Ginkgo Biloba Extract Neuroprotective Action Is Dependent on Heme Oxygenase 1 in Ischemic Reperfusion Brain Injury

Abstract

Background and Purpose 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. Conclusion 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.

Oxidative Stress and C-Reactive Protein in Patients with Cerebrovascular Accident ( Ischaemic Stroke ) : The Role of Ginkgo Biloba Extract

“…53,54 Saleem et al showed that the standardised EGb761 significantly improved the outcome in mice after cerebral ischaemia and reperfusion in terms of neurobehavioral function and infarct size without affecting physiological parameters. 55 Our findings suggest a potential role of G. biloba in acute ischaemic stroke, and the findings are important in view of the fact that stroke is, at present, the third leading cause of death worldwide. 1 The mechanisms by which G. biloba normalise the cerebral damage, and reduce oxidative stress and inflammation, can probably be attributed to the antioxidant effects of flavonoids combined with the anti-inflammatory properties of the terpenoids bilobalide and ginkgolides A, B, C, M, J, and the terpenoids antagonists of platelet-activating factor (PAF), making this natural extract plausible to use in the treatment of ischaemic stroke, which is characterised by both oxidative damage and inflammation.…”

Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1

“…In contrast, induction of HO-1 exerts potent protective effects in numerous preclinical disease models including sepsis, trauma, vascular proliferative disease, acute lung and liver injury, and cancer (1)(2)(3)(4)(5). A number of recent reports have demonstrated the benefits of HO-1 in the CNS, including the eye (6) and brain (7)(8)(9)(10)(11)(12). In the brain, expression of each HO isoform follows a distinct spatial and cell-specific distribution pattern.…”

Repair and regeneration properties of Ginkgo biloba after ischemic brain injury

“…We and others have unequivocally proven HO1 to be one of the prime targets of EGb 761-mediated protection, as observed in animal models of stroke and other conditions of oxidative stress (Chen et al, 2001; Zhuang et al, 2002; Saleem et al, 2008; Shah et al, 2011; Nada and Shah, 2012). EGb 761 enhances neurogenesis, and the crosstalk between HO1-induction and enhanced neurogenesis has only been recently discovered (Vanella et al, 2013; Nada et al, 2014).…”