Bilobalide, a constituent of Ginkgo biloba, has neuroprotective properties. Its mechanism of action is unknown but it was recently found to block GABA A receptors. The goal of this study was to test the potential role of a GABAergic mechanism for the neuroprotective activity of bilobalide. In rat hippocampal slices exposed to NMDA, release of choline indicates breakdown of membrane phospholipids. NMDA-induced choline release was almost completely blocked in the presence of bilobalide (10 μM) and under low-chloride conditions. Bicuculline (100 μM), a competitive antagonist at GABA A receptors, reduced NMDA-induced choline release to a small extent (−23%). GABA (100 μM) partially antagonized the inhibitory action of bilobalide. Exposure of hippocampal slices to NMDA also caused edema formation as measured by increases of tissue water content. NMDA-induced edema formation was suppressed by bilobalide and by low-chloride conditions. Bicuculline exerted partial protection (by 30%) while GABA reduced bilobalide's effect by about one third.To investigate bilobalide's interaction with GABA A receptors directly, we measured binding of [ 35 S-TBPS] to rat cortical membranes. TBPS binding was competitively inhibited by bilobalide in the low micromolar range (IC 50 =3.7 μM). As a functional test, we determined 36 chloride flux in rat corticohippocampal synaptoneurosomes. GABA (100μM) significantly increased 36 chloride flux (+65 %), and this increase was blocked by bilobalide, but with low potency (IC 50 : 39 μM). We conclude that, while antagonism of GABA A receptors may contribute to bilobalide's neuroprotective effects, additional mechanisms must be postulated to fully explain bilobalide's actions.

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