Tetramethylpyrazine Nitrone Improved Motor Deficits and Alleviated Dystrophic Muscle Pathology in the <i>mdx</i>Mouse Model of Duchenne Muscular Dystrophy

• 作者: Fengjiao Wang Gaoxiao Zhang Guiliang Zhang Haijing Zhong Jing Wen Pei Yu Yewei Sun Yuqiang Wang Zaijun Zhang Zheng Liu
• 来源期刊: 生物科学与医学(英文)
• 学科: 化学
• 关键词: Duchenne Muscular Dystrophy Fibrosis DYSFERLIN TBN mdx Mouse
• 年，卷（期）: 2020,（8）
• 页码范围: 56-66
• 页数: 11页
• 分类号: O62

摘要

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive neuromuscular disorder caused by mutations in the dystrophin encoding gene, with the characteristics of a severe and progressive destruction of muscle structure and function. Skeletal muscle fibrosis is one of the pathological features of DMD. Tetramethylpyrazine (2,3,5,6-tetramethylpyrazine, TMP) has been demonstrated to reduce heart and liver fibrosis. Meanwhile, previous studies showed that Tetramethylpyrazine nitrone (TBN), a nitrone derivative of TMP, has promising therapeutic effects in several neurodegenerative models and is more potent than TMP. In this study, we investigated the potential effect of TBN on the <em>mdx</em> mouse model of DMD. Eight-week-old <em>mdx</em> mice were administered with TBN (30 mg/kg) intragastrically twice daily, with deflazacort (1 mg/kg) once a day as a positive control, for a total of 24 weeks. Behavioral tests including pole-climbing open-field test were monitored every 4 weeks. Histopathological assessment was conducted in the gastrocnemius and diaphragm muscles. The effects of TBN on protein levels of dysferlin were measured by immunohistochemistry. TBN significantly reduced the climbing time in pole test and increased the total distance moved in an open-field test of <em>mdx</em> mice. TBN attenuated fibrosis in the gastrocnemius and diaphragmatic muscles. In addition, TBN protected gastrocnemius muscle fibers via increasing expression of the dysferlin in <em>mdx </em>mice. In conclusion, this study demonstrated that TBN could improve the motor deficits and muscle pathology of <em>mdx</em> mouse, and it is worth further exploring the mechanism of action of TBN for DMD treatment.