Ginkgolides protect PC12 cells against hypoxia-induced injury by p42/p44 MAPK pathway-dependent upregulation of HIF-1alpha 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-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.

• Authors: Zhu Li, Ke Ya, Wu Xiao-Mei, Yang Lei, Lu Yang, Qian Zhong Ming
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 103 Issue 2 Pg. 564-75 (Feb 01 2008) ISSN: 1097-4644 [Electronic] United States
• PMID: 17647269 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• Flavonoids
• Ginkgolides
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neuroprotective Agents
• Plant Extracts
• RNA, Messenger
• Ginkgo biloba extract
• Cobalt
• DNA
• Genistein
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• cobaltous chloride
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Cell Hypoxia (drug effects)
• Cobalt (toxicity)
• DNA (metabolism)
• Enzyme Induction (drug effects)
• Flavonoids (pharmacology)
• Genistein (pharmacology)
• Ginkgo biloba
• Ginkgolides (pharmacology)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics, physiology)
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinase 1 (biosynthesis, genetics)
• Mitogen-Activated Protein Kinase 3 (biosynthesis, genetics)
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• PC12 Cells (drug effects, metabolism)
• Plant Extracts (pharmacology)
• RNA, Messenger (biosynthesis)
• Rats