20(S)-ginsenoside Rh₂, a newly identified active ingredient of ginseng, inhibits NMDA receptors in cultured rat hippocampal neurons

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.