The Ginkgo biloba extract EGb 761 rescues the PC12 neuronal cells from beta-amyloid-induced cell death by inhibiting the formation of beta-amyloid-derived diffusible neurotoxic ligands

beta Amyloid (A beta) treatment induced free radical production and increas ed glucose uptake, apoptosis and cell death in PC12 nerve cells. Addition o f the standardized extract of Ginkgo biloba leaves, EGb 761 together with t he A beta protein prevented, in a dose-dependent manner, the A beta -induce d free radical production, increased glucose uptake, apoptosis and cell dea th. However, pretreatment of the cells with EGb 761 did not rescue the cell s from the A beta -induced toxicity although it prevented the A beta -induc ed reactive oxygen species generation. Moreover, the terpene and flavonoid- free EGb 761 extract, HE 208, Although inhibited the A beta -induced increa sed glucose uptake, it failed to protect the cells from apoptosis and cytot oxicity induced by A beta. In conclusion, these results indicate that the t erpenoid and flavonoid constituents of EGb 761, acting probably in combinat ion with components present in HE 208, are responsible for rescuing the neu ronal cells from A beta -induced apoptosis and cell death: their mechanism of action being distinct of their antioxidant properties. Because pre- and post-treatment with EGb 761 did not protect the cells from A beta -induced neurotoxicity, we examined whether EGb 761 interacts directly with A beta. Indeed, in vitro reconstitution studies demonstrated that EGb 761 inhibits, in a dose-dependent manner, the formation of beta -amyloid-derived diffusi ble neurotoxic soluble ligands (ADDLs), suggested to be involved in the pat hogenesis of Alzheimer's disease. (C) 2001 Elsevier Science B.V. All rights reserved.