title: H2O2 and PAF mediate Abeta1-42-induced Ca2+ dyshomeostasis that is blocked by EGb761.
abstract: Calcium (Ca2+) dyshomeostasis may be of pivotal importance in mediating the neurotoxic action of amyloid beta peptide (Abeta), but the mechanism whereby Abeta disrupts Ca2+ homeostasis remains unclear. Using hippocampal neuronal cultures, the present study investigated possible mechanisms underlying Ca2+ dyshomeostasis induced by the oligomeric form of Abeta1-42 and two possible mediators of its toxicity, hydrogen peroxide (H2O2) and platelet-activating factor (PAF). It was found that, both H2O2 and PAF were able to reproduce each of the events induced by oligomeric Abeta1-42, including (a) Ca2+ influx via N-methyl-D-aspartic acid (NMDA) receptors, (b) enhancement of Ca2+ 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 Ca2+ ([Ca2+]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 Ca2+ dyshomeostasis induced by Abeta1-42 and PAF, but not by H2O2. These results suggested the possibility that Abeta1-42-induced Ca2+ dyshomeostasis might be mediated by formation of toxic mediators such as H2O2 and PAF. Therefore, increased production of toxic mediators such as H2O2 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.
authors.affiliation: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University Guangzhou, Guangdong 510080, China. shiyui431@126.com
authors.forename: Chun
authors.initials: C
authors.lastname: Shi
authors.forename: Fengming
authors.initials: F
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020441:Ginkgo biloba / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000096983:Ginkgo Extract
chemical_list: D016229:Amyloid beta-Peptides; D002118:Calcium; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D010446:Peptide Fragments; D010936:Plant Extracts; D010972:Platelet Activating Factor; C075222:amyloid beta-protein (1-42); C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract