Gastrodin inhibits hexokinase-2 mediated glycolysis to rescue rotenone-damaged PC12 cells

Abstract

Glycolysis, a fundamental pathway in cellular energy metabolism, exhibits dysregulation that is intricately linked to the pathogenesis of Parkinson's disease (PD). Although the compensatory upregulation of aerobic glycolysis helps sustain ATP levels, its precise effects on dopaminergic neurons remain poorly understood. This study investigated the mechanism of rotenone-induced injury in PC12 cells and explored the potential protective effect of gastrodin. We found that rotenone exposure significantly enhanced glycolysis, with increased lactate production, lactate dehydrogenase (LDH) activity and decreased pyruvate concentrations. However, gastrodin treatment effectively attenuated rotenone-induced glycolysis, normalizing lactate production, LDH activity, and pyruvate levels. Furthermore, gastrodin inhibited the increase in glycolytic enzymes hexokinase 2(HK2), Pyruvate kinase M2(PKM2), and Lactate dehydrogenase A(LDHA) levels induced by rotenone. Notably, the combination of the HK2-specific inhibitor 2-DG with gastrodin demonstrated synergistic effects in inhibiting rotenone-induced glycolysis in PC12 cells. These findings collectively indicated that HK2-mediated aberrant glycolysis plays a pivotal role in rotenone-induced cell death, and that gastrodin confers neuroprotection through modulation of this metabolic pathway.

Keywords: Gastrodin; Glycolysis; Parkinson’s disease; Rotenone.