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

J. Klein; O. Weichel; M. Hilgert; J. Rupp; S. S. Chatterjee; H. Nawrath

doi:10.1055/s-2003-40453

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2003; 36: 78-83
DOI: 10.1055/s-2003-40453

Original Paper

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

J. Klein¹ ^{, 2} , O. Weichel¹ , M. Hilgert¹ , J. Rupp¹ , S. S. Chatterjee³ , H. Nawrath¹

¹Department of Pharmacology, Johannes Gutenberg University of Mainz, Mainz, Germany
²Department of Pharmaceutical Sciences, Texas Tech School of Pharmacy, Amarillo, TX, USA
³Section of Pharmacology, Dr. Willmar Schwabe Arzneimittel, Karlsruhe, Germany

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 A₂ 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.

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Jochen Klein, Ph. D.

Department of Pharmaceutical Sciences

Texas Tech School of Pharmacy

1300 Coulter Dr.

Amarillo, TX 79106

USA

Email: jklein@ama.ttuhsc.edu