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

beta Amyloid (A beta) treatment induced free radical production and increased glucose uptake, apoptosis and cell death in PC12 nerve cells. Addition of the standardized extract of Ginkgo biloba leaves, EGb 761 together with the A beta protein prevented, in a dose-dependent manner, the A beta -induced free radical production, increased glucose uptake, apoptosis and cell death. However, pretreatment of the cells with EGb 761 did not rescue the cells from the A beta -induced toxicity although it prevented the A beta -induced reactive oxygen species generation. Moreover, the terpene and flavonoid-free EGb 761 extract, HE 208, Although inhibited the A beta -induced increased glucose uptake, it failed to protect the cells from apoptosis and cytotoxicity induced by A beta. In conclusion, these results indicate that the terpenoid and flavonoid constituents of EGb 761, acting probably in combination with components present in HE 208, are responsible for rescuing the neuronal 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 diffusible neurotoxic soluble ligands (ADDLs), suggested to be involved in the pathogenesis of Alzheimer's disease. (C) 2001 Elsevier Science B.V. All rights reserved.