotrophic lateral sclerosis (ALS). The inhibitory effect of GT863 on superoxide dismutase 1 (SOD1) aggregation was evaluated in cell-free assays. GT863 interfered with the conformational changes of the SOD1 protein and later, oligomeric aggregation. Furthermore, its antioxidant, anti-inflammatory, and neuroprotective effects were evaluated in cell-free and cultured cell assays. GT863 inhibited H2O2− and glutamate-induced cytotoxicity and activated an antioxidant responsive element pathway. Additionally, in vivo effects of GT863 in the ALS mice model were evaluated by its oral administration to H46R mutant SOD1 transgenic mice. Rotarod test showed that GT863 administration significantly slowed the progression of motor dysfunction in the mice. In addition, GT863 substantially reduced highly-aggregated SOD1, further preserving large neurons in the spinal cord of GT863-treated mice. Collectively, these results indicated that GT863 could be a viable therapeutic agent with multiple vital actions for the treatment of ALS.
KW - Superoxide dismutase 1 (SOD1)
KW - aggregation inhibitor
KW - curcumin derivative
UR - http://www.scopus.com/inward/record.url?scp=85121366524&partnerID=8YFLogxK
U2 - 10.1080/21678421.2021.2012699
DO - 10.1080/21678421.2021.2012699
M3 - 学術論文
C2 - 34894926
AN - SCOPUS:85121366524
SN - 2167-8421
VL - 23
SP - 489
EP - 495
JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
IS - 7-8
ER -