The effect Aerobic Exercise on the level of expression of Toll-like receptor 4 and inflammatory mediators in the sensory spinal cord of Male Rats with diabetic neuropathic pain

Document Type : Original Article

Authors

1 Shahid Chamran University of Ahwaz - Faculty of Physical Education and Sport Sciences - Sports Physiology Department

2 Department of Sport Physiology, Faculty of Physical Education and Sports Science, Ahwaz Shahid Chamran University, Ahvaz, Iran

3 Department of Physiology, Faculty of Medicine, Ahwaz Jundishapur University of Medical Sciences, Ahwaz, Iran

4 dr

Abstract

Background: Increased expression of TLR4 in the nervous system is one of the factors involved in the pathophysiology of Diabetic Peripheral Neuropathy. The purpose of this study was to determine the effect of aerobic training on the expression of TLR4 gene and inflammatory mediators in the sensory spinal cord of male rats with DPN
Methods: 40 male rats with weight(220 ± 2.2 g) were divided into four groups: diabetic neuropathy, diabetic neuropathy training, healthy control training and healthy control. Diabetes was induced by STZ injection. After confirming the development of conditions for DPN by behavioral tests, exercise groups performed 6 weeks of continuous aerobic exercise on treadmill. The level of expression of TLR4, TNF-α and IL-1β genes in sensory neurons of spinal cord L4-L6 was measured by Real-Time PCR technique. Two-way ANOVA and post-hoc LSD test were used for statistical analysis.
Results: the expression of TLR4, TNF-α and IL-1β genes in the diabetic neuropathy training group was significantly lower than the diabetic neuropathy group (P <0.05). Also, there was a significant difference between healthy control groups and diabetic neuropathy and the gene expression in the diabetic neuropathy group was increased (P <0.05).
Conclusion:Endurance training can reduce the expression of TLR4 gene and inflammatory markers in the sensory part of the spinal cord and improve the sensitivity of the nosepectors to painful factors. Therefore, it is suggested that endurance training be used as a non-prescriptive therapeutic intervention for diabetic patients to reduce neuropathic pain.

Keywords

References

1-Shi, X., et al., Beneficial effect of TNF-α inhibition on diabetic peripheral neuropathy. Journal of neuroinflammation, 2013. 10(1): p. 836.
2-Van Acker, K., et al., Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes & metabolism, 2009. 35(3): p. 206-213.
3-Vincent, A.M., et al., Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nature Reviews Neurology, 2011. 7(10): p. 573.
4-Wilson, N. and D. Wright, Inflammatory mediators in diabetic neuropathy. J Diabetes Metab S, 2011. 5: p. 2.
5-Campbell, J.N. and R.A. Meyer, Mechanisms of neuropathic pain. Neuron, 2006. 52(1): p. 77-92.
6-Toth, C., et al., Diabetes mellitus and the sensory neuron. Journal of Neuropathology & Experimental Neurology, 2004. 63(6): p. 561-573.
7-Schreiber, A.K., et al., Diabetic neuropathic pain: physiopathology and treatment. World journal of diabetes, 2015. 6(3): p. 432.
8-Gore, M., et al., Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. Journal of pain and symptom management, 2005. 30(4): p. 374-385.
9-Li, X., et al., TNF-Alpha in Peripheral Neuropathy Patients with Impaired Glucose Regulation. Journal of diabetes research, 2017. 2017.
10-González‐Clemente, J., et al., Diabetic neuropathy is associated with activation of the TNF‐α system in subjects with type 1 diabetes mellitus. Clinical endocrinology, 2005. 63(5): p. 525-529.
11-Thakur, V., et al., Effect of exercise on neurogenic inflammation in spinal cord of Type 1 diabetic rats. Brain research, 2016. 1642: p. 87-94.
12- Thacker, M.A., et al., Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesthesia & Analgesia, 2007. 105(3): p. 838-847.
13-Yan, J.-e., et al., Streptozotocin-induced diabetic hyperalgesia in rats is associated with upregulation of Toll-like receptor 4 expression. Neuroscience letters, 2012. 526(1): p. 54-58.
14-Abbas, A.K., A.H. Lichtman, and S. Pillai, Cellular and molecular immunology E-book. 2014: Elsevier Health Sciences.
15-Okun, E., et al., Toll-like receptors in neurodegeneration. Brain research reviews, 2009. 59(2): p. 278-292.
16-Devaraj, S., et al., Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. The journal of clinical endocrinology & metabolism, 2008. 93(2): p. 578-583.
17-Devaraj, S., et al., Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes. Diabetologia, 2009. 52(8): p. 1665-1668.
18-Zhu, T., et al., Toll-like receptor 4 and tumor necrosis factor-alpha as diagnostic biomarkers for diabetic peripheral neuropathy. Neuroscience letters, 2015. 585: p. 28-32.
19-Jin, H.Y. and T.S. Park, Role of inflammatory biomarkers in diabetic peripheral neuropathy. Journal of Diabetes Investigation, 2018. 9(5): p. 1016.
20-Chen, T., et al., Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy. Scientific reports, 2017. 7(1): p. 14923.
21-Jurga, A.M., et al., Blockade of toll-like receptors (TLR2, TLR4) attenuates pain and potentiates buprenorphine analgesia in a rat neuropathic pain model. Neural plasticity, 2016. 2016.
22-Chen, Y.-W., et al., Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve. Anesthesia & Analgesia, 2012. 114(6): p. 1330-1337.
23-Yoon, H., et al., Moderate exercise training attenuates inflammatory mediators in DRG of Type 1 diabetic rats. Experimental neurology, 2015. 267: p. 107-114.
24-Bortolon, J.R., et al., Persistence of inflammatory response to intense exercise in diabetic rats. Experimental Diabetes Research, 2012. 2012.
25-Wei, M., et al., The streptozotocin‐diabetic rat as a model of the chronic complications of human diabetes. Heart Lung & Circulation, 2003. 12(1): p. 44-50.
26-Malmberg, A.B. and A.W. Bannon, Models of nociception: hot‐plate, tail‐flick, and formalin tests in rodents. Current protocols in neuroscience, 1999. 6(1): p. 8.9. 1-8.9. 15.
27-Sharma, N.K., et al., Aerobic exercise alters analgesia and neurotrophin-3 synthesis in an animal model of chronic widespread pain. Physical therapy, 2010. 90(5): p. 714-725.
28-D'Amour, F.E. and D.L. Smith, A method for determining loss of pain sensation. J Pharmacol Exp Ther, 1941. 72(1): p. 74-9.
29-Dubuisson, D. and S.G. Dennis, The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain, 1977. 4: p. 161-174.
30-Chae, C.-H., et al., Treadmill exercise suppresses muscle cell apoptosis by increasing nerve growth factor levels and stimulating p-phosphatidylinositol 3-kinase activation in the soleus of diabetic rats. Journal of physiology and biochemistry, 2011. 67(2): p. 235-241.
31-Gelderd, J.B. and S.F. Chopin, The vertebral level of origin of spinal nerves in the rat. The Anatomical Record, 1977. 188(1): p. 45-47.
32-Lee, J.Y., et al., GS-KG9 ameliorates diabetic neuropathic pain induced by streptozotocin in rats. Journal of Ginseng Research, 2017.
33-Wada, J. and H. Makino, Innate immunity in diabetes and diabetic nephropathy. Nature Reviews Nephrology, 2016. 12(1): p. 13.
34-Dasu, M.R., et al., High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes, 2008.
35-Zhou, D.-m., et al., Effects of Duloxetine on the Toll-Like Receptor 4 Signaling Pathway in Spinal Dorsal Horn in a Rat Model of Diabetic Neuropathic Pain. Pain Medicine, 2017. 19(3): p. 580-588.
36-Lin, S., et al., Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. Journal of neuroinflammation, 2012. 9(1): p. 46.
37-Kuphal, K.E., E.E. Fibuch, and B.K. Taylor, Extended swimming exercise reduces inflammatory and peripheral neuropathic pain in rodents. The Journal of Pain, 2007. 8(12): p. 989-997.
38-Chen, Y.-W., et al., Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats. Anesthesia & Analgesia, 2013. 116(2): p. 482-490.
39-Stagg, N.J., et al., Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain modelrole of endogenous opioids. Anesthesiology: The Journal of the American Society of Anesthesiologists, 2011. 114(4): p. 940-948.
40-Gleeson, M., B. McFarlin, and M. Flynn, Exercise and Toll-like receptors. Exerc Immunol Rev, 2006. 12(1): p. 34-53.
41-Mita, Y., et al., Toll-like receptor 4 surface expression on human monocytes and B cells is modulated by IL-2 and IL-4. Immunology letters, 2002. 81(1): p. 71-75.
42-Curtale, G., et al., Negative regulation of Toll-like receptor 4 signaling by IL-10–dependent microRNA-146b. Proceedings of the National Academy of Sciences, 2013. 110(28): p. 11499-11504.
43-Petersen, A.M.W. and B.K. Pedersen, The anti-inflammatory effect of exercise. Journal of applied physiology, 2005. 98(4): p. 1154-1162.
44-Pedersen, B., et al., Exercise-induced immunomodulation-possible roles of neuroendocrine and metabolic factors. International journal of sports medicine, 1997. 18(S 1): p. S2-S7.
45-Bhattacharyya, S., et al., Macrophage glucocorticoid receptors regulate Toll-like receptor 4–mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood, 2007. 109(10): p. 4313-4319.
46-Beaudry, J.L. and M.C. Riddell, Effects of glucocorticoids and exercise on pancreatic β‐cell function and diabetes development. Diabetes/metabolism research and reviews, 2012. 28(7): p. 560-573.
47-Padmalayam, I., The heat shock response: its role in pathogenesis of type 2 diabetes and its complications, and implications for therapeutic intervention. Discov Med, 2014. 18(97): p. 29-39.
48-Hooper, P.L. and P.L. Hooper, Inflammation, heat shock proteins, and type 2 diabetes. Cell Stress and Chaperones, 2009. 14(2): p. 113-115.
Jundishapur Scientific Medical Journal
Volume 17, Issue 5 - Serial Number 116
January and February 2019
Pages 503-517

Files

History

  • Receive Date: 17 December 2018
  • Revise Date: 12 January 2019
  • Accept Date: 19 January 2019

Share

How to cite

Statistics