Protection by EGb 761 against beta-amyloid-induced neurotoxicity: involvement of NF-kappaB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation.
Abeta 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-kappaB and MAPK pathways. We demonstrate on neuroblastoma cell line N2a that EGb 761 could prevent the activation of NF-kappaB, ERK1/2, and JNK pathways induced by Abeta. 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 Abeta to insoluble fibrils is a crucial step in Abeta-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 Abeta fibril (fAbeta) formation in vitro. Finally we show that Abeta 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 fAbeta formation. Interestingly it could also protect cells against Abeta toxicity. Our study demonstrates that the protection of neuronal cells by EGb 761 against Abeta could involve different mechanisms as the regulation of several key intracellular pathways and the inhibition of fAbeta formation and implicate more than its free radical scavenging property.
Longpré
Fanny
F
INRS, Institut Armand Frappier, Université du Québec, 245 boulevard Hymus, Pointe Claire, H9R1G6/ INAF, Univ. Laval, Quebec, Canada.
Garneau
Philippe
P
Christen
Yves
Y
Ramassamy
Charles
C
D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D052160:Benzothiazoles; D002470:Cell Survival / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D020441:Ginkgo biloba / Q000737:chemistry; D046934:Ginkgolides / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008854:Microscopy, Electron; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D010936:Plant Extracts / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000187:drug effects*; D056564:Sirtuin 1; D037761:Sirtuins / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000096983:Ginkgo Extract
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005419:Flavonoids; D046934:Ginkgolides; D007783:Lactones; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010936:Plant Extracts; D056564:Sirtuin 1; D037761:Sirtuins; D013844:Thiazoles; C518518:CP 205; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract; C009462:thioflavin T; C045856:ginkgolide B; C447939:SIRT1 protein, human