Ginkgo biloba extract neuroprotective action is dependent on heme oxygenase 1 in ischemic reperfusion brain injury.
OBJECTIVE
Ginkgo biloba extracts are now prescribed in several countries for their reported health benefits, particularly for medicinal properties in the brain. The standardized Ginkgo extract, EGb761, has been reported to protect neurons against oxidative stress, but the underlying mechanisms are not fully understood.


METHODS
To characterize the oral consumption of EGb761 in transient ischemia, we performed the middle cerebral artery occlusion (MCAO) filament model in wild-type and heme oxygenase 1 (HO-1) knockouts. Mice were pretreated for 7 days before the transient occlusion or posttreated acutely during reperfusion; then neurobehavioral scores and infarct volumes were assessed. Furthermore, primary cortical neuronal cultures were used to investigate the contribution of the antioxidant enzyme HO-1 in the EGb761-associated cytoprotection.


RESULTS
Mice that were pretreated with EGb761 had 50.9+/-5.6% less neurological dysfunction and 48.2+/-5.3% smaller infarct volumes than vehicle-treated mice; this effect was abolished in HO-1 knockouts. In addition to the prophylactic properties of EGb761, acute posttreatment 5 minutes and 4.5 hours after reperfusion also led to significant reduction in infarct size (P<0.01). After our previous demonstration that EGb761 significantly induced HO-1 levels in a dose- and time-dependent manner in neuronal cultures, here we revealed that this de novo HO-1 induction was required for neuroprotection against free radical damage and excitotoxicity as it was significantly attenuated by the enzyme inhibitor.


CONCLUSIONS
These results demonstrate that EGb761 could be used as a preventive or therapeutic agent in cerebral ischemia and suggest that HO-1 contributes, at least in part, to EGb761 neuroprotection.
Saleem
Sofiyan
S
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Zhuang
Hean
H
Biswal
Shyam
S
Christen
Yves
Y
Doré
Sylvain
S
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005663:Furans / Q000494:pharmacology; D020441:Ginkgo biloba; D046934:Ginkgolides / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D020218:Response Elements / Q000187:drug effects; D000096983:Ginkgo Extract
D000975:Antioxidants; D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D005663:Furans; D046934:Ginkgolides; D018698:Glutamic Acid; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010936:Plant Extracts; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract; C496542:Hmox1 protein, mouse; C073710:bilobalide