Excitotoxic Hippocampal Membrane Breakdown and its Inhibition by Bilobalide: Role of Chloride Fluxes

Abstract

We have previously shown that hypoxia and N-methyl-D-aspartate (NMDA) receptor activation induce breakdown of choline-containing phospholipids in rat hippocampus, a process which is mediated by calcium influx and phospholipase A (2) activation. Bilobalide, a constituent of Ginkgo biloba, inhibited this process in a potent manner (Weichel et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 360, 609-615, 1999). In this study, we used fluorescence microscopy and radioactive flux measurements to show that bilobalide does not interfere with NMDA-induced calcium influx. Instead, bilobalide seems to inhibit NMDA-induced fluxes of chloride ions through ligand-operated chloride channels. In our experiments, substitution of chloride in the superfusion medium fully blocked the effect of NMDA on choline release from hippocampal slices, while the presence of chloride transport inhibitors (furosemide, DIDS) was partially antagonistic. The inhibitory effect of bilobalide and of HA-966, a glycine B receptor antagonist, on NMDA-induced choline release was attenuated in the presence of glycine. The inhibitory effect of bilobalide, but not that of HA-966, was also antagonized by GABA. The inhibitory effect of MK-801, an NMDA channel blocker, on choline release was insensitive to glycine. We conclude from our findings that bilobalide inhibits an NMDA-induced chloride flux through glycine/GABA-operated channels, thereby preventing NMDA-induced breakdown of membrane phospholipids. This effect is expected to contribute to the neuroprotective effects of ginkgo biloba extracts.

Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation

“…Furthermore, bilobalide had an anti-edemic effect in the ipsilateral hemisphere but did not have any effect on the contralateral hemisphere. Bilobalide’s anti-edema effect was involved in improving the maintenance of ionic balances, and astrocytes might be the target [ 66 , 67 ]. Since an outstanding anti-inflammatory effect of bilobalide has been reported recently [ 33 ], we assume that the anti-edema mechanisms of bilobalide might also relate to its anti-inflammatory activity.…”

Gene Regulatory Effects of Ginkgo biloba Extract and Its Flavonol and Terpenelactone Fractions in Mouse Brain

“…However, dietary treatment with the terpenelactone fraction led also in our study to a significant decrease in App mRNA, at least in hippocampus. Several studies reported that in particular the terpenelactones could be the most relevant constituents with regard to the neuroprotective properties of EGb761 [6–10]. In this context, Ahlemeyer and Kriegelstein analysed data from in vitro and in vivo studies regarding potential beneficial effects of EGb761; they concluded that the terpenelactones including ginkgolide B and bilobalide may be the most effective constituents of EGb761 against oxidative damage in the brain [9].…”

“…In a study with neuronal PC12 cells, the Ginkgo biloba terpenelactone bilobalide diminished the cytotoxic effects of Amyloid β (Aβ) fragments that play a decisive role in AD pathology [6, 7]. Other studies also found evidence that the terpenelactone fraction of EGb761 might be more relevant for the neuroprotective activities of the extract [7–10]. A gene array study suggested that the gene-regulatory activity of Ginkgo biloba on gene expression in the brain could be involved in its neuroprotective activity [11].…”

A double-blind, randomised cross-over study to evaluate the absorption of a commercially available Ginkgo biloba extract compared to the liposomal extract Ginkgosome

“…A main area of interest for GBE research has focused on its beneficial effects for reducing the symptoms of age-related cognitive decline, including mild memory impairment, cerebral insufficiency and dementia including Alzheimer's disease [4][5][6][7][8]. GBE may also protect from the damaging effects of ischaemic events including neuronal degeneration [9,10]. As such, sustainable practices are vital for the preservation/conservation of the Ginkgo biloba tree while allowing for the continued production of products using Ginkgo biloba.…”