ot: Ginkgolides protect against amyloid-beta1-42-mediated synapse damage in vitro

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Ginkgolides protect against amyloid-beta1-42-mediated synapse damage in

vitro

Clive Bate email, Mourad Tayebi email and Alun email

Molecular Neurodegeneration 2008, 3:1doi:10.1186/1750-1326-3-1

Published: 7 January 2008

http://www.molecularneurodegeneration.com/content/3/1/1/abstract

http://www.molecularneurodegeneration.com/content/pdf/1750-1326-3-1.pdf

Abstract (provisional)

Background

The early stages of Alzheimer's disease (AD) are closely associated with

the production of the Abeta1-42 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 Abeta1-42 were examined.

Results

The addition of Abeta1-42 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 Abeta1-42 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 50nM Abeta1-42. Pre-treatment of cortical or hippocampal neuronal

cultures with ginkgolides A or B, but not with myrecitin or quercetin,

protected against Abeta1-42-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 Abeta1-42-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 Abeta1-42 and

caused a dose-dependent reduction in the synaptophysin content of

neurons. This effect of PAF was greatly reduced by pre-treatment with

ginkgolide B. In contrast, ginkgolide B did not affect the loss of

synaptophysin in neurons incubated with prostaglandin E2.

Conclusion

Pre-treatment with ginkgolides A or B protects neurons against

Abeta1-42-induced synapse damage. These ginkgolides also reduced the

effects of PAF, but not those of prostaglandin E2, 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.