Ginkgolides protect PC12 cells against hypoxia-induced injury by p42/p44 MAPK pathway-dependent upregulation of HIF-1alpha expression and HIF-1DNA-binding activity.
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-1alpha, 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-1alpha 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.
Li
Zhu
Z
Institute for Nautical Medicine and Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, PR China. zhulili65@yahoo.com
Ya
Ke
K
Xiao-Mei
Wu
W
Lei
Yang
Y
Yang
Lu
L
Ming
Qian Zhong
QZ
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects*; D003035:Cobalt / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D020441:Ginkgo biloba; D046934:Ginkgolides / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis* / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D000096983:Ginkgo Extract
D003035:Cobalt; D004247:DNA; D005419:Flavonoids; D019833:Genistein; D046934:Ginkgolides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018696:Neuroprotective Agents; D010936:Plant Extracts; D012333:RNA, Messenger; C497444:Hif1a protein, rat; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract; C018021:cobaltous chloride; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one