Neuroprotection by bilobalide in ischemia: improvement of mitochondrial function.
Bilobalide, an active constituent of Ginkgo biloba, is known to have neuroprotective properties, but its mode of action remains unclear. In this study, bilobalide significantly reduced brain damage in mice (indicated by TTC staining) when given before transient middle cerebral artery occlusion (tMCAO). As measured by microdialysis in the ischemic striatum, local perfusion with bilobalide (10 microM) reduced ischemia-induced glutamate release by 70% while glucose levels were not affected. Mitochondria isolated from ischemic brain showed a decrease of respiration compared to non-ischemic controls. Treatment with bilobalide (10 mg/kg) before tMCAO improved respiratory capacity of complex I significantly when measured ex vivo. In addition, mitochondrial swelling induced ex vivo by calcium was used to estimate opening of the mitochondrial permeability transition pore. In this assay, the changes induced by tMCAO were completely reversed when mice had received pretreatment with bilobalide. We conclude that neuroprotection by bilobalide involves a mechanism in which the drug reverses ischemia-induced changes in mitochondria, leading to a reduction of glutamate release.
Pharmakologisches Institut für Naturwissenschaftler, Goethe Universittit Frankfurt am Main, Germany.
T M
TM
Schwarzkopf
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S
Hagl
G P
GP
Eckert
J
J
Klein
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D003517:Cyclopentanes / Q000494:pharmacology*; D005260:Female; D005663:Furans / Q000494:pharmacology*; D046934:Ginkgolides / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D051379:Mice; D017551:Microdialysis; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents; D010101:Oxygen Consumption / Q000502:physiology; D010539:Permeability
D003517:Cyclopentanes; D005663:Furans; D046934:Ginkgolides; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D005947:Glucose; C073710:bilobalide