Ginkgolide B inhibits the neurotoxicity of prions or amyloid-β1-42

Background: Neuronal loss in Alzheimer's or prion diseases is preceded by the accumulation of fibrillar aggregates of toxic proteins (amyloid-beta(1-42) or the prion protein). Since some epidemiological studies have demonstrated that the EGb 761 extract, from the leaves of the Ginkgo biloba tree, has a beneficial effect on Alzheimer's disease, the effect of some of the major components of the EGb 761 extract on neuronal responses to amyloid-beta(1-42), or to a synthetic miniprion (sPrP106), were investigated. Methods: Components of the EGb 761 extract were tested in 2 models of neurodegeneration. SH-SY5Y neuroblastoma cells were pre-treated with ginkgolides A or B, quercetin or myricetin, and incubated with amyloid-beta(1-42), sPrP106, or other neurotoxins. After 24 hours neuronal survival and the production of prostaglandin E-2 that is closely associated with neuronal death was measured. In primary cortical neurons apoptosis (caspase-3) in response to amyloid-beta(1-42) or sPrP106 was measured, and in co-cultures the effects of the ginkgolides on the killing of amyloid- beta(1-42) or sPrP106 damaged neurons by microglia was tested. Results: Neurons treated with ginkgolides A or B were resistant to amyloid-beta(1-42) or sPrP106. Ginkgolide-treated cells were also resistant to platelet activating factor or arachidonic acid, but remained susceptible to hydrogen peroxide or staurosporine. The ginkgolides reduced the production of prostaglandin E-2 in response to amyloid-beta(1-42) or sPrP106. In primary cortical neurons, the ginkgolides reduced caspase-3 responses to amyloid-beta(1-42) or sPrP106, and in co-culture studies the ginkgolides reduced the killing of amyloid-beta(1-42) or sPrP106 damaged neurons by microglia. Conclusion: Nanomolar concentrations of the ginkgolides protect neurons against the otherwise toxic effects of amyloid-beta(1-42) or sPrP106. The ginkgolides also prevented the neurotoxicity of platelet activating factor and reduced the production of prostaglandin E-2 in response to platelet activating factor, amyloid-beta(1-42) or sPrP106. These results are compatible with prior reports that ginkgolides inhibit platelet-activating factor, and that platelet-activating factor antagonists block the toxicity of amyloid-beta(1-42) or sPrP106. The results presented here suggest that platelet-activating factor antagonists such as the ginkgolides may be relevant treatments for prion or Alzheimer's diseases.