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. 2014 Sep;22(5):445-52.
doi: 10.4062/biomolther.2014.051. Epub 2014 Sep 30.

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic Db/Db Mice

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Free PMC article

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic Db/Db Mice

Eunjung Moon et al. Biomol Ther (Seoul). .
Free PMC article

Abstract

The purpose of this study was to investigate the therapeutic effects of DA-9801, an optimized extract of Dioscorea species, on diabetic peripheral neuropathy in a type 2 diabetic animal model. In this study, db/db mice were treated with DA-9801 (30 and 100 mg/kg, daily, p.o.) for 12 weeks. DA-9801 reduced the blood glucose levels and increased the withdrawal latencies in hot plate tests. Moreover, it prevented nerve damage based on increased nerve conduction velocity and ultrastructural changes. Decrease of nerve growth factor (NGF) may have a detrimental effect on diabetic neuropathy. We previously reported NGF regulatory properties of the Dioscorea genus. In this study, DA-9801 induced NGF production in rat primary astrocytes. In addition, it increased NGF levels in the sciatic nerve and the plasma of type 2 diabetic animals. DA-9801 also increased neurite outgrowth and mRNA expression of Tieg1/Klf10, an NGF target gene, in PC12 cells. These results demonstrated the attenuation of diabetic peripheral neuropathy by oral treatment with DA-9801 via NGF regulation. DA-9801 is currently being evaluated in a phase II clinical study.

Keywords: DA-9801; Diabetic peripheral neuropathy; Dioscorea japonica Thunb; Dioscorea nipponica Makino; Nerve growth factor; Type 2 diabetes mellitus.

Figures

Fig. 1.
Fig. 1.
Effects of DA-9801 on diabetic peripheral neuropathy in type 2 diabetic db/db mice. To investigate the effects of DA-9801 on the improvement of diabetic peripheral neuropathy, we administered DA-9801 (30 and 100 mg/kg) once per day orally for 12 weeks in type 2 diabetic db/db mice. Then we evaluated (A) the blood glucose levels and (B) the thermal hyperalgesia latencies using hot plate test, and measured (C) nerve conduction velocity (NCV) in motor and sensory nerves. Statistical comparisons between different groups were performed using a one-way ANOVA test followed by Newman-Keuls multiple range test. Values with a superscript are significantly different from the control group (Ap<0.05 and Bp<0.01) or LA-treated group (ap<0.05) or GABA-treated group (αp<0.05). We also confirmed (D) the sciatic nerve histology using electron microscopy, and then (E) the axon diameter and (F) the thickness of the myelin sheath in the sciatic nerves. *p<0.05 and **p<0.01 indicate statistically significant differences from the control group (Student’s t-test). α-Lipoic acid (LA, 50 mg/kg) and gabapentin (GABA, 100 mg/kg) were used as positive controls. All data are expressed as mean ± S.E.M.
Fig. 2.
Fig. 2.
Effects of DA-9801 on NGF regulation. To determine the effect of DA-9801 on NGF production, rat primary astrocytes were treated with various concentrations of DA-9801. After 24 h, (A) NGF content in the medium was measured using a rat βNGF assay kit. (B) NGF mRNA expression was confirmed via reverse transcription PCR after 2 h of DA-9801 treatment. Also, we measured (C) NGF levels in the sciatic nerves and (D) the plasma of DA-9801-treated db/db mice. To investigate the NGF-mimetic activity of DA-9801, we treated PC12 cells with 125 μg/ml of DA-9801. The neurite outgrowth per cell was observed every other day, and (E) images were taken of randomly selected fields using a camera attached to a microscope at 4 days. (F) The neurite length was determined using the Optimas 6.5 program (Media Cybernetics, MD, USA). The differentiation of PC12 cells was scored as follows: cells without neurite outgrowth (0); cells bearing neurites as long as one cell diameter (1); cells bearing neurites two times longer in length than their diameter (2); and cells that had synapse-like neurites (4). (G) We also detected Tieg1/Klf10 mRNA by reverse transcription PCR after 6 h of DA-9801 treatment. In this study, 50 ng/ml NGF was used as a positive control. (A) and (F) were expressed as mean ± S.D. and ***p<0.001 indicate statistically significant differences from the control group (Student’s t-test). (C) and (D) were expressed as mean ± S.E.M. Statistical comparisons between different groups were performed using a one-way ANOVA test followed by Newman-Keuls multiple range test. (Ap<0.05, Bp<0.01 and Cp<0.001 compared with control mice. ap<0.05 and bp<0.01 compared with LA-treated mice. αp<0.05, βp<0.01 and γp<0.001 compared with GABA-treated mice).

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