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Theranostics 2021; 11(15):7294-7307. doi:10.7150/thno.56070 This issue Cite

Research Paper

R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function

Xiao Li1,2#, Chongyang Chen2#, Xu Zhan2#, Binyao Li3, Zaijun Zhang4, Shupeng Li5, Yongmei Xie6, Xiangrong Song7, Yuanyuan Shen8, Jianjun Liu1, Ping Liu2✉, Gong-Ping Liu2,9✉, Xifei Yang1✉

1. Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Subject of Modern Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China.
2. Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3. Tianjin Institute of Pharmaceutical Research New Drug Assessment Co. Ltd, Tianjin 300301, China.
4. Institute of New Drug Research and Guangzhou, Key Laboratory of Innovative Chemical Drug Research in Cardio-Cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou 510632, China.
5. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
6. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
7. Department of Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
8. National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
9. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Dr. Xifei Yang, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 8, Longyuan Road, Nanshan District, Shenzhen, China 518055. Tel: +86 75525601914, Fax: +86 75525508584, E More

Citation:
Li X, Chen C, Zhan X, Li B, Zhang Z, Li S, Xie Y, Song X, Shen Y, Liu J, Liu P, Liu GP, Yang X. R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function. Theranostics 2021; 11(15):7294-7307. doi:10.7150/thno.56070. https://www.thno.org/v11p7294.htm
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Abstract

Graphic abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far, there is no effective treatment for ALS.

Methods: In this study, R13, a prodrug of 7,8-dihydroxyflavone, selectively activating tyrosine kinase receptor B (TrkB) signaling pathway, was administered prophylactically to 40-day old SOD1G93A mice for 90 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test and hanging endurance test. Afterwards, the spinal cord and medulla oblongata of 130-day old mice were harvested, and the proteomics revealed the effect of R13 on mouse protein expression profile. Astrocytes and microglial proliferation were assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord is determined by Nissl staining. The effect of R13 on gastrocnemius morphology was assessed by HE staining. The effect of R13 on the survival rate was accomplished with worms stably expressing G93A SOD1.

Results: Behavioral tests showed that R13 significantly attenuated abnormal motor performance of SOD1G93A mice. R13 reduced the advance of spinal motor neuron pathology and gastrocnemius muscle atrophy. The proliferation of microglia and astrocytes was reduced by R13 treatment. Mitochondriomics analysis revealed that R13 modified the mitochondrial protein expression profiles in the medulla oblongata and spinal cord of SOD1G93A mice, particularly promoting the expression of proteins related to oxidative phosphorylation (OXPHOS). Further study found that R13 activated AMPK/PGC-1α/Nrf1/Tfam, promoted mitochondrial biogenesis and ameliorated mitochondrial dysfunction. Lastly, R13 prolonged the survival rate of worms stably expressing G93A SOD1.

Conclusions: These findings suggest oral R13 treatment slowed the advance of motor system disease in a reliable animal model of ALS, supporting that R13 might be useful for treating ALS.

Keywords: Amyotrophic lateral sclerosis, 7,8-dihydroxyflavone, Mitochondria, Mitochondriomics, Motor performance

Citation styles

APA
Li, X., Chen, C., Zhan, X., Li, B., Zhang, Z., Li, S., Xie, Y., Song, X., Shen, Y., Liu, J., Liu, P., Liu, G.P., Yang, X. (2021). R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function. Theranostics, 11(15), 7294-7307. https://doi.org/10.7150/thno.56070.

ACS
Li, X.; Chen, C.; Zhan, X.; Li, B.; Zhang, Z.; Li, S.; Xie, Y.; Song, X.; Shen, Y.; Liu, J.; Liu, P.; Liu, G.P.; Yang, X. R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function. Theranostics 2021, 11 (15), 7294-7307. DOI: 10.7150/thno.56070.

NLM
Li X, Chen C, Zhan X, Li B, Zhang Z, Li S, Xie Y, Song X, Shen Y, Liu J, Liu P, Liu GP, Yang X. R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function. Theranostics 2021; 11(15):7294-7307. doi:10.7150/thno.56070. https://www.thno.org/v11p7294.htm

CSE
Li X, Chen C, Zhan X, Li B, Zhang Z, Li S, Xie Y, Song X, Shen Y, Liu J, Liu P, Liu GP, Yang X. 2021. R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function. Theranostics. 11(15):7294-7307.

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