Ginkgolide K inhibited neurovascular unit injury against oxygen-glucose deprivation and reperfusion by regulating hypoxia-inducible factor-1α pathway / 中国药理学通报

ABSTRACT

Aim To investigate the protective effects of ginkgolide K (GK) on neurovascular unit injured by ischemic stroke and the potential mechanism associated with hypoxia-inducible factor-1α (HIF-1α) pathway. Methods The BV-2 cells and EA. hy926 cells suffered from oxygen-glucose deprivation and reperfusion (OGD/R) were applied to mimic the injury of neurovascular unit induced by cerebral ischemia in vitro. After 4 h OGD insult, BV-2 cells and EA. hy926 cells received reperfusion and treated with GK. The levels of inflammatory cytokines in the supernatant of BV-2 cells were detected, while the protective effects of GK on EA. hy926 cells were also evaluated after GK administration for 24 h. The p-Akt and p-Erk expressions were examined by Western blot after 1 h of GK treatment, while HIF-1α was detected after 6 h of GK treatment. In addition, PI3K inhibitor LY294002 was applied to further verify the potential mechanisms underlying the beneficial effects of GK. The expressions of p-Akt after 1 h of GK treatment, and the protein levels of HIF-1α pathway after 6 h of GK treatment were also analyzed by Western blot. Results GK significantly inhibited the levels of TNF-α, IL-6 and IL-1β in supernatant of BV-2 cells injured by OGD/R, through increasing p-Akt and decreasing p-Erk expressions, and then affecting HIF-1α pathway. In addition, LY294002 reduced the regulatory effect of GK. Furthermore, GK significantly improved viability and inhibited the release of LDH in supernatant of EA. hy926 cells suffered from OGD/R, and up-regulated the expressions of p-Akt, HIF-1α, HO-1 and VEGF, while cleaved caspase-3/9 was inhibited. Conclusions GK exerts multi-effects on reducing neurovascular unit injury induced by ischemic stroke, and the potential mechanism might be associated with the different regulatory effects of HIF-1α in different cells.