Document Type : Research Paper I Open Access I Released under CC BY-NC 4.0 license


1 .PhD Student, Department of Physical Education and Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran

2 Assosiate Professor, Department of Physical Education and Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran

3 Assistant Professor, Department of Physical Education and Sport Sciences, Faculty of Literature and Humanities, Lorestan University, Khoram Abaad, Iran

4 Professor, Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran


Glycogen synthase kinase 3 beta is a regulator key of many signaling pathways. It is reported that inhibition of this kinase increases neuronal survival. Accordingly, in this study, the effect of 6 weeks of endurance training on the gene expression of GSK-3β in the motor area of the spinal cord of male Wistar rats with diabetic neuropathy was investigated. For this aim, 16 male Wistar rats were randomly assigned to four groups: healthy control, healthy trained, neuropathy control, neuropathy trained. Intraperitoneal injection of a STZ (streptozotocin) solution (45 mg/kg) was used to induce diabetes. 2 weeks after STZ injection, the mechanical allodynia and thermal hyperalgesia tests demonstrated the diabetic neuropathy. A moderate endurance training protocol was performed for 6 weeks. 24 hours after the last training session, the rats were sacrificed and the L4-L6 motor neurons of the spinal cord tissue were removed. GSK-3β mRNA expression was performed using Real Time-PCR. Statistical analysis showed that neuropathy trained group experienced a decrease in the GSK-3β expression compared with neuropathy control group (P=0.02). On the other hand, there was a significant difference between healthy control and neuropathy control groups (P=0.02), that is to say the gene expression increased in neuropathy control group. However, there was no significant difference between healthy control and neuropathy trained groups. The results show that one of the factors involved in the spread of damage to motor neurons of diabetic neuropathy is incremental regulation of mRNAGSK-3β and training as a non-pharmacotherapy strategy can modulate and return it to normal levels. Therefore, it is suggested that GSK-3β should receive attention as a novel treatment target in diabetes.



    1. Alkon DL, Sun MK, Nelson TJ. (2007) PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends in pharmacological sciences. 28(2):51-60.
    2. Aschenbach WG, Ho RC, Sakamoto K, Fujii N, Li Y, Kim YB. (2006) Regulation of Dishevelled and β-catenin in rat skeletal muscle: an alternative exercise-induced GSK-3β signaling pathway. American Journal of Physiology-Endocrinology And Metabolism. 291(1):E152-E8.
    3. Aschenbach WG, Suzuki Y, Breeden K, Prats C, Hirshman MF, Dufresne SD. (2001) The muscle-specific protein phosphatase PP1G/RGL (GM) is essential for activation of glycogen synthase by exercise. Journal of Biological Chemistry. 276(43):39959-67.
    4. Beyreuther B, Callizot N, Stohr T. (2006) Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy. Eur J Pharmacol 539:64-70.
    5. Bijur GN, Jope RS. (2003) Glycogen synthase kinase-3 [beta] is highly activated in nuclei and mitochondria. Neuroreport. 14(18):2415-9.
    6. Cadigan KM, Nusse R. (1997) Wnt signaling: a common theme in animal development. Genes & development. 11(24):3286-305.
    7. Cai Q, Sheng ZH. (2009) Moving or stopping mitochondria: Miro as a traffic cop by sensing calcium. Neuron. 61(4):493-6.
    8. Calcutt N, Freshwater J, O'Brien J. (2000) Protection of sensory function and antihyperalgesic properties of prosaposin-derived peptide in diabetic rats. Anesthesiology 93: 1271–1278.
    9. Calcutt NA, Jorge MC, Yaksh TL, Chaplan SR. (1996) Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine. Pain 68: 293-299.
    10. Calcutt NA. (2004) Modeling diabetic sensory neuropathy in rats. Methods Mol Med 99:55-65.
    11. Carra, S., Crippa, V., Rusmini, P., Boncoraglio, A., Minoia, M., Giorgetti, E., ... & Poletti, A. (2012). Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins. Progress in neurobiology, 97(2), 83-100.
    12. Centeno C, Repici M, Chatton JY, Riederer BM, Bonny C, Nicod P, Price M, Clarke PG, Papa S, Franzoso G, BorselloT. (2007) Role of the JNK pathway in NMDA-mediatedexcitotoxicity of cortical neurons. Cell Death Differ 14, 240- 253.
    13. Chae, C.H., Jung, S.L., An, S.H., Park, B.Y., Wang, S.W., Cho, I.H., Cho, J.Y., Kim, H.T. (2009) Treadmill exercise improves cognitive function and facilitates nerve growth factor signaling by activating mitogen-activated protein kinase/ extracellular signalregulated kinase1/2 in the streptozotocin-induced diabetic rat hippocampus. Neuroscience; 164, 1665–1673.
    14. Chen G, Huang LD, Jiang YM, Manji HK. (2008) The Mood‐Stabilizing Agent Valproate Inhibits the Activity of Glycogen Synthase Kinase‐3. Journal of neurochemistry. 72(3):1327-30.
    15. Chen Y-W. Li Y-T. Chen YC. Li Z-Y. Hung C-H. (2012) Exercise Training Attenuates Neuropathic Pain and Cytokine Expression After Chronic Constriction Injury of Rat Sciatic Nerve. AnesthAnalg 114: 1330–7.
    16. Collino M, Aragno M, Castiglia S, Tomasinelli C, Thiemermann C, Boccuzzi G. (2009) Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats A Role for Glycogen Synthase Kinase-3β. Diabetes. 58(1):235-42.
    17. Cross DAE, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD. (2001) Selective small‐molecule inhibitors of glycogen synthase kinase‐3 activity protect primary neurones from death. Journal of neurochemistry. 77(1):94-102.
    18. Davis RJ. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252.
    19. Detera-Wadleigb SD. (2001) Lithium-related genetics of bipolar disorder. Annals of medicine. 33(4):272-85.
    20. Dill J, Wang H, Zhou F, Li S. (2008) Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. The Journal of Neuroscience. 28(36):8914-28.
    21. Doble BW, Woodgett JR. (2003) GSK-3: tricks of the trade for a multi-tasking kinase. Journal of cell science. 116(7):1175-86.
    22. Edwards JL, Vincent AM, Cheng HT, Feldman EL. (2008) Diabetic neuropathy: mechanisms to management PharmacolTher;120(1):1-34.
    23. Eldar-Finkelman H. (2002) Glycogen synthase kinase 3: an emerging therapeutic target. Trends in molecular medicine. 8(3):126-32.
    24. Embi N, RYLATT DB, COHEN P. (2005) Glycogen Synthase Kinase‐3 from Rabbit Skeletal Muscle. European Journal of biochemistry. 107(2):519-27.
    25. Fernández-Martos CM, González-Fernández C, González P, Maqueda A, Arenas E, Rodríguez FJ. (2011) Differential expression of wnts after spinal cord contusion injury in adult rats. PloS one. 6(11):e27000.
    26. Frame S, Cohen P, Biondi RM. (2001) A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Molecular cell. 7(6):1321-7.
    27. Frame S, Cohen P. (2001) GSK3 takes centre stage more than 20 years after its discovery. Biochemical Journal. 359(Pt 1):1.
    28. Gharakhanlou R, Chadan S, Gardiner P. (1999) Increased activity in the form of endurance training increases calcitonin gene-related peptide content in lumbar motoneuron cell bodies and in sciatic nerve in the rat. Neuroscience. 89(4):1229-39.
    29. Gould TD, Manji HK. (2002) The Wnt signaling pathway in bipolar disorder. The Neuroscientist. 8(5):497-511.
    30. Grimes CA, Jope RS. (2001) The multifaceted roles of glycogen synthase kinase 3b in cellular signaling. Progress in neurobiology. 65(4):391.
    31. Hall AC, Brennan A, Goold RG, Cleverley K, Lucas FR, Gordon-Weeks PR. (2002) Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons. Molecular and cellular neurosciences. 20(2):257.
    32. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88.
    33. Holmberg C, Katz S, Lerdrup M, Herdegen T, Jaattela M, Aronheim A, Kallunki T. (2002) A novel specific role for I kappa B kinase complex-associated protein in cytosolic stress signaling. J BiolChem 277, 31918-31928.
    34. Hongisto V, Vainio JC, Thompson R, Courtney MJ, Coffey ET. (2008) The Wnt pool of glycogen synthase kinase 3β is critical for trophic-deprivation-induced neuronal death. Molecular and cellular biology. 28(5):1515-27.
    35. Kuhad A, Chopra K. (2009) Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 57(4):456-62.
    36. Liu S, Bréjot T, Cressant A, Bacci J, Saïd G, Tadié M. (1995) Reinnervation of hind limb extremity after lumbar dorsal root ganglion injury. 65(4):391.
    37. Millan MJ. (1999) The induction of pain: an integrative review. ProgNeurobiol 57: 1-164.
    38. Pan J, Li H, Ma J-F, Tan Y-Y, Xiao Q, Ding J-Q. (2012) Curcumin inhibition of JNKs prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease through suppressing mitochondria dysfunction. TranslNeurodegener 1 (1): 16.
    39. Prodanov D, Feirabend HKP. (2007) Morphometric analysis of the fiber populations of the rat sciatic nerve, its spinal roots, and its major branches. J Comp Neurol 503:85–100.
    40. Rossi D M. Valenti V E. Navega MT. (2011) Exercise training attenuates acute hyperalgesia in streptozotocin-induced diabetic female rats. CLINICS 66(9):1615-1619.
    41. Sakamoto, Kei, Arnolds, David EW, Ekberg, Ingvar, Thorell, Anders, & Goodyear, Laurie J. (2004). Exercise regulates Akt and glycogen synthase kinase-3 activities in human skeletal muscle. Biochemical and biophysical research communications, 319(2), 419-425.
    42. Sharma NK. Ryals JM. Gajewski BJ. (2010) Wright DE. Aerobic Exercise Alters Analgesia and Neurotrophin-3 Synthesis in an Animal Model of Chronic Widespread Pain. PHYS THER 90:714-725.
    43. Sluka KA and Rasmussen LA. (2010) Fatiguing exercise enhances hyperalgesia to muscle Inflammation. Pain 148(2): 188.
    44. Wan, W., Xia, S., Kalionis, B., Liu, L., & Li, Y. (2014). The Role of Wnt Signaling in the Development of Alzheimer’s Disease: A Potential Therapeutic Target?. BioMed research international, 2014.
    45. Wattiez AS, Barrière DA, Dupuis A, Courteix C. (2012) Rodent Models of Painful Diabetic Neuropathy: What Can We Learn from Them?. Diabetes Metab, 43: 008.
    46. Woodgett, J.R. (2001). Judging a protein by more than its name: GSK-3. Science Signalling, 2001(100), re12.
    47. Zochodne DW, Ramji N, Toth C. (2008) Neuronal targeting in diabetes mellitus: a story of sensory neurons and motor neurons. Neuroscientist, 14: 311-8.