H2O2 and PAF mediate Aβ1-42-induced Ca2+ dyshomeostasis that is blocked by EGb761

Abstract Calcium (Ca 2+ ) dyshomeostasis may be of pivotal importance in mediating the neurotoxic action of amyloid β peptide (Aβ), but the mechanism whereby Aβ disrupts Ca 2+ homeostasis remains unclear. Using hippocampal neuronal cultures, the present study investigated possible mechanisms underlying Ca 2+ dyshomeostasis induced by the oligomeric form of Aβ1-42 and two possible mediators of its toxicity, hydrogen peroxide (H 2 O 2 ) and platelet-activating factor (PAF). It was found that, both H 2 O 2 and PAF were able to reproduce each of the events induced by oligomeric Aβ1-42, including (a) Ca 2+ influx via N-methyl- d -aspartic acid (NMDA) receptors, (b) enhancement of Ca 2+ response to NMDA via activation of protein kinase C (PKC), (c) the increase of extracellular concentrations of glutamate and (d) the increase in cytosolic free Ca 2+ ([Ca 2+ ] i ). Moreover, each of these events could be blocked by Ginkgo biloba extract EGb761, a free radical scavenger with PAF antagonism, and by quercetin, a constituent with well-established free radical scavenging property. In contrast, ginkgolide B, another constituent of EGb761 with well-established PAF-antagonizing activity protected the neurons against Ca 2+ dyshomeostasis induced by Aβ1-42 and PAF, but not by H 2 O 2 . These results suggested the possibility that Aβ1-42-induced Ca 2+ dyshomeostasis might be mediated by formation of toxic mediators such as H 2 O 2 and PAF. Therefore, increased production of toxic mediators such as H 2 O 2 and PAF in the brain may be critical in the pathological mechanism of neurodegenerative diseases, particularly Alzheimer's disease (AD), and may serve as major therapeutic targets for these diseases.