Anti-diabetic Effects of CCCA, CMESS, and Cordycepin from Cordyceps militaris and the Immune Responses in Streptozotocin-induced Diabetic Mice

  • Published : 2003.12.01


Anti-diabetic effect of various fractions of Cordyceps militaris (CM), CCCA (crude cordycepin containing adenosine), CMESS (ethanol soluble supernatant), and cordycepin were evaluated in streptozotocin (STZ) induced diabetic mice, CMESS showed potent inhibitory activity of 34.7% in starch-loaded mice (2 g/kg) while acarbose as a positive standard exhibited 37.8% of inhibition rate. After 3 days administration (50 mg/kg), cordycepin (0.2 mg/kg), and acarbose (10 mg/kg) dramatically reduced blood glucose level (inhibition ratio: 46.9%, 48.4% and 37.5% respectively). CCCA that has high contents of cordycepin (0.656 mg/4 mg) did not influence on reducing blood glucose level. The proliferation of splenocytes and peritoneal macrophages derived from STZ-induced diabetic mice administered samples were evaluated out by addition of mitogens to see the stability of the usage of these herbal medicines. Proliferation of T-lymphocyte was significantly decreased; while NO production was increased more than two fold to STZ control in the cordycepin-administered group. Changes of serum enzyme levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) were also evaluated. Cordycepin administered group was appeared to acarbose. We conclude that CMESS and cordycepin may be useful tools in the control of blood glucose level in diabetes and promising new drug as an anti-hyperglycemic agent without defects of immune responses and other side effects.


  1. Anjli, K., and Noel, K., Maclaren, Autoimmunity and diabetes. J. Clin. Endocrinol. 84,4371-4378 (1999)
  2. Balon, T. W., and Nadler, J. L., Evidence that nitric oxide increase glucose transport in skeletal muscle. J. Appl. Physiol. 82, 359-363 (1997)
  3. Bentley, H. R, Cunningham, K. G., and Spring, F. S., Cordycepin a metabolic product from cultures of Cordyceps militaris link part Ⅱ.The structure of cordycepin. J. Chem. Soc. 2301-2305 (1951)
  4. Catanzaro, O. L., Marina-Prendes, M. G., Hope, S. L., Zuccollo, A, and Dominguez, A, Streptozotocin-induced hyperglycemia is decreased by nitric oxide inhibition. Braz. J. Med. Biol. Res. 27, 2043-2047 (1994)
  5. Chen, S. Z., and Chu, J. Z., NMR and IR studies on the characterization of cordycepin and 2-deoxyadenosine. Zhongguo Kangshengsu Zazhi 21,9-12 (1996)
  6. Cunningham, K. G., Hutchinson, S. A, Manson, W., and Spring, F. S., Cordycepin. A metabolic product from cultures Cordyceps militaris Link. Part I. Isolation and characterization. J. Chem. Soc. 2299-3000 (1951)
  7. Deitch, A .D., and Sawicki, S. G., Effects of cordycepin on microtubules of cultured mammalian cells. Exp. Cell Res. 118, 1-13 (1979)
  8. Ioannidis, P., Courtis, N., Havredaki, M., Michailakis, E., Tsiapalis, C. M., and Trangas, T., The polyadenylation inhibitor cordycepin (3'dA) causes a decline in c-MYC mRNA levels without affecting c-MYC protein levels. Oncogene 18,117-125 (1999)
  9. Julian-Ortiz, J. V., Galvez, L, Munoz-Collado, C, Garcia-Domenech, R, and Gimena-Cardona, C., VIrtual combinatorial syntheses and computational screening of new potential anti-herpes compounds. J. Med. Chem. 42,3308-3314 (1999)
  10. Kaczka, E. A, Trenner, N. R., Arison, B., Walker, R. W., and Folkers, K Identification of cordycepin, a metabolite of Cordyceps militaris, as 3'-deoxyadenosine. Biochim. Biophys. Res. Commun. 14,456-457 (1964)
  11. Kiho, T., Hui, J, Yamane, A, and Ukai, S., Polysaccharides in fungi. XXXII. Hypoglycemic activity and chemical properties of a polysaccharide from the cultural mycelium of Cordyceps sinensis. Biol. Pharm. Bull. 16, 1291-1293 (1993)
  12. Kiho, T., Yamane, A, Hui, J, Usui, S., and Ukai, S., Polysaccharides in fungi. XXXVI. Hypoglycemic activity of a polysaccharide (CS-F30) from the cultural mycelium of Cordyceps sinensis and its effect on glucose metabolism in mouse liver. Biol. Pharm. Bull. 19,294-296 (1996)
  13. Koc, Y., Urbano, A. G., Sweeney, E. B., and McCaffrey, R, Induction of apoptosis by cordycepin in ADA-inhibited TdTpositive leukemia cells. Leukemia 10, 1019-1024 (1996)
  14. Kodama, E. N., McCaffrey, R. P., Yusa, K., and Mitsuya, H., Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferase-positive (TdT+) leukemic cells. Biochem. Pharm. 59,273-281 (2000)
  15. Lukic, M. L., Stosic-Grujicic, Ostojic, N., Chan, N. L., and Liew, F. Y., Inhibition of nitric oxide generation affects the induction of diabetes by streptozotocin in mice. Biochem. Biophys. Res. Commun. 178,913-920 (1991)
  16. Nakata, M., and Yada, T., Nitric oxide-mediated insulin secretion in response to citrulline in islet beta-cells, pancreas. Endocrinology 27, 209-213 (2003)
  17. Park, K .S., Chong, J. C., Moon, C. K., and Chung, J. H., Toxicity of streptozotocin in isolated rat hepatocytes. Yakhak Hoeji 36, 80-86 (1992)
  18. Roy, D., Perreault, M., and Marette, A, Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. Am. J. Physiol. 274, E692-E699 (1998)
  19. Sugar, A. M., and McCaffrey, R. P., Antifungal activity of 3'deoxyadenosine (cordycepin). Agents Chemother. 42, 1424-1427 (1998)
  20. Sugimoto, Y., Yamada, J., Yoshikawa, T., and Horisaka, K, Inhibitory effects of a nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), on 2-deoxy-D-glucose-induced hyperglycemia in rats. Biol. Pharm. Bull. 20, 1307-1309 (1997)
  21. Trigg, P. I., Gutteridge, W. E., and Williamson, J., The effects of cordycepin on malaria parasites. Trans. R Soc. Trop. Med: Hyg. 65,514-520 (1971)
  22. Xiaoxia, Z., Claudius, U. M., Peter, S., and Fred, Z., Effect of cordycepin on interleukin-l0 production of human peripheral blood mononuclear cells. Eur. J. Pharmacol. 453, 309-317 (2002)
  23. Yu, W., Niwa, T., Miura, Y., Horio, F., Teradaira, S., Ribar, T. J., Means, A. R, Hasegawa, Y., Senda, T., and Niki, I., Calmodulin overexpression causes $Ca^2^+$ dependent apoptosis of pancreatic beta cells, which can be prevented by inhibition of nitric oxide synthase. Lab. Invest. 82, 1229-1239 (2002)
  24. Zhu, J. S., Halpern, G. M., and Jones, K, The scientific rediscovery of an ancient Chinese herbal medicine: Cordyceps sinensis: part I. J. Altern. Complement. Med. 4, 289-303 (1998)