Ginkgolides protect against amyloid-β1-42-mediated synapse damage in vitro

Background: The early stages of Alzheimer's disease (AD) are closely associated with the production of the A beta(1-42) peptide, loss of synapses and gradual cognitive decline. Since some epidemiological studies showed that EGb 761, an extract from the leaves of the Ginkgo biloba tree, had a beneficial effect on mild forms of AD, the effects of some of the major components of the EGb 761 extract (ginkgolides A and B, myricetin and quercetin) on synapse damage in response to A beta(1-42) were examined. Results: The addition of A beta(1-42) to cortical or hippocampal neurons reduced the amounts of cell associated synaptophysin, a pre-synaptic membrane protein that is essential for neurotransmission, indicating synapse damage. The effects of A beta(1-42) on synapses were apparent at concentrations approximately 100 fold less than that required to kill neurons; the synaptophysin content of neuronal cultures was reduced by 50% by 50 nM A beta(1-42). Pre-treatment of cortical or hippocampal neuronal cultures with ginkgolides A or B, but not with myrecitin or quercetin, protected against A beta(1-42)-induced loss of synaptophysin. This protective effect was achieved with nanomolar concentrations of ginkgolides. Previous studies indicated that the ginkgolides are platelet-activating factor (PAF) receptor antagonists and here we show that A beta(1-42)-induced loss of synaptophysin from neuronal cultures was also reduced by pre- treatment with other PAF antagonists (Hexa-PAF and CV6209). PAF, but not lyso-PAF, mimicked the effects A beta(1-42) and caused a dose-dependent reduction in the synaptophysin content of neurons. This effect of PAF was greatly reduced by pretreatment with ginkgolide B. In contrast, ginkgolide B did not affect the loss of synaptophysin in neurons incubated with prostaglandin E-2. Conclusion: Pre-treatment with ginkgolides A or B protects neurons against A beta(1-42)-induced synapse damage. These ginkgolides also reduced the effects of PAF, but not those of prostaglandin E-2, on the synaptophysin content of neuronal cultures, results consistent with prior reports that ginkgolides act as PAF receptor antagonists. Such observations suggest that the ginkgolides are active components of Ginkgo biloba preparations and may protect against the synapse damage and the cognitive loss seen during the early stages of AD.