Protection by EGb 761 against β-amyloid-induced neurotoxicity: Involvement of NF-κB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation

Aβ peptide-induced toxicity is mediated through oxidative stress and is associated with an activation of intracellular signaling such as the redox-sensitive transcription factor NF-κB and MAPK pathways. We demonstrate on neuroblastoma cell line N2a that EGb 761 could prevent the activation of NF-κB, ERK1/2, and JNK pathways induced by Aβ. Furthermore, our results show that EGb 761 can also activate SIRT1. This activation could explain the reduction of NF-kB activity by promoting the deacetylation of Lys310 of subunit p65. On the other hand, aggregation of Aβ to insoluble fibrils is a crucial step in Aβ-induced neurotoxicity. Using fluorescence spectroscopy with thioflavin T and electron microscopy, we demonstrate that EGb 761 and its flavonoid fraction (CP 205) could prevent the Aβ fibril (fAβ) formation in vitro. Finally we show that Aβ is less toxic to N2a neuroblastoma cells when the peptide is previously incubated with the flavonoid fraction or EGb 761 during the fibril formation period. On the other hand, the ginkgolide compound BN 52021 was not able to prevent fAβ formation. Interestingly it could also protect cells against Aβ toxicity. Our study demonstrates that the protection of neuronal cells by EGb 761 against Aβ could involve different mechanisms as the regulation of several key intracellular pathways and the inhibition of fAβ formation and implicate more than its free radical scavenging property.