Ginkgolides protect PC12 cells against hypoxia‐induced injury by p42/p44 MAPK pathway‐dependent upregulation of HIF‐1α expression and HIF‐1DNA‐binding activity

Abstract We hypothesized that the neuroprotective role of the standardized Ginkgo biloba (Ginkgoaceae) extract EGb 761 under hypoxic conditions might be associated with its function to increase HIF‐1 activity based on the fact that oxygen availability is crucial for cellular metabolism and viability and that HIF‐1 plays an essential role in cellular oxygen homeostasis under hypoxic conditions. In this study, we therefore investigated the effects of ginkgolides, the main constituent of the non‐flavone fraction of EGb 761, on the content and activity of HIF‐1α, a key factor to determine HIF‐1 activity, in hypoxic PC12 cells induced by cobalt chloride. Our data demonstrated that ginkgolides have a significant protective role against hypoxia‐induced injury in the PC12 cells. The findings also strongly support our hypothesis that the protective role of ginkgolides is due to the up‐regulation of HIF‐1α protein expression and modification through the ginkgolides‐induced activation of the p42/p44 MAPK pathway. In addition, it was evident that ginkgolides could significantly increase the HIF‐1 DNA binding activity, which might also be associated with the protective effects of ginkgolides by promoting the expression of target genes of HIF‐1 under hypoxic conditions. J. Cell. Biochem. 103: 564–575, 2008. © 2007 Wiley‐Liss, Inc.