Peripheral nerve degeneration (PND) is a preparative process for peripheral nerve regeneration and is regulated by Schwann cells, a unique glial cell in the peripheral nervous system. Dysregulated PND induces irreversible peripheral neurodegenerative diseases (e.g., diabetic peripheral neuropathy). To develop novel synthetic drugs for these diseases, we synthesized a set of new cinnamaldehyde (CAH) derivatives and evaluated their activities in vitro, ex vivo, and in vivo. The 12 CAH derivatives had phenyl or naphthyl groups with different substitution patterns on either side of the α,β-unsaturated ketone. Among them, 3f, which had a naphthaldehyde group, was the most potent at inhibiting PND in vitro, ex vivo, and in vivo. To assess their interactions with transient receptor potential cation channel subfamily A member 1 (TRPA1) as a target of CAH, molecular docking studies were performed. Hydrophobic interactions had the highest binding affinity. To evaluate the underlying pharmacological mechanism, we performed bioinformatics analysis of the effect of 3f on PND based on coding genes and miRNAs regulated by CAH, suggesting that 3f affects oxidative stress in Schwann cells. The results show 3f to be a potential lead compound for the development of novel synthetic drugs for the treatment of peripheral neurodegenerative diseases.

中文翻译：

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新型肉桂醛衍生物通过靶向雪旺细胞抑制外周神经变性

周围神经变性 (PND) 是周围神经再生的准备过程，受周围神经系统中独特的神经胶质细胞雪旺细胞的调节。失调的 PND 会诱发不可逆的周围神经退行性疾病（例如糖尿病周围神经病变）。为了开发针对这些疾病的新型合成药物，我们合成了一组新的肉桂醛 (CAH) 衍生物，并评估了它们在体外、离体和体内的活性。12 种 CAH 衍生物在α,β-不饱和酮的任一侧具有不同取代模式的苯基或萘基。其中，3f具有萘醛基团的 , 在体外、离体和体内抑制 PND 方面最有效。为了评估它们与作为 CAH 靶标的瞬时受体电位阳离子通道亚家族 A 成员 1 (TRPA1) 的相互作用，进行了分子对接研究。疏水相互作用具有最高的结合亲和力。为了评估潜在的药理机制，我们基于 CAH 调节的编码基因和 miRNA 对3f对 PND的影响进行了生物信息学分析，表明3f影响雪旺氏细胞中的氧化应激。结果表明， 3f是一种潜在的先导化合物，可用于开发治疗周围神经退行性疾病的新型合成药物。