Role of GABAergic antagonism in the neuroprotective effects of bilobalide

Abstract

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.

Identification of a Novel GABAA Receptor Channel Ligand Derived from Melissa officinalis and Lavandula angustifolia Essential Oils

“…Although the (Mo) constituent(s) demonstrated antagonistic effects, potential therapeutic effects of (Mo) and its constituent(s) need to be investigated further. Bilobalide, a single natural product sesquiterpene trilactone derived from Ginkgo biloba, which has been used for the treatment of AD displayed a similar inhibitory effect on GABA A receptor as seen herein, and also neuroprotective effects, presumably through other mechanisms [21], again similar to that observed for Melissa essential oil. Electrophysiological studies have shown that (Mo) depress membrane excitability at low concentrations [18], despite this effect upon GABA A receptor at higher concentrations.…”

GABA‐modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence

“…One investigation examined further the GABA‐A mechanisms of action for bilobalide in rat hippocampal tissue and reported a blocking of GABA‐induced chloride uptake in these cells at low potency. In turn, GABA was found to partially antagonise bilobalide's inhibitory actions (Kiewert et al, ). One recent study reported that both bilobalide and ginkgolide B selectively inhibited structurally‐varied GABA‐A positive modulator agent actions when tested in Xenopus oocytes (Ng, Duke, Hinton, & Johnston, ).…”

Ginkgo Extract EGb761 Confers Neuroprotection by Reduction of Glutamate Release in Ischemic Brain

“…Bilobalide has been found to improve mitochondrial activity and to preserve ATP levels during ischemia [3,13]. We have investigated interactions of bilobalide with amino acid neurotransmitters such as GABA, glycine, and glutamate [14,15]. Very recently, several constituents of EGb761 were implied in the induction of heme oxygenase-1 in ischemic neurons [16].…”