The Existence of Aldose Reductase Inhibitors in Some Kampo Medicines (Oriental Herb Prescriptions)

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Abstract
Traditionally in Japan, some kampo medicines which contain Glycyrrhizae radix (GR) and Paeoniae radix (PR) have long been used for the treatment of diabetic neuropathy. Since we have previously shown that GR und PR have potent aldose reductase inhibitory activities, we further investigated the constituents of these two. The boiled water extract of GR was applied to Sephadex LH-20 column chromatography and 6 fractions (Frs. A, B, Cs, Cp, D, and E) were obtained. Frs. Cp and D were retreated in the same manner and 7 pure compounds (GUs 1-7) were obtained. The boiled water extract of PR was fractionated with ethyl acetate followed by n-butanol and 3 fractions (Frs. 1-3) were collected. Fr. 1 was retreated in the same manner and 2 pure compounds (PRs 1 and 2) were obtained. Among the GU compounds, GU-2 was the most potent inhibitor of rat lens aldose reductase (RLAR) by inhibiting 86% at the concentration of 1.0 µg/ml. The IC50 of GU-2 was 7.2 × 10-7 M. Furthermore, GU-2 markedly inhibited sorbitol accumulation in human red blood cells, having an IC50 of 2.9 × 10-5 M. GU-5 and PR-1 also inhibited RLAR (IC50:5.6 × 10-7 M and 6.3 × 10-7 M, respectively). The structures of GU-2, GU-5, and PR-1 were identitied as isoliquiritin, licuraside, and 1, 2, 3, 6-tetra-O-galloyl-β-D-glucose, respectively. Therefore, the present study has revealed that GR and PR contain aldose reductase inhibitors, and suggests that the mechanism by which kampo medicines are effective for diabetic neuropathy can be, at least in part, explained by their inhibition of aldose reductase activity in peripheral nerves.