Inhibitory effect of 20(S)-ginsenoside Rh2 on NMDA receptor-mediated signals in rat hippocampal neurons

다국어 초록 (Multilingual Abstract)

The glutamate receptors are ligand-gated ion channels that mediate the excitatory neurotransmission in the brain. Among the subtypes of glutamate receptors, N-methyl-D-aspartate (NMDA) receptors play important roles in development, formation of synaptic plasticity, and neurotoxicity due to its high permeability through calcium entry. The NMDA receptors have at least six modulation sites including NMDA-, glycine-, Mg2+, Zn2+, H+, and polyamine-binding sites. Ginsenosides are the main molecular components responsible for the action of ginseng and more than 40 types of ginsenosides have been identified. In the previous study, it has been reported that ginseng inhibited hippocampal NMDA receptors and ginsenoside Rg3, among 11 different ginsenosides tested, is the main active component for the inhibition. In the present study, I have employed cultures of rat hippocampal neurons and examined the direct modulation of 20(S)-ginsenoside Rh2, the metabolite of 20(S)-ginsenoside Rg3, on NMDA receptor-induced changes in [Ca2+]i and -gated currents using fura-2-based digital imaging and whole-cell patch-clamp techniques, respectively. 20(S)-Ginsenoside Rh2 significantly inhibited NMDA-induced [Ca2+]i elevation: it produced in a similar potency with 20(S)-ginsenoside Rg3 and there was no effect by 20(R)-ginsenoside Rh2. However, 20(S)-ginsenoside Rh2 had a little on non-NMDA receptors. The effect of 20(S)-ginsenoside Rh2 occurred in a non-competitive way on NMDA- binding site and not significantly modified by glycine. However, spermine (200 μM), one of endogenous polyamines, shifted the 20(S)-ginsenoside Rh2 concentration response curves to the right without changing the maximal response, suggesting that 20(S)-ginsenoside Rh2 could competitively interact with the polyamine-binding site of NMDA receptors. Therefore, these results suggest that 20(S)-ginsenoside Rh2 protects NMDA-induced hippocampal neuronal death via a possible interaction with the polyamine-binding site of NMDA receptors in cultured hippocampal neurons