Inhibitory activities of selected Kampo formulations on human aldose reductase.

Toshihisa Onoda,Masahiko Obayashi,Takahiro Fukazawa,Kazuo Koike,Chikako Ishikawa,Wei Li

doi:10.1186/1472-6882-14-435

Toshihisa Onoda, Masahiko Obayashi + Show 4 more

Open Access

https://doi.org/10.1186/1472-6882-14-435

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Abstract

BackgroundDiabetes complications include various symptoms such as diabetic neuropathy and cognitive disorders. Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway and is one of the causal factors of diabetes complications. In this study, the bioactivities of eight selected Kampo formulations that are currently in clinical use for diabetes complications were assessed using human AR (hAR) inhibitory activity as the primary parameter to explore the possibilities of novel clinical applications of these formulations in the treatment of diabetes complications.MethodsThe hAR inhibitory activities of four Kampo formulations that are clinically used for diabetic neuropathy, four Kampo formulations that are used for cognitive disorders, and a total of 21 component crude drugs were measured. Furthermore, the hAR inhibitory activity of Glycyrrhizae Radix preparata was measured to determine the effect of frying, which is one of the specific processing of Glycyrrhizae Radix. hAR inhibitory activity was determined by measuring the rate of decline in the absorbance of NAPH at 340 nm using 0.5 mM NADPH, 10 mM D,L-glyceraldehyde, and 3.6 mU/mL hAR in phosphate buffer solution (0.2 M, pH 6.2).ResultsAll of the Kampo formulations exhibited significant hAR inhibitory activity; Chotosan exhibited particularly strong activity. Among the 21 crude drugs tested, adequate inhibitory activities were found for the following, in descending order of activity: Glycyrrhizae Radix > Paeoniae Radix > Chrysanthemi Flos > Cinnamomi Cortex > Phellodendri Cortex > Uncariae Uncis cum Ramulus > Bupleuri Radix. Glycyrrhizae Radix preparata exhibited an inhibitory activity that was nearly identical to that of Glycyrrhizae Radix.ConclusionsDespite their seemingly different treatment objectives, all of the Kampo formulations that are clinically used for diabetes complications demonstrated significant hAR inhibitory activity. This activity might underlie the characteristic multi-target effects of Kampo formulations. Although the overall effect of a Kampo formulation is certainly difficult to evaluate based on specific herbal medications or components, the approach as taken in this study might nonetheless contribute to further advancement in the development of new drugs via the review of proper usage and re-examination of the chemical compounds from a new perspective.

Highlights

Diabetes complications include various symptoms such as diabetic neuropathy and cognitive disorders
The pathogeneses of diabetes complications are mediated by a broad array of factors, such as the formation of vascular lesions via the reconstruction of vascular walls due to the formation of advanced glycation end products (AGE) that are associated with the accelerated nonenzymatic protein glycosylation, enhancement of oxidative stress due to active enzyme generation following glycation, blood flow disorders and neovascularization via PKC-β2 activation in vascular smooth muscle and endothelial cells, and enhanced metabolism in the polyol pathway via aldose reductase (AR) [5,6,7,8]
Because examinations of the crude drugs have been performed in the past [19], we focused on the crude drugs of the Kampo formulations, including Uncariae Uncis cum Ramulus, in the present study

Summary

Introduction

Diabetes complications include various symptoms such as diabetic neuropathy and cognitive disorders. Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway and is one of the causal factors of diabetes complications. The pathogeneses of diabetes complications are mediated by a broad array of factors, such as the formation of vascular lesions via the reconstruction of vascular walls due to the formation of advanced glycation end products (AGE) that are associated with the accelerated nonenzymatic protein glycosylation (glycation), enhancement of oxidative stress due to active enzyme generation following glycation, blood flow disorders and neovascularization via PKC-β2 activation in vascular smooth muscle and endothelial cells, and enhanced metabolism in the polyol pathway via aldose reductase (AR) [5,6,7,8]. Sorbitol accumulates in cells and causes increases in osmotic pressure that lead to the suppression of cell functions and eventually peripheral neuropathy [8]. Depletion of the coenzyme NADPH causes the suppression of nitric oxide synthase activity, reduction of reduced glutathione production, and aberrant activation of PKC, which lead to the onset of peripheral neuropathy [9]

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