Protection of mitochondrial respiration activity by bilobalide.
Mitochondria alteration is an early event in ischemia-induced damage, and its prevention improves tissue survival upon reperfusion. Adenine translocase and complex I activities are rapidly affected by ischemia. Ginkgo biloba extract demonstrates anti-ischemic properties attributable to the terpenoid fraction, mainly due to the presence of bilobalide. The mechanism of the protection afforded by bilobalide is not yet known. In this work, the effects of bilobalide on mitochondrial respiration were investigated. Mitochondria isolated from rats treated with bilobalide (2 to 8 mg/kg) showed a dose-dependent increase in the respiratory control ratio, due to a lower oxygen consumption during state 4. Bilobalide also decreased the sensitivity of oxygen consumption to inhibition of complex I by Amytal or to inhibition of complex III by antimycin A or myxothiazol. There was no protection of complexes IV and V. It also increased the activity of complex I but not of adenine translocase. Similar effects were also obtained in vitro when control mitochondria were preincubated for 1 hr with 0.8 microg/mL bilobalide. Treatment of the rats with 8 mg/kg bilobalide also prevented the ischemia-induced decrease in state 3 of the mitochondrial respiration and thus the decrease in RCR. The protective effect of bilobalide on cellular ATP content observed under ischemic conditions can be correlated with the above observations. By protecting complex I and III activities, bilobalide allows mitochondria to maintain their respiratory activity under ischemic conditions as long as some oxygen is present, thus delaying the onset of ischemia-induced damage. This mechanism provides a possible explanation for the anti-ischemic properties of bilobalide and of Ginkgo biloba extract in therapeutic interventions.
Laboratoire de Biochimie et Biologie Cellulaire, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium.
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D
Janssens
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J
Remacle
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K
Drieu
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C
Michiels
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D003517:Cyclopentanes / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004224:Diterpenes; D005260:Female; D005663:Furans / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046934:Ginkgolides; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D003517:Cyclopentanes; D004224:Diterpenes; D005663:Furans; D046934:Ginkgolides; D020011:Protective Agents; D016660:NAD(P)H Dehydrogenase (Quinone); C073710:bilobalide