Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Effects of Treadmill Exercise on Memory and Hippocampal BDNF Expression in Streptozotocin-induced Diabetic Rats

트레드밀 운동이 당뇨흰쥐에서 기억력과 해마 BDNF 발현에 미치는 영향

  • Lee, Hee-Hyuk (Department of Sports Science, College of Natural Sciences, Hannam University) ;
  • Yoon, Jin-Hwan (Department of Sports Science, College of Natural Sciences, Hannam University) ;
  • Kim, Seung-Hee (Department of Physical Education, College of Education, Korea University)
  • Published : 2007.11.30
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Abstract

Diabetes mellitus is a chronic metabolic disorder, leading to many complications including cognitive deficit. Regular exercise has often been recommended as a therapeutic maneuver to the diabetic patients for the prevention of secondary complications. In the present study, the effects of treadmill exercise on memory and brain-derived neurotrophic factor (BDNF) in the hippocampus of streptozotocin (STZ)-induced diabetic rats were investigated. Male SD rats, aged 6 weeks, were randomly assigned to the following three groups: control group(n=8), STZ-induced diabetic group(n=8), and STZ-induced diabetes and exercise group(n=8). Diabetes was induced by a single injection of STZ (50 mg/kg body weight). Treadmill running was conducted with duration and frequency of 30 minutes and 5 times per week, respectively, for 8 weeks. Memories were tested in the Morris water maze. Western blotting was performed to detect BDNF expression in the hippocampus. In this study, we found that compared to the control group, the STZ-induced diabetes group had a significantly impaired cognitive performance along with suppressed BDNF expression in the hippocampus and the exercise group had a higher cognitive function in diabetic rats. Therefore, the current findings of the study show that a treadmill running exercise can improve diabetes-induced impairment of cognitive function. And the improved cognitive function appears to be related to an alleviation in diabetes-induced BDNF expression in hippocampus.

당뇨병은 만성적 대사질환으로 말초뿐만 아니라 중추신경계에서도 다양한 합병증을 유발시키는 것으로 알려져 있다. 특히, 당뇨환자는 인지기능의 손상으로 인해 치매 유병율이 높은 것으로 보고되고 있다. 규칙적인 운동은 당뇨병의 이차 합병증을 예방하기 위한 치료적 방법으로 흔히 권장된다. 이에 본 연구는 당뇨흰쥐를 대상으로 트레드밀 운동이 기억력과 해마 BDNF 발현에 미치는 효과를 조사하였다. SD계열 흰쥐를 실험동물로 하여 STZ (50 mg/kg) 투여로 유발시킨 당뇨흰쥐를 8주간 주 5회 30분씩 트레드밀에서 달리도록 하였다. 운동프로그램 종료 후, Morris water maze로 기억력을 측정하고, 해마조직을 적출하여 Western으로 brain-derived neurotrophic factor (BDNF) 발현을 정량화하였다. 본 연구결과 8주간의 당뇨는 선행연구과 유사하게 기억력 손상과 함께 해마 조직의 BDNF 발현을 유의하게 감소시키는 것으로 나타났다. 하지만 트레드밀 운동은 당뇨흰쥐에서 기억력과 해마 BDNF 발현을 유의하게 향상시키는 것으로 나타났다. 이러한 결과는 당뇨동물에서 운동이 해마 BDNF 발현의 증가를 통해 인지기능의 손상을 완화시킬 수 있음을 보여주는 것이다.

Keywords

References

  1. Adlard, P. A. and C. W. Cotman. 2004. Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression. Neuroscience 124, 985-992. https://doi.org/10.1016/j.neuroscience.2003.12.039
  2. Adlard, P. A., V. M. Perreau and C. W. 2005. The exercise- induced expression of BDNF within the hippocampus varies across life-span. Neurobiol. Aging 26, 511-520. https://doi.org/10.1016/j.neurobiolaging.2004.05.006
  3. Allen, K. V., B. M. Frier and M. W. Strachan. 2004. The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. Eur. J. Pharmacol. 490, 169-175. https://doi.org/10.1016/j.ejphar.2004.02.054
  4. Anderson, B. J., D. N. Rapp, D. H. Baek, D. P. McCloskey, P. S. Coburn-Litvak and J. K. Robinson. 2000. Exercise influences spatial learning in the radial arm maze. Physiology and Behavior 70, 425-429. https://doi.org/10.1016/S0031-9384(00)00282-1
  5. Arvanitakis, Z., R. S. Wilson, J. L. Bienias, D. A. Evans and D. A. Bennett. 2004. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch. Neurol. 61, 661-666. https://doi.org/10.1001/archneur.61.5.661
  6. Awad, N., M. Gagnon and C. Messier. 2004. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J. Clin. Exp. Neuropsychol. 26, 1044-1080. https://doi.org/10.1080/13803390490514875
  7. Baydas, G., V. S. Nedzvetskii, P. A. Nerush, S. V. Kirichenko and T. Yoldas. 2003. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci. 73, 1907-1916. https://doi.org/10.1016/S0024-3205(03)00561-7
  8. Berchtold, N. C., G. Chinn, M. Chou, J. P. Kesslak and C. W. Cotman. 2005. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience 133, 853-861. https://doi.org/10.1016/j.neuroscience.2005.03.026
  9. Biessels, G.J., A. Kamal, G. M. Ramakers, I. J. Urban, B. M. Spruijt, D. W. Erkelens and W. H. Gispen. 1996. Place learning and hippocampal synaptic plasticity in streptozotocin- induced diabetic rats. Diabetes 45, 1259-1266. https://doi.org/10.2337/diabetes.45.9.1259
  10. Biessels, G. J., A. Kamal, I. J. Urban, B. M. Spruijt, D. W. Erkelens and W. H. Gispen. 1998. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res. 800, 125-135. https://doi.org/10.1016/S0006-8993(98)00510-1
  11. Brands, A. M., G. J. Biessels, E. H. de Haan, L. J. Kappelle and R. P. Kessels. 2005. The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28, 726-735. https://doi.org/10.2337/diacare.28.3.726
  12. Chen, X., Y. Li, A. E. Kline, C. E. Dixon, R. D. Zafonte and A. K. Wagner. 2005. Gender and Environmental effects on regional brain-derived neurotrophic factor expression after experimental traumatic brain injury. Neuroscience 135, 11-17. https://doi.org/10.1016/j.neuroscience.2005.05.041
  13. Colberg, S. R., K. B. Stansberry, P. M. McNitt and A. I. Vinik. 2002. Chronic exercise is associated with enhanced cutaneous blood flow in type 2 diabetes. J. Diabetes Complications 16, 139-145. https://doi.org/10.1016/S1056-8727(01)00222-7
  14. Connor, B., D. Young, Q. Yan, R. L. Faull, B. Synek and M. Dragunow. 1997. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res. Mol. Brain Res. 49, 71-81. https://doi.org/10.1016/S0169-328X(97)00125-3
  15. Cukierman, T,, H. C. Gerstein and J. D. Williamson. 2005. Cognitive decline and dementia in diabetes--systematic overview of prospective observational studies. Diabetologia 48, 2460-2409. https://doi.org/10.1007/s00125-005-0023-4
  16. Debling, D., M. Amelang, P. Hasselbach and T. Sturmer. 2006. Diabetes and cognitive function in a populationbased study of elderly women and men. J. Diabetes Complications 20, 238-245. https://doi.org/10.1016/j.jdiacomp.2005.06.016
  17. Di Mario, U., S. Morano, E. Valle and G. Pozzessere. 1995. Electrophysiological alterations of the central nervous system in diabetes mellitus. Diabetes Metab. Rev. 11, 259-277. https://doi.org/10.1002/dmr.5610110306
  18. Ding, Y. H., J. Li, W. X. Yao, J. A. Rafols, J. C. Clark and Y. Ding. 2006. Exercise preconditioning upregulates cerebral integrins and enhances cerebrovascular integrity in ischemic rats. Acta. Neuropathol. 112, 74-84. https://doi.org/10.1007/s00401-006-0076-6
  19. Emery, C. F. and M. Gatz. 1990. Psychological and cognitive effects of an exercise program for community-residing older adults. Gerontologist 30, 184-188. https://doi.org/10.1093/geront/30.2.184
  20. Engesser-Cesar, C., A. J. Anderson and C. W. Cotman. 2007. Wheel running and fluoxetine antidepressant treatment have differential effects in the hippocampus and the spinal cord. Neuroscience 144, 1033-1044. https://doi.org/10.1016/j.neuroscience.2006.10.016
  21. Farmer, J., X. Zhao, H. van Praag, K. Wodtke, F. H. Gage and B. R. Christie. 2004. Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124, 71-79. https://doi.org/10.1016/j.neuroscience.2003.09.029
  22. Fordyce, D. E. and R. P. Farrar. 1991. Enhancement of spatial learning in F344 rats by physical activity and related learning-associated alterations in hippocampal and cortical cholinergic functioning. Behavioural Brain Research 46, 123-133. https://doi.org/10.1016/S0166-4328(05)80105-6
  23. Gispen, W. H. and G. J. Biessels. 2000. Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci. 23, 542-549. https://doi.org/10.1016/S0166-2236(00)01656-8
  24. Gomez-Pinilla, F., Z. Ying, R. R. Roy, R. Molteni and V. R. Edgerton. 2002. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J. Neurophysiol. 88, 2187-2195. https://doi.org/10.1152/jn.00152.2002
  25. Goodyear, L. J. and B. B. Kahn. 1998. Exercise, glucose tolerance, and insulin sensitivity. Ann. Rev. Med. 49, 235-261. https://doi.org/10.1146/annurev.med.49.1.235
  26. Griesbach, G. S., F. Gomez-Pinilla and D. A. Hovda. 2007. Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent. J. Neurotrauma. 24, 1161-1171. https://doi.org/10.1089/neu.2006.0255
  27. Hatta, A., Y. Nishihira, S. R. Kim, T. Kaneda, T. Kida, K. Kamijo, M. Sasahara and S. Haga. 2005. Effects of habitual moderate exercise on response processing and cognitive processing in older adults. Jpn. J. Physiol. 55, 29-36. https://doi.org/10.2170/jjphysiol.R2068
  28. Johnson, R. A., J. S. Rhodes, S. L. Jeffrey, T. Garland and G. S. Mitchell. 2003. Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience 121, 1-7. https://doi.org/10.1016/S0306-4522(03)00422-6
  29. Kamal, A., G. J. Biessels, S. E. Duis and W. H. Gispen. 2000. Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing. Diabetologia 43, 500-506. https://doi.org/10.1007/s001250051335
  30. Kamal, A., G. J. Biessels, W. H. Gispen and G. M. Ramakers. 2006. Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocin-induced diabetes mellitus in rats. Brain Res. 16, 1073-1074.
  31. Kamal, A., G. J. Biessels, G. M. Ramakers and W. Hendrik. 2005. The effect of short duration streptozotocin- induced diabetes mellitus on the late phase and threshold of long-term potentiation induction in the rat. Brain Res. 1053, 126-130. https://doi.org/10.1016/j.brainres.2005.06.036
  32. Kim, H. B., M. H. Jang, M. C. Shin, B. V. Lim, Y. P. Kim, K. J. Kim, E. H. Kim and C. J. Kim. 2003. Treadmill exercise increases cell proliferation in dentate gyrus of rats with streptozotocin-induced diabetes. J. Diabetes Complications 17, 29-33. https://doi.org/10.1016/S1056-8727(02)00186-1
  33. Kim, Y. P., H. B. Kim, M. H. Jang, B. V. Lim, Y. J. Kim, H. Kim, S. S. Kim, E. H. Kim and C. J. Kim. 2003. Magnitude and time-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Int. J. Sports Med. 24, 108-113. https://doi.org/10.1055/s-2003-38201
  34. Korte, M., V. Staiger, O. Griesbeck, H. Thoenen and T. Bonhoeffer. 1996. The involvement of brain-derived neurotrophic factor in hippocampal long-term potentiation revealed by gene targeting experiments. J. Physiol. 90, 157-164.
  35. Krabbe, K. S., A. R. Nielsen, R. Krogh-Madsen, P. Plomgaard, P. Rasmussen, C. Erikstrup, C. P. Fischer, B. Lindegaard, A. M. Petersen, S. Taudorf, N. H. Secher, H. Pilegaard, H. Bruunsgaard and B. K. Pedersen. 2007. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 50, 431-438. https://doi.org/10.1007/s00125-006-0537-4
  36. Lee, H. H., M. S. Shin, Y. S. Kim, H. Y. Yang, H. K. Chang, T. H. Lee, C. J. Kim, S. H. Cho and S. P. Hong. 2005. Early treadmill exercise decreases intrastriatal hemorrhage- induced neuronal cell death and increases cell proliferation in the dentate gyrus of streptozotocin-induced hyperglycemic rats. J. Diabetes Complications 19, 339-346. https://doi.org/10.1016/j.jdiacomp.2005.03.006
  37. Lindvall, O., O. Kokaia, J. Bengzon, E. Elmer and M. Kokaia. 1994. Neurotrophins and brain insults. Trends Neurosci. 17, 490-496. https://doi.org/10.1016/0166-2236(94)90139-2
  38. Lupien, S. B., E. J. Bluhm and D. N. Ishii. 2003. Systemic insulin-like growth factor-I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult rats. J. Neurosci. Res. 74, 512-523. https://doi.org/10.1002/jnr.10791
  39. Mattson, M. P., S. Maudsley and B. Martin. 2004. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 27, 589-594. https://doi.org/10.1016/j.tins.2004.08.001
  40. Mijnhout, G. S., P. Scheltens, M. Diamant, G. J. Biessels, A. M. Wessels, S. Simsek, F. J. Snoek and R. J. Heine. 2006. Diabetic encephalopathy: A concept in need of a definition. Diabetologia 49, 1447-1448. https://doi.org/10.1007/s00125-006-0221-8
  41. Mizuno, M., K. Yamada, A. Olariu, H. Nawa and T. Nabeshima. 2000. Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J. Neurosci. 20, 7116-7121. https://doi.org/10.1523/JNEUROSCI.20-18-07116.2000
  42. Nitta, A., R. Murai, N. Suzuki, H. Ito, H. Nomoto, G. Katoh, Y. Furukawa and S. Furukawa. 2002. Diabetic neuropathies in brain are induced by deficiency of BDNF. Neurotoxicol. Teratol. 24, 695-701. https://doi.org/10.1016/S0892-0362(02)00220-9
  43. Ogonovszky, H., I. Berkes, S. Kumagai, T. Kaneko, S. Tahara, S. Goto and Z. Radak. 2005. The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain. Neurochem. Int. 46, 635-640. https://doi.org/10.1016/j.neuint.2005.02.009
  44. Peila, R., B. L. Rodriguez and L. J. Launer. 2002. Honolulu-Asia Aging Study. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51, 1256-1262. https://doi.org/10.2337/diabetes.51.4.1256
  45. Ploughman, M., S. Granter-Button, G. Chernenko, Z. Attwood, B. A. Tucker, K. M. Mearow and D. Corbett. 2007. Exercise intensity influences the temporal profile of growth factors involved in neuronal plasticity following focal ischemia. Brain Res. 1150, 207-216. https://doi.org/10.1016/j.brainres.2007.02.065
  46. Pysh, J. J. and G. M. Weiss. 1979. Exercise during development induces an increase in Purkinje cell dendritic tree size. Science 206, 230-232. https://doi.org/10.1126/science.482938
  47. Schinder, A. F., M. M. Poo, 2000. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 23, 639-645. https://doi.org/10.1016/S0166-2236(00)01672-6
  48. Shin, M. S., H. Kim, H. K. Chang, T. H. Lee, M. H. Jang, M. C. Shin, B. V. Lim, H. H. Lee, Y. P. Kim, J. H. Yoon, I. G. Jeong and C. J. 2003. Treadmill exercise suppresses diabetes-induced increment of neuropeptide Y expression in the hypothalamus of rats. Neurosci. Lett. 346, 157-160. https://doi.org/10.1016/S0304-3940(03)00537-8
  49. Soya, H., T. Nakamura, C. C. Deocaris, A. Kimpara, M. Iimura, T. Fujikawa, H. Chang, B. S. McEwen and T. Nishijima. 2007. BDNF induction with mild exercise in the rat hippocampus. Biochem. Biophys. Res. Commun. 358, 961-967. https://doi.org/10.1016/j.bbrc.2007.04.173
  50. Swain, R. A., A. B. Harris, E. C. Wiener, M. V. Dutka, H. D. Morris, B. E. Theien, S. Konda, K. Engberg, P. C. Lauterbur and W. T. Greenough. 2003. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 117, 1037-1046. https://doi.org/10.1016/S0306-4522(02)00664-4
  51. Tsai, S. J. 2003. Brain-derived neurotrophic factor: a bridge between major depression and Alzheimer's disease?. Med. Hypotheses 61, 110-113. https://doi.org/10.1016/S0306-9877(03)00141-5
  52. Tyler, W. J., M. Alonso, C. R. Bramham and L. D. Pozzo-Miller. 2002. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn. Mem. 9, 224-237. https://doi.org/10.1101/lm.51202
  53. Vaynman, S., Z. Ying and F. Gomez-Pinilla. 2004. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur. J. Neurosci. 20, 2580-2590. https://doi.org/10.1111/j.1460-9568.2004.03720.x
  54. Vorhees, C. V. and M. T. Williams. 2006. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848-858. https://doi.org/10.1038/nprot.2006.116
  55. Wijkstrom, M., N. Kirchhof, M. Graham, E. Ingulli, R. B. Colvin, U. Christians, B. J. Hering and H. J. Schuurman. 2005. Cyclosporine toxicity in immunosuppressed streptozotocin- diabetic nonhuman primates. Toxicology 207, 117-127. https://doi.org/10.1016/j.tox.2004.09.010
  56. Wolf, S. A., G. Kronenberg, K. Lehmann, A. Blankenship, R. Overall, M. Staufenbiel and G. Kempermann. 2006. Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer's disease. Biol. Psychiatry 60, 1314-1323. https://doi.org/10.1016/j.biopsych.2006.04.004

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