Therapeutic effect of a novel curcumin derivative GT863 on a mouse model of amyotrophic lateral sclerosis

Abstract

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.

Keywords:

• Superoxide dismutase 1 (SOD1)
• aggregation inhibitor
• curcumin derivative

Author contributions

Hajime Kato, Hiroyasu Sato, Michiaki Okuda, Jun Wu, Tomonori Waku, Shingo Koyama, Mitsuyoshi Iino, Masashi Aoki, Shigeki Arawaka, Yasuyuki Ohta, Kenichi Ishizawa, Yasuomi Urano, Tomohiro Miyasaka, Noriko Noguchi, Yasuhiko Izumi, Toshiaki Kume, Akinori Akaike, Hachiro Sugimoto and Takeo Kato contributed to conception and design of the study. Hajime Kato, Hiroyasu Sato, Michiaki Okuda, Jun Wu, Yasuhiko Izumi and Kanan Kawasaki contributed to the acquisition and analysis of data. Hajime Kato, Hiroyasu Sato, Michiaki Okuda, Yasuhiko Izumi, Yasuomi Urano, Noriko Noguchi, Toshiaki Kume and Takeo Kato contributed to writing the manuscript. Masashi Aoki and Hachiro Sugimoto contributed to providing resources. Hachiro Sugimoto and Takeo Kato contributed to project administration. All authors contributed to manuscript correction and then agreed to the published version of the manuscript.

Declaration of interest

Hajime Kato, Hiroyasu Sato, Michiaki Okuda, Masashi Aoki, Hachiro Sugimoto and Takeo Kato are the inventors of a patent relevant to this work (PCT/JP2020/019877, issued by the patent agency). Michiaki Okuda was an employee of Green Tech Co., Ltd. when conducting this research. Hachiro Sugimoto doubles as a president of Green Tech Co., Ltd. and a chair professor at Doshisha University. The other authors declare no competing financial interests.

Data availability statement

The datasets in the present study will be available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by Japan Agency for Medical Research and Development (AMED) (#16ek0109013s0803).