BACKGROUND

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.

PURPOSE

This study aims to explore the therapeutic potential and underlying mechanisms of gastrodin in the treatment of DPN.

METHOD

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.

RESULTS

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.

CONCLUSION

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.