Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

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

  • Received : 2014.05.07
  • Accepted : 2014.07.04
  • Published : 2014.09.30
Download PDF
⟨ Previous Next ⟩

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

References

  1. Anand, P., Terenghi, G., Warner, G., Kopelman, P., Williams-Chestnut, R. E. and Sinicropi, D. V. (1996) The role of endogenous nerve growth factor in human diabetic neuropathy. Nat. Med. 2, 703-707. https://doi.org/10.1038/nm0696-703
  2. Apfel, S. C., Arezzo, J. C., Brownlee, M., Federoff, H. and Kessler, J. A. (1994) Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res. 634, 7-12. https://doi.org/10.1016/0006-8993(94)90252-6
  3. Boden, G. (2001) Pathogenesis of type 2 diabetes. Insulin resistance. Endocrinol. Metab. Clin. North Am. 30, 801-815, v. https://doi.org/10.1016/S0889-8529(05)70216-4
  4. Calcutt, N. A. (2004) Experimental models of painful diabetic neuropathy. J. Neurol. Sci. 220, 137-139. https://doi.org/10.1016/j.jns.2004.03.015
  5. Canta, A., Chiorazzi, A., Meregalli, C., Carozzi, V., Oggioni, N., Lauria, G., Lombardi, R., Bianchi, R., Porretta-Serapiglia, C. and Cavaletti, G. (2009) Continuous buprenorphine delivery effect in streptozotocine-induced painful diabetic neuropathy in rats. J. Pain 10, 961-968. https://doi.org/10.1016/j.jpain.2009.04.003
  6. Choi, S. Z. and Son, M. W. (2011) Novel botanical drug for the treatment of diabetic neuropathy. Arch. Pharm. Res. 34, 865-867. https://doi.org/10.1007/s12272-011-0621-2
  7. Gao, X., Li, B., Jiang, H., Liu, F., Xu, D. and Liu, Z. (2007) Dioscorea opposita reverses dexamethasone induced insulin resistance. Fitoterapia 78, 12-15. https://doi.org/10.1016/j.fitote.2006.09.015
  8. Gerbitz, K. D., van den Ouweland, J. M., Maassen, J. A. and Jaksch, M. (1995) Mitochondrial diabetes mellitus: a review. Biochim. Biophys. Acta 1271, 253-260. https://doi.org/10.1016/0925-4439(95)00036-4
  9. Hayes, A. G., Sheehan, M. J. and Tyers, M. B. (1987) Differential sensitivity of models of antinociception in the rat, mouse and guineapig to mu-and kappa-opioid receptor agonists. Br. J. Pharmacol. 91, 823-832. https://doi.org/10.1111/j.1476-5381.1987.tb11281.x
  10. Hellweg, R. and Hartung, H. D. (1990) Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: a possible role for NGF in the pathogenesis of diabetic neuropathy. J. Neurosci. Res. 26, 258-267. https://doi.org/10.1002/jnr.490260217
  11. Hellweg, R., Raivich, G., Hartung, H. D., Hock, C. and Kreutzberg, G. W. (1994) Axonal transport of endogenous nerve growth factor (NGF) and NGF receptor in experimental diabetic neuropathy. Exp. Neurol. 130, 24-30. https://doi.org/10.1006/exnr.1994.1181
  12. Hikino, H., Konno, C., Takahashi, M., Murakami, M., Kato, Y., Karikura, M. and Hayashi, T. (1986) Isolation and hypoglycemic activity of dioscorans A, B, C, D, E, and F; glycans of Dioscorea japonica rhizophors. Planta Med. 168-171.
  13. Hiransai, P., Ratanachaiyavong, S., Itharat, A., Graidist, P., Ruengrairatanaroj, P. and Purintrapiban, J. (2010) Dioscorealide B suppresses LPS-induced nitric oxide production and inflammatory cytokine expression in RAW 264.7 macrophages: The inhibition of NF-kappaB and ERK1/2 activation. J. Cell. Biochem. 109, 1057-1063. https://doi.org/10.1002/jcb.22535
  14. Hsu, F. L., Lin, Y. H., Lee, M. H., Lin, C. L. and Hou, W. C. (2002) Both dioscorin, the tuber storage protein of yam (Dioscorea alata cv. Tainong No. 1), and its peptic hydrolysates exhibited angiotensin converting enzyme inhibitory activities. J. Agric. Food Chem. 50, 6109-6113. https://doi.org/10.1021/jf0203287
  15. Jin, H. Y., Kim, S. H., Yu, H. M., Baek, H. S. and Park, T. S. (2013) Therapeutic potential of dioscorea extract (DA-9801) in comparison with alpha lipoic acid on the peripheral nerves in experimental diabetes. J. Diabetes Res. 2013, 631218.
  16. Jung, S., Chung, J. S., Jang, S. M., Guh, J. O., Lee, H. J., Chon, S. U., Kim, K. M., Ha, S. B. and Back, K. (2003) Either soluble or plastidic expression of recombinant protoporphyrinogen oxidase modulates tetrapyrrole biosynthesis and photosynthetic efficiency in transgenic rice. Biosci. Biotechnol. Biochem. 67, 1472-1478. https://doi.org/10.1271/bbb.67.1472
  17. Kakinoki, B., Sekimoto, S., Yuki, S., Ohgami, T., Sejima, M., Yamagami, K. and Saito, K. (2006) Orally active neurotrophin-enhancing agent protects against dysfunctions of the peripheral nerves in hyperglycemic animals. Diabetes 55, 616-621. https://doi.org/10.2337/diabetes.55.03.06.db05-1091
  18. Kang, T. H., Moon, E., Hong, B. N., Choi, S. Z., Son, M., Park, J. H. and Kim, S. Y. (2011) Diosgenin from Dioscorea nipponica ameliorates diabetic neuropathy by inducing nerve growth factor. Biol. Pharm. Bull. 34, 1493-1498. https://doi.org/10.1248/bpb.34.1493
  19. Kim, K. H., Kim, M. A., Moon, E., Kim, S. Y., Choi, S. Z., Son, M. W. and Lee, K. R. (2011a) Furostanol saponins from the rhizomes of Dioscorea japonica and their effects on NGF induction. Bioorg. Med. Chem. Lett. 21, 2075-2078. https://doi.org/10.1016/j.bmcl.2011.02.003
  20. Kim, M. W. (1998) Effect of H2O fraction of Dioscorea japonica Thunb. with selenium on plasma glucose and lipid metabolism in streptozotocin induced diabetic rats. Kor. J. Nutr. 31, 1377-1384.
  21. Kim, N., Kim, S. H., Kim, Y. J., Kim, J. K., Nam, M. K., Rhim, H., Yoon, S. K., Choi, S. Z., Son, M., Kim, S. Y. and Kuh, H. J. (2011b) Neurotrophic activity of DA-9801, a mixture extract of Dioscorea japonica Thunb. and Dioscorea nipponica Makino, in vitro. J. Ethnopharmacol. 137, 312-319. https://doi.org/10.1016/j.jep.2011.05.032
  22. Maithili, V., Dhanabal, S. P., Mahendran, S. and Vadivelan, R. (2011) Antidiabetic activity of ethanolic extract of tubers of Dioscorea alata in alloxan induced diabetic rats. Indian J. Pharmacol. 43, 455-459. https://doi.org/10.4103/0253-7613.83121
  23. Mbiantcha, M., Kamanyi, A., Teponno, R. B., Tapondjou, A. L., Watcho, P. and Nguelefack, T. B. Analgesic and Anti-Inflammatory Properties of Extracts from the Bulbils of Dioscorea bulbifera L. var sativa (Dioscoreaceae) in Mice and Rats. Evid. Based Complement. Alternat. Med. 2011.
  24. Nguelefack, T. B., Dutra, R. C., Paszcuk, A. F., Andrade, E. L., Tapondjou, L. A. and Calixto, J. B. (2010) Antinociceptive activities of the methanol extract of the bulbs of Dioscorea bulbifera L. var sativa in mice is dependent of NO-cGMP-ATP-sensitive-K(+) channel activation. J. Ethnopharmacol. 128, 567-574. https://doi.org/10.1016/j.jep.2010.01.061
  25. Obrosova, I. G. (2003) Update on the pathogenesis of diabetic neuropathy. Curr. Diab. Rep. 3, 439-445. https://doi.org/10.1007/s11892-003-0005-1
  26. Obrosova, I. G. (2009) Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 6, 638-647. https://doi.org/10.1016/j.nurt.2009.07.004
  27. Oh, P. S. and Lim, K. T. (2008) Plant glycoprotein modulates the expression of interleukin-1beta via inhibition of MAP kinase in HMC-1 cells. Biosci. Biotechnol. Biochem. 72, 2133-2140. https://doi.org/10.1271/bbb.80204
  28. Ordonez, G., Fernandez, A., Perez, R. and Sotelo, J. (1994) Low contents of nerve growth factor in serum and submaxillary gland of diabetic mice. A possible etiological element of diabetic neuropathy. J. Neurol. Sci. 121, 163-166. https://doi.org/10.1016/0022-510X(94)90346-8
  29. Pearlstone, A. C., Oei, M. L. and Wu, T. C. (1992) The predictive value of a single, early human chorionic gonadotropin measurement and the influence of maternal age on pregnancy outcome in an infertile population. Fertil. Steril. 57, 302-304. https://doi.org/10.1016/S0015-0282(16)54834-1
  30. Pedicino, D., Liuzzo, G., Trotta, F., Giglio, A. F., Giubilato, S., Martini, F., Zaccardi, F., Scavone, G., Previtero, M., Massaro, G., Cialdella, P., Cardillo, M. T., Pitocco, D., Ghirlanda, G. and Crea, F. (2013) Adaptive immunity, inflammation, and cardiovascular complications in type 1 and type 2 diabetes mellitus. J. Diabetes Res. 2013, 184258.
  31. Sima, A. A. and Sugimoto, K. (1999) Experimental diabetic neuropathy: an update. Diabetologia 42, 773-788. https://doi.org/10.1007/s001250051227
  32. Singh, U. and Jialal, I. (2008) Alpha-lipoic acid supplementation and diabetes. Nutr. Rev. 66, 646-657. https://doi.org/10.1111/j.1753-4887.2008.00118.x
  33. Spittau, G., Happel, N., Behrendt, M., Chao, T. I., Krieglstein, K. and Spittau, B. (2010) Tieg1/Klf10 is upregulated by NGF and attenuates cell cycle progression in the pheochromocytoma cell line PC12. J. Neurosci. Res. 88, 2017-2025.
  34. Srinivasan, K. and Ramarao, P. (2007) Animal models in type 2 diabetes research: an overview. Indian J. Med. Res. 125, 451-472.
  35. Toth, C., Schmidt, A. M., Tuor, U. I., Francis, G., Foniok, T., Brussee, V., Kaur, J., Yan, S. F., Martinez, J. A., Barber, P. A., Buchan, A. and Zochodne, D. W. (2006) Diabetes, leukoencephalopathy and rage. Neurobiol. Dis. 23, 445-461. https://doi.org/10.1016/j.nbd.2006.03.015
  36. Traverse, S., Gomez, N., Paterson, H., Marshall, C. and Cohen, P. (1992) Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem. J. 288, 351-355. https://doi.org/10.1042/bj2880351
  37. U.S. Food and Drug Administration (2009) Neurontin packaging insert. http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm154552.htm. cited 2012 Aug 24.
  38. van Dam, P. S. (2002) Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab. Res. Rev. 18, 176-184. https://doi.org/10.1002/dmrr.287
  39. Vincent, A. M., Russell, J. W., Low, P. and Feldman, E. L. (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr. Rev. 25, 612-628. https://doi.org/10.1210/er.2003-0019
  40. Vinik, A. I., Park, T. S., Stansberry, K. B. and Pittenger, G. L. (2000) Diabetic neuropathies. Diabetologia 43, 957-973. https://doi.org/10.1007/s001250051477
  41. Vinik, A. I., Suwanwalaikorn, S., Stansberry, K. B., Holland, M. T., Mc-Nitt, P. M. and Colen, L. E. (1995) Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 18, 574-584. https://doi.org/10.1002/mus.880180603
  42. Wu, C. L., Lee, C. L. and Pan, T. M. (2009) Red mold dioscorea has a greater antihypertensive effect than traditional red mold rice in spontaneously hypertensive rats. J. Agric. Food Chem. 57, 5035-5041. https://doi.org/10.1021/jf900349v
  43. Xu, L. and Wang, W. (2002) Chinese materia media: Combinations & applications. Donica Publishing Ltd., Hertfordshire. UK.
  44. Zorrilla Hernandez, E., Frati Munari, A., Lozano Castaneda, O., Villalpando Hernandez, S. and Boulton, A. J. (1994) [Diabetic neuropathy. Current concepts on etiopathogenesis, diagnosis, and treatment]. Gac. Med. Mex. 130, 18-25.

Cited by

  1. Goshajinkigan for Low Back Pain: An Observational Study vol.23, pp.3, 2017, https://doi.org/10.1089/acm.2016.0276
  2. Combined Application of UHPLC-QTOF/MS, HPLC-ELSD and 1 H-NMR Spectroscopy for Quality Assessment of DA-9801, A Standardised Dioscorea Extract vol.28, pp.3, 2017, https://doi.org/10.1002/pca.2659
  3. Phytochemicals That Regulate Neurodegenerative Disease by Targeting Neurotrophins: A Comprehensive Review vol.2015, 2015, https://doi.org/10.1155/2015/814068
  4. Evaluating Pharmacological Effects of Two Major Components of Shuangdan Oral Liquid: Role of Danshensu and Paeonol in Diabetic Nephropathy Rat vol.24, pp.5, 2016, https://doi.org/10.4062/biomolther.2015.191
  5. Lactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway vol.99, 2016, https://doi.org/10.1016/j.neuint.2016.06.010
  6. P2X1 Receptor-Mediated Ca2+ Influx Triggered by DA-9801 Potentiates Nerve Growth Factor-Induced Neurite Outgrowth vol.7, pp.11, 2016, https://doi.org/10.1021/acschemneuro.6b00082
  7. The Dioscorea Genus (Yam)—An Appraisal of Nutritional and Therapeutic Potentials vol.9, pp.9, 2014, https://doi.org/10.3390/foods9091304
  8. Therapeutic Potential of Ursolic Acid in Cancer and Diabetic Neuropathy Diseases vol.22, pp.22, 2014, https://doi.org/10.3390/ijms222212162