تأثیر تمرین هوازی بر سطوح پروتئین HMGB1 و برخی شاخص‌های استرس اکسیداتیو در موش‌های صحرایی دارای درد نوروپاتی دیابت

نویسندگان

1 گروه فیزیولوژی ورزشی، دانشکده تربیت بدنی و علوم ورزشی، دانشگاه شهید چمران اهواز، اهواز، ایران

2 گروه فیزیولوژی پزشکی، دانشکده پزشکی، مرکز تحقیقات فیزیولوژی، دانشگاه علوم پزشکی جندی شاپور اهواز، اهواز، ایران

چکیده

مقدمه و هدف: التهاب عصبی نقش محوری در توسعه درد نوروپاتی دیابت بازی می‌کنند. هدف از پژوهش حاضر بررسی تأثیر تمرین هوازی بر سطوح پروتئین HMGB1 و برخی شاخص‌های استرس اکسیداتیو در موش‌های صحرایی با درد نوروپاتی دیابت است.
 
مواد و روش­ها: در این بررسی، 40 سر موش صحرایی نر ویستار 8 هفته­­ای (محدوده وزنی 2/10±220 گرم) به طور تصادفی در چهار گروه نوروپاتی دیابت، نوروپاتی دیابت تمرین، سالم تمرین و کنترل سالم قرار گرفتند. دیابت با تزریق STZ(mg/kg 50) القاء شد. پس از تائید ایجاد نوروپاتی دیابت توسط تست­های رفتاری، گروه­های تمرین، شش هفته تمرین هوازی تداومی با شدت متوسط 15 متر در دقیقه برای 30 دقیقه روی تردمیل اجرا کردند. سطح سرمی پروتئین HMGB1 با تکنیک الایزا و غلظت مالون­دی­آلدهید (MAD) و فعالیت آنزیم­های سوپراکسید دیسموتاز (SOD) و کاتالاز (CAT) در بافت نخاع توسط روش­های بیوشیمیایی اندازه‌گیری شد. آزمون آنالیز واریانس دو راهه و آزمون تعقیبی توکی برای تحلیل آماری استفاده گردید.
 
نتایج: تمرین هوازی باعث کاهش معنی­ دار سطح سرمی پروتئین HMGB1 و غلظت MAD و افزایش فعالیت آنزیم‌های SOD و CAT نسبت به گروه نوروپاتی دیابت شد (P<0.05). همچنین سطوح پروتئین HMGB1 و غلظت MAD افزایش و فعالیت آنزیم­های SOD و CAT در گروه نوروپاتی دیابت کاهش داشت P<0.05)).
 
نتیجه‌گیری: به نظر می‌رسد تمرین هوازی سطوح پروتئین HMGB1 و استرس اکسیداتیو را تعدیل و حساسیت نوسیسپتورها به عوامل درد زا را بهبود می­بخشد. پیشنهاد می­شود که تمرین هوازی به عنوان یک مداخله درمانی غیردارویی برای بیماران دیابتی به منظور کاهش درد نوروپاتیک استفاده شود.

کلیدواژه‌ها


عنوان مقاله [English]

The effect of aerobic exercise on HMGB1 protein levels and some oxidative stress indices in rats with diabetic neuropathic pain

نویسندگان [English]

  • Ahmad Kaki 1
  • Masoud Nikbakht 1
  • AbdolHamid Habibi 1
  • Hadi Fathi Moghadam 2
چکیده [English]

Background and Objective: Neuroinflammation plays a pivotal role in the development of diabetic neuropathic pain. The purpose of this study was to investigate the effect of aerobic exercise on HMGB1 protein levels and some oxidative stress biomarkers in a rat model of diabetic neuropathic pain.
 
Materials and Methods: 40 male Wistar rats (weighing 220 ± 10.2 g) were randomly divided into four groups: diabetic neuropathy, diabetic neuropathy + exercise, healthy exercise, and healthy control. Diabetes was induced by STZ injection (50 mg/kg). After confirming the development of diabetes neuropathy by behavioral tests, exercise groups received 6 weeks of continuous aerobic exercise with an average intensity of 15 m/min for 30 minutes on a treadmill. Serum levels of HMGB1 were measured by ELISA and malondialdehyde (MAD) concentrations and the activity of superoxide dismutase (SOD) and catalase (CAT) enzymes in spinal cord were determined by biochemical methods. Two-way ANOVA and Tukey's post hoc tests were used for statistical analysis.
 
Results: Aerobic exercise significantly reduced the serum level of HMGB1 protein and MDA concentration and increased the activity of SOD and CAT enzymes compared to diabetic neuropathy group (p <0.05). Also, HMGB1 levels and MDA increased and the activity of SOD and CAT enzymes decreased in the diabetic neuropathy group (p <0.05).
 
Conclusion: Aerobic exercise seems to modify the HMGB1 protein levels and oxidative stress and improve the sensitivity of the nociceptors to painful agents. It is suggested that aerobic exercise be used as a non-prescriptive therapeutic intervention for diabetic patients to reduce neuropathic pain.

کلیدواژه‌ها [English]

  • Aerobic exercise
  • HMGB1
  • Oxidative stress
  • Diabetic peripheral neuropathy
1. Wilson N, Wright D. Inflammatory mediators in diabetic neuropathy. The Journal of Diabetes & Metabolism 2011;5:2. 2. Van Acker K, Bouhassira D, De Bacquer D, Weiss S, Matthys K, Raemen H, 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. The Journal of Diabetes & Metabolism 2009;35(3):206-13. 3. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nature Reviews Neurology 2011;7(10):573. 4. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006;52(1):77-92. 5. Yoo M, Sharma N, Pasnoor M, Kluding PM. Painful diabetic peripheral neuropathy: presentations, mechanisms, and exercise therapy. The Journal of Diabetes & Metabolism 2013. 6. Chen T, Li H, Yin Y, Zhang Y, Liu Z, Liu H. 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):14923. 7. González‐Clemente J, Mauricio D, Richart C, Broch M, Caixas A, Megia A, 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):525-9. 8. Thakur V, Gonzalez M, Pennington K, Nargis S, Chattopadhyay M. Effect of exercise on neurogenic inflammation in spinal cord of Type 1 diabetic rats. Brain Research 2016;1642:87-94. 9. Wang X, Feng C, Qiao Y, Zhao X. Sigma 1 receptor mediated HMGB1 expression in spinal cord is involved in the development of diabetic neuropathic pain. Neuroscience Letters 2018;668:164-8. 10. Wu H, Chen Z, Xie J, Kang L-N, Wang L, Xu B. High mobility group Box-1: a missing link between diabetes and its complications. Mediators of Inflammation 2016;2016. 11. Wang Y, Zhong J, Zhang X, Liu Z, Yang Y, Gong Q, et al. The role of HMGB1 in the pathogenesis of type 2 diabetes. Journal of Diabetes Research 2016;2016. 12. Yu Y, Tang D, Kang R. Oxidative stress-mediated HMGB1 biology. Frontiers in Physiology 2015;6:93. 13. Bestall SM, Hulse RP, Blackley Z, Swift M, Ved N, Paton K, et al. Sensory neuronal sensitisation occurs through HMGB-1–RAGE and TRPV1 in high-glucose conditions. Journal of Cell Science 2018;131(14):jcs215939. 14. Horiuchi T, Sakata N, Narumi Y, Kimura T, Hayashi T, Nagano K, et al. Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. Journal of Biological Chemistry 2017;292(20):8436-46. 15. Griggs RB, Donahue RR, Adkins BG, Anderson KL, Thibault O, Taylor BK. Pioglitazone inhibits the development of hyperalgesia and sensitization of spinal nociresponsive neurons in type 2 diabetes. The Journal of Pain 2016;17(3):359-73. 16. Chen Y-W, Chiu C-C, Hsieh P-L, Hung C-H, Wang J-J. Treadmill training combined with insulin suppresses diabetic nerve pain and cytokines in rat sciatic nerve. Anesthesia & Analgesia 2015;121(1):239-46. 17. Chen Y-W, Hsieh P-L, Chen Y-C, Hung C-H, Cheng J-T. Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats. Anesthesia & Analgesia 2013;116(2):482-90. 18. Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays in Biochemistry 2006;42:105-17. 19. Ribeiro-Samora G, Rabelo L, Ferreira A, Favero M, Guedes G, Pereira L, et al. Inflammation and oxidative stress in heart failure: effects of exercise intensity and duration. Brazilian Journal of Medical and Biological Research 2017;50(9). 20. Yoon H, Thakur V, Isham D, Fayad M, Chattopadhyay M. Moderate exercise training attenuates inflammatory mediators in DRG of Type 1 diabetic rats. Experimental Neurology 2015;267:107-14. 21. Chen Y-W, Li Y-T, Chen YC, Li Z-Y, Hung C-H. Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve. Anesthesia & Analgesia 2012;114(6):1330-7. 22. Giallauria F, Gentile M, Chiodini P, Berrino F, Mattiello A, Maresca L, et al. Exercise training reduces high mobility group box-1 protein levels in women with breast cancer: findings from the DIANA-5 study. Monaldi Archives for Chest Disease 2014;82(2). 23. Goh J, Behringer M. Exercise alarms the immune system: a HMGB1 perspective. Cytokine 2018;110:222-225 24. Alessio HM. Exercise-induced oxidative stress. Medicine and Science in Sports and Exercise 1993;25(2):218-24. 25. Yan J-e, Yuan W, Lou X, Zhu T. Streptozotocin-induced diabetic hyperalgesia in rats is associated with upregulation of Toll-like receptor 4 expression. Neuroscience Letters 2012;526(1):54-8. 26. Morrow TJ. Animal models of painful diabetic neuropathy: the STZ rat model. Current Protocols in Neuroscience 2004;29(1):9-18. 27. Wei M, Ong L, Smith MT, Ross FB, Schmid K, Hoey AJ, et al. The streptozotocin‐diabetic rat as a model of the chronic complications of human diabetes. Heart Lung & Circulation 2003;12(1):44-50. 28. Malmberg AB, Bannon AW. Models of nociception: hot‐plate, tail‐flick, and formalin tests in rodents. Current Protocols in Neuroscience 1999;6(1):8.9. 1-8.9. 15. 29. D'Amour FE, Smith DL. A method for determining loss of pain sensation. The Journal of Pharmacology and Experimental Therapeutics 1941;72(1):74-9. 30. Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977;4:161-74. 31. Chae C-H, Jung S-L, An S-H, Jung C-K, Nam S-N, Kim H-T. 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):235-41. 32. Gelderd JB, Chopin SF. The vertebral level of origin of spinal nerves in the rat. The Anatomical Record 1977;188(1):45-7. 33. Wan W, Cao L, Khanabdali R, Kalionis B, Tai X, Xia S. The emerging role of HMGB1 in neuropathic pain: a potential therapeutic target for neuroinflammation. Journal of Immunology Research 2016. 34. Dai Y, Wong B, Yen Y-M, Oettinger MA, Kwon J, Johnson RC. Determinants of HMGB proteins required to promote RAG1/2-recombination signal sequence complex assembly and catalysis during V (D) J recombination. Molecular and Cellular Biology 2005;25(11):4413-25. 35. Kuphal KE, Fibuch EE, Taylor BK. Extended swimming exercise reduces inflammatory and peripheral neuropathic pain in rodents. The Journal of Pain 2007;8(12):989-97. 36. Merry TL, Ristow M. Nuclear factor erythroid‐derived 2‐like 2 (NFE2L2, Nrf2) mediates exercise‐induced mitochondrial biogenesis and the anti‐oxidant response in mice. The Journal of Physiology 2016;594(18):5195-207. 37. Giallauria F, Cirillo P, D’agostino M, Petrillo G, Vitelli A, Pacileo M, et al. Effects of exercise training on high-mobility group box-1 levels after acute myocardial infarction. Journal of Cardiac Failure 2011;17(2):108-14. 38. Tang D, Kang R, Xiao W, Wang H, Calderwood SK, Xiao X. The anti-inflammatory effects of heat shock protein 72 involve inhibition of high-mobility-group box 1 release and proinflammatory function in macrophages. The Journal of Immunology 2007;179(2):1236-44. 39. Tang D, Kang R, Xiao W, Jiang L, Liu M, Shi Y, et al. Nuclear heat shock protein 72 as a negative regulator of oxidative stress (hydrogen peroxide)-induced HMGB1 cytoplasmic translocation and release. The Journal of Immunology 2007;178(11):7376-84. 40. Gleeson M, McFarlin B, Flynn M. Exercise and Toll-like receptors. Exercise Immunology Review 2006;12(1):34-53. 41. Golbidi S, Badran M, Laher I. Antioxidant and anti-inflammatory effects of exercise in diabetic patients. Experimental Diabetes Research 2011;2012. 42. Mita Y, Dobashi K, Endou K, Kawata T, Shimizu Y, Nakazawa T, 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):71-5. 43. Curtale G, Mirolo M, Renzi TA, Rossato M, Bazzoni F, Locati M. Negative regulation of Toll-like receptor 4 signaling by IL-10–dependent microRNA-146b. Proceedings of the National Academy of Sciences 2013;110(28):11499-504. 44. Elfeky M, Kaede R, Okamatsu-Ogura Y, Kimura K. Adiponectin inhibits LPS-induced HMGB1 release through an AMP kinase and heme oxygenase-1-dependent pathway in RAW 264 macrophage cells. Mediators of Inflammation 2016. 45. Petersen AMW, Pedersen BK. The anti-inflammatory effect of exercise. Journal of Applied Physiology 2005;98(4):1154-62. 46. Zanchi NE, Lira FS, de Siqueira Filho MA, Rosa JC, de Oliveira Carvalho CR, Seelaender M, et al. Chronic low frequency/low volume resistance training reduces pro-inflammatory cytokine protein levels and TLR4 mRNA in rat skeletal muscle. European Journal of Applied Physiology 2010;109(6):1095-102. 47. Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-β, IL-10, and IL-22 in immunity and autoimmunity. Current Opinion in Pharmacology 2009;9(4):447-53. 48. Padmalayam I. The heat shock response: its role in pathogenesis of type 2 diabetes and its complications, and implications for therapeutic intervention. Discovery Medicine 2014;18(97):29-39. 49. Hooper PL, Hooper PL. Inflammation, heat shock proteins, and type 2 diabetes. Cell Stress and Chaperones 2009;14(2):113-5. 50. Amorim FT, Zuhl MN. Heat Shock Proteins, Exercise and Inflammation. Heat Shock Proteins in Signaling Pathways: Springer; 2019;101-19.