Modifications of Aliphatic Side Chain of 20(S)-Ginsenoside Rg₃ Cause an Enhancement or Loss of Brain Na⁺ Channel Current Inhibitions

Abstract

A line of evidence has shown that ginsenoside Rg₃ (Rg₃) could be one of bioactive ligands in brain Na⁺ channel regulations. Rg₃ exists as stereoisomer of 20(R)- or 20(S)-form. Rg₃ consists of three different parts; steroid- like backbone structure, carbohydrate portion, and aliphatic side chain [–CH₂CH₂CH=C(CH₃)₂], which is coupled to the carbon-20 of backbone structure. In the previous report, we demonstrated that 20(S)- but not 20(R)-Rg₃ and carbohydrate portion of Rg₃ play important roles in rat brain Na_V1.2 channel regulations. However, little is known about the role of aliphatic side chain coupled to the carbon-20 in brain Na⁺ channel regulations. In the present study, we prepared Rg₃ derivatives by modifying the aliphatic side chain of Rg₃, remaining with backbone structure and carbohydrate portion intact, and examined the effects of Rg₃ derivatives on Na⁺ channel activity. We found that reduction of double bond in aliphatic side chain of Rg₃ exhibited agonistic actions in Na⁺ channel current inhibitions by shifting concentration–response curve to leftward by three-fold, whereas deletion, hydroxylation, or oxygenation of aliphatic side chain caused an attenuation or loss of Na⁺ channel current inhibitions. These results provide evidences that the aliphatic side chain of Rg₃ is also involved in Na⁺ channel regulations and further show a possibility that the aliphatic side chain of Rg₃ could be the target of chemical modifications for abolishment or potentiation of Rg₃ actions in Na⁺ channel regulations.