Preconditioning with Ginkgo biloba (EGb 761®) provides neuroprotection through HO1 and CRMP2

Abstract

Ginkgo biloba/EGb 761® (EGb 761) is a popular and standardized natural extract used worldwide for the treatment of many ailments. Although EGb 761 is purported to have a plethora of benefits, here, we were interested to study the neuroprotective properties of EGb 761 and its components and determine whether nuclear factor E2 (Nrf2)/heme oxygenase 1 (HO1) induction of the collapsin response mediator protein 2 (CRMP2) pathway contributes to neuroprotection. Mice were pretreated with EGb 761 or one of its constituents (bilobalide, ginkgolide A, ginkgolide B, and terpene free material [TFM]) for 7 days and then subjected to transient middle cerebral artery occlusion (tMCAO) and 48 h of reperfusion. All components except TFM significantly reduced infarct volumes and neurologic deficits. Next, we examined the antioxidant and neuritogenic properties of EGb 761 in primary neurons. Compared with vehicle-treated cells, pretreatment with EGb 761 significantly enhanced the survival of neurons exposed to tertiary butylhydroperoxide (t-BuOOH), hydrogen peroxide (H2O2), and N-methyl-D-aspartate (NMDA). Bilobalide and ginkgolide A also protected cells against NMDA-induced excitotoxicity. Immunofluorescence and Western blot analysis showed that EGb 761 pretreatment significantly increased the protein expression levels of Nrf2, HO1, GAPDH, β-actin, CRMP2, and histone H3 during t-BuOOH-induced oxidative stress. These findings suggest that EGb 761 not only has antioxidant activity but also neuritogenic potential. Demonstrating such effects for possible drug discovery may prove beneficial in stroke and ischemic brain injury.

EGb761 improves histological and functional recovery in rats with acute spinal cord contusion injury

“…[4][5][6] For example, EGb761 has neuroprotective effects and enhances neurogenesis after ischemic stroke. [7][8][9] As an antioxidant agent, EGb761 not only has neuritogenic and angiogenic potential but also has the potential to augment repair and has regeneration mechanisms following stroke. However, the therapeutic effect of EGb761 on SCI has not been evaluated.…”

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).…”

“…This has broadened the scope of EGb 761 beyond the traditional realm of neuroprotection to the restorative and recovery potential for stroke therapy. An important, recently established example is the discovery of the multifaceted actions of EGb 761-mediated upregulation of hemeoxygenase 1 (HO1) (Shah et al, 2011; Nada and Shah, 2012; Nada et al, 2014). HO1 is a stress-inducible anti-oxidant enzyme responsible for catabolizing pro-oxidant heme into carbon monoxide, bilirubin and biliverdin.…”

“…We have previously demonstrated that EGb 761 upregulates the expression of VEGF concomitant with that of HO1 (Shah et al, 2011). In addition, we have established the link between HO1 and collapsin response mediator protein 2 (CRMP2) in a study examining its neuritogenic potential (Nada and Shah, 2012). CRMP2 is a protein involved in neuronal development and neurite outgrowth, the inactivation of which is known to cause growth cone collapse (Crews et al, 2011; Higurashi et al, 2012).…”

Modulation Effects of Piracetam and Ginkgo Biloba on the Cognitive and Working Memory Functions: Psychometric Study

“…Mechanisms accredited to ginkgo comprise free-radical scavenging, antioxidant, anti-inflammatory and modulation of central neurotransmitter [2][3][4][5]. Additionally; it inhibits nitric oxide production during ischemia [6,7], ginkgolides present in ginkgo biloba have been classified as nootropic agent also; the haemorheological property of ginkgo and the assumed effects on neurotransmitters are reasonable mechanisms by which the ginkgo might not merely apply a protective effect against dementia but also improve standard cognition in normal healthy subjects [8,9].…”