Bilobalide, a component of the Ginkgo biloba extract (EGb 761), protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity.
In this study, the effect of bilobalide, a purified terpene lactone component of the Ginkgo biloba extract (EGb 761), and EGb 761 against ischemic injury and against glutamate-induced excitotoxic neuronal death was compared. In the case of ischemic injury, neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in the hippocampal regions of gerbils was measured. A significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons at 7-days of reperfusion after 5 min of transient global forebrain ischemia. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before ischemia progressively protected hippocampal CA1 neurons against ischemia-induced neuronal death and reductions in COX III mRNA. In rat cerebellar neuronal cultures, addition of bilobalide or EGb 761 protected in a dose-dependent manner against glutamate-induced excitotoxic neuronal death [effective concentration (EC50) = 5 microg/ml (12 microM) forbilobalide and 100 microg/ml for EGb 761]. These results suggest thatboth EGb 761 and bilobalide protect against ischemia-induced neuronal death in vivo and glutamate-induced neuronal death in vitro by synergistic mechanisms involving anti-excitotoxicity, inhibition of free radical generation, scavenging of reactive oxygen species, and regulation of mitochondrial gene expression.
Chandrasekaran
Krish
K
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore 21201, USA. kchandra@anesthlab.umm.edu
Mehrabian
Zara
Z
Spinnewyn
Brigitte
B
Chinopoulos
Christos
C
Drieu
Katy
K
Fiskum
Gary
G
D000284:Administration, Oral; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects; D003517:Cyclopentanes / Q000008:administration & dosage / Q000494:pharmacology*; D004224:Diterpenes; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology*; D005849:Gerbillinae; D020441:Ginkgo biloba; D046934:Ginkgolides; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D015427:Reperfusion Injury / Q000188:drug therapy; D000096983:Ginkgo Extract
D003517:Cyclopentanes; D004224:Diterpenes; D003576:Electron Transport Complex IV; D005663:Furans; D046934:Ginkgolides; D018698:Glutamic Acid; D018696:Neuroprotective Agents; D010936:Plant Extracts; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract; C073710:bilobalide