title: Neurodegeneration after transient brain ischemia in aged mice: beneficial effects of bilobalide.
abstract: Bilobalide, an active constituent of Ginkgo biloba, has neuroprotective properties in experimental stroke models, but nearly all published studies were carried out in young animals. As ischemic strokes in humans are much more frequent in old age, we investigated bilobalide's effects in aged mice (age 18-22 month) using a model of transient ischemia induced by occlusion of the middle cerebral artery (MCAO) for 60 min. When bilobalide was administered locally into the striatum via microdialysis, a significant reduction of infarct size by almost 70% was observed. Concomitantly, the extensive, twelve-fold increase of extracellular glutamate which was observed in untreated animals was strongly reduced during the infusion of bilobalide. Glucose levels, in contrast, were not affected by bilobalide. In further experiments, bilobalide was given as an intraperitoneal injection (10/mg/kg) 1h before MCAO onset. ATP levels (measured in brain homogenates) were significantly reduced by transient MCAO but pretreatment with bilobalide prevented this loss. In ex vivo experiments with isolated mitochondria from aged mice, we found that the activity of the mitochondrial respiratory chain was only slightly impaired after 60 min of ischemia, and bilobalide showed no benefit in this experiment. However, aged mitochondria proved to be very sensitive to calcium-induced swelling which was significantly increased after ischemia. In this assay, pretreatment with bilobalide lowered the extent of swelling nearly to control levels. In behavioural tests, pretreatment of aged mice with bilobalide significantly improved the outcome in the Rotarod and the Corner test. In conclusion, aged mice show some differences in their response to transient ischemia when compared with young mice. Bilobalide has prominent neuroprotective properties in mice of all ages.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Schwarzkopf
authors.forename: Konrad A
authors.initials: KA
authors.lastname: Koch
authors.forename: Jochen
authors.initials: J
authors.lastname: Klein
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D003517:Cyclopentanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005663:Furans / Q000627:therapeutic use*; D046934:Ginkgolides / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017551:Microdialysis; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009097:Multienzyme Complexes / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010085:Oxidative Phosphorylation / Q000187:drug effects
chemical_list: D003517:Cyclopentanes; D005663:Furans; D046934:Ginkgolides; D009097:Multienzyme Complexes; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; C073710:bilobalide
keywords: Ageing; ETS; MCAO; Microdialysis; Middle cerebral artery occlusion; Mitochondrial respiration; Mitochondrial swelling; OXPHOS; Stroke; electron transfer system; mPT; middle cerebral artery occlusion; mitochondrial permeability transition pore; oxidative phosphorylation