Honokiol alleviated neurodegeneration by reducing oxidative stress and improving mitochondrial function in mutant SOD1 cellular and mouse models of amyotrophic lateral sclerosis.
10.1016/j.apsb.2022.07.019
- Author:
Yujun ZHOU
1
;
Jingshu TANG
1
;
Jiaqi LAN
1
;
Yong ZHANG
1
;
Hongyue WANG
1
;
Qiuyu CHEN
1
;
Yuying KANG
1
;
Yang SUN
2
;
Xinhong FENG
3
;
Lei WU
1
;
Hongtao JIN
4
;
Shizhong CHEN
2
;
Ying PENG
1
Author Information
1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
2. Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
3. Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China.
4. New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- Keywords:
Amyotrophic lateral sclerosis;
Glutathione;
Honokiol;
Mitochondrial biogenesis;
Mitochondrial dynamics;
NRF2;
Oxidative stress;
SOD1-G93A
- From:
Acta Pharmaceutica Sinica B
2023;13(2):577-597
- CountryChina
- Language:English
-
Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons (MNs) with large unmet medical needs. Multiple pathological mechanisms are considered to contribute to the progression of ALS, including neuronal oxidative stress and mitochondrial dysfunction. Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease. Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo. Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins (SOD1-G93A cells for short). Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway. Also, honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells. Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function. The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice. Overall, honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.
