Most herbal medicines that are orally administrated have been known to be metabolized before they are absorbed from the gastrointestinal tract. We, therefore, examined the effects of 20(S)-ginsenosides Rb1, Rg1 and Rg3, the three most commonly studied ginsenosides in the central nervous system, and their main metabolites on NMDA receptors using fura-2-based digital imaging and perforated whole-cell patch-clamp techniques. Among the nine ginsenosides tested, 20(S)-ginsenoside Rh2 (20(S)-Rh2) along with 20(S)-ginsenoside Rg3 (20(S)-Rg3) produced the highest inhibitory effect in cultured hippocampal neurons. Although 20(S)-Rg3 and 20(S)-Rh2 selectively targeted NMDA receptors with similar potency, they produced additive effects and seemed to modulate different NMDA receptor regulatory sites. As a competitive antagonist, 20(S)-Rh2 seems to inhibit the receptor via its interaction with polyamine-binding sites, and 20(S)-Rg3 does so using glycine-binding sites. Therefore, these results suggest that the treatment of 20(S)-Rh2, a newly identified active ingredient of ginseng, might be a novel preventive candidate in treating neurodegenerative disorders.
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