Heme oxygenase 1 beneficial role in permanent ischemic stroke and in Gingko biloba (EGb 761) neuroprotection

摘要

Ginkgo biloba extract, EGb 761, a popular and standardized natural extract, contains 24% ginkgo-flavonol glycosides and 6% terpene lactones. EGb 761 is used worldwide to treat many ailments, and while a number of studies have shown its neuroprotective properties, the mechanisms of action have not been elucidated fully. We hypothesize that EGb 761 and some of its bioactive components [Bilobalide (BB), Ginkgolide A (GA), Ginkgolide B (GB), and Terpene Free Material (TFM)] could provide neuroprotection ischemic conditions through heme oxygenase 1 (HO1). Mice were subjected permanent distal middle cerebral artery occlusion (pMCAO) and survived for 7 days. HO1^-/- mice showed significantly higher (p<0.05) infarct volume and Neurologic Deficit Scores (NDS) as compared to their wildtype (WT) counterparts. In another cohort, mice subjected to pMCAO and treated at 4 h of pMCAO with 100mg/kg EGb 761 6mg/kg BB, GA, GB, or 10mg/kg TFM showed significantly lower (p<0.05) infarct volumes (BB; 29.0±3.9%, GA; 31.3±4.0%, GB; 32.0±3.8%, TFM; 32.5±3.5%, and 761; 27.4±4.5%) than those in the vehicle-treated mice (46.0±3.7%). Similarly, were lower in BB: 7.1±1.8, GA; 7.4±2.1, GB; 7.9±1.8, TFM; 7.7±1.7, and EGb 6.8±2.0 groups as compared with the vehicle-treated group (13.8±1.5). Interestingly, the protective effect of EGb 761 was essentially lost when HO1 knockout mice were treated with EGb 761. In another cohort, HO1, VEGF and eNOS protein levels in the cortices appeared to be higher in EGb 761 and BB but not in GA, GB and TFM treated groups. Together, these results suggest that HO1 plays, at least in part, an important role in the neuroprotective mechanism of EGb 761 and in delayed ischemia. Targeting this pathway could lead to neuroprotective agents against ischemic stroke.