Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Institute of Clinical Medicine, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Phytomedicine. 2024 Dec;135:156033. doi: 10.1016/j.phymed.2024.156033. Epub 2024 Sep 7.
Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes that lacks effective treatment. Gastrodin, the primary bioactive compound derived from Rhizoma Gastrodiae, has a long history in treating epilepsy and various central nervous system disorders. However, its effect on DPN remains uncertain.
This study aims to explore the therapeutic potential and underlying mechanisms of gastrodin in the treatment of DPN.
DPN model rats were induced with streptozotocin (STZ) injection and divided into four groups receiving either gastrodin at two doses (30 and 60 mg kg per day), α-lipoic acid (positive drug, 60 mg kg per day), or placebo. Healthy rats were administrated with placebo. The administrations began eight weeks post-STZ injection and continued for six weeks. Following a comprehensive evaluation of the neuroprotective effects, a systematic pharmacology-based approach was subsequently employed to investigate the underlying mechanism of gastrodin in vivo and in vitro.
Gastrodin was demonstrated to effectively enhance peripheral nerve function and reduce pathological damages in DPN rats. Furthermore, gastrodin facilitated the expression of remyelination-related proteins and mitigated oxidative stress in DPN rats. Transcriptomic analysis indicated that the modulation of energy metabolism was pivotal in the neuroprotective effect of gastrodin, corroborated by targeted metabolomic analysis using high-performance ion chromatography coupled with mass spectrometry. Using network pharmacology analysis, 12 potential targets of gastrodin were identified. Among these, matrix metallopeptidase 9 (MMP9) was further validated as the primary target through molecular docking and cellular thermal shift assays. Functional Analysis of the potential targets underscored the pivotal role of AMPK signaling, and gastrodin demonstrated the capability to activate AMPK and inhibit MMP9 in vivo. In vitro studies further found that gastrodin enhanced antioxidant capacity and mitochondrial function of high glucose-cultured rat Schwann cells RSC96 in an AMPK-dependent manner. Inhibition of AMPK hindered the decrease of MMP9 induced by gastrodin in vitro.
This study revealed the new role of gastrodin in alleviating DPN by restoring the homeostasis of energy metabolism through activating AMPK and inhibiting MMP9. These findings highlight gastrodin's potential as a novel therapeutic candidate against DPN, and underscores an appealing strategy of regulating energy metabolism for DPN therapy.
糖尿病周围神经病变（DPN）是糖尿病的一种严重并发症，目前缺乏有效的治疗方法。天麻素是天麻的主要生物活性化合物，在治疗癫痫和各种中枢神经系统疾病方面已有悠久的历史。然而，其对 DPN 的疗效尚不确定。
本研究旨在探讨天麻素治疗 DPN 的治疗潜力及其潜在机制。
采用链脲佐菌素（STZ）注射诱导 DPN 模型大鼠，分为天麻素高、低剂量（30 和 60 mg/kg/天）组、α-硫辛酸（阳性药物，60 mg/kg/天）组和对照组，每组 10 只。健康大鼠给予安慰剂。给药于 STZ 注射后 8 周开始，持续 6 周。在全面评估神经保护作用后，采用基于系统药理学的方法，从体内和体外两个方面探讨天麻素的潜在作用机制。
天麻素能有效改善 DPN 大鼠的周围神经功能，减轻其病理损伤。此外，天麻素能促进髓鞘形成相关蛋白的表达，减轻 DPN 大鼠的氧化应激。转录组学分析表明，天麻素的神经保护作用主要与能量代谢的调节有关，高效离子色谱-质谱联用靶向代谢组学分析也证实了这一点。通过网络药理学分析，鉴定出 12 个天麻素的潜在作用靶点。其中，基质金属蛋白酶 9（MMP9）通过分子对接和细胞热转移实验进一步验证为主要靶点。潜在靶点的功能分析表明，AMPK 信号通路发挥着关键作用，天麻素在体内能激活 AMPK 并抑制 MMP9。体外研究还发现，天麻素能以 AMPK 依赖的方式增强高糖培养的大鼠雪旺细胞 RSC96 的抗氧化能力和线粒体功能。在体外，抑制 AMPK 可阻断天麻素诱导的 MMP9 减少。
本研究揭示了天麻素通过激活 AMPK 和抑制 MMP9 恢复能量代谢平衡来缓解 DPN 的新作用。这些发现表明天麻素可能成为治疗 DPN 的一种新的治疗候选药物，并强调了调节能量代谢治疗 DPN 的一种有吸引力的策略。
