Induction of analgesia using atorvastatin in experimental diabetic neuropathy through NMDA receptor and inflammatory cytokine inhibition

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Keywords

Atorvastatin
Diabetic neuropathy
Inflammatory cytokines
NMDA receptor
Oxidative stress factors

How to Cite

Hemati, K., Karimi, M. Y., Hosseinzadeh, A., Abolmaali, M., Najjar, N., Aghanoori, M.-R., & Nikoui, V. (2021). Induction of analgesia using atorvastatin in experimental diabetic neuropathy through NMDA receptor and inflammatory cytokine inhibition. Iranian Red Crescent Medical Journal, 23(1). https://doi.org/10.32592/ircmj.2021.23.1.454

Abstract

Background: Diabetic neuropathy is a complication of diabetes causing damage to the nerves.

Objectives: Considering the neuroprotective anti-inflammatory antioxidant characteristics of statins, the current study aimed at determining the effects of atorvastatin on diabetic neuropathy through assessing the involvement of N-methyl-D-aspartic acid (NMDA) receptor, factors of oxidative stress, and inflammatory cytokines in rats with diabetes.

Methods: Male rats were randomly assigned into six groups of the saline- and atorvastatin-treated controls, and streptozotocin (STZ)-induced diabetic animals treated with vehicle, diabetic animals treated with morphine (5 mg/kg), and rats treated with atorvastatin (10 mg/kg/day for 10 weeks) alone or in combination with NMDA receptor agonist. The hot plate and formalin tests were carried out on the rats. Moreover, malondialdehyde level, catalase and superoxide dismutase activities, levels of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the dorsal root ganglia (DRG) of the animals were measured. Finally, the expression of the NMDA receptor in DRG was investigated in the current study.

Results: Diabetes resulted in analgesia in all tests, and pretreatment with atorvastatin exacerbated diabetes-induced analgesic effects in the hot plate and early phase of the formalin test (P≤0.01 and P≤0.05 in comparison to those reported for the diabetic vehicle-treated group, respectively). The injection of NMDA could reverse the atorvastatin-induced analgesia in the hot plate test (P≤0.05). Diabetes caused to increase the levels of IL-1β, IL-6, and TNF-α in DRG in comparison to those reported for the control group (P≤0.05). Furthermore, the pretreatment of rats using atorvastatin could significantly reverse the increase in TNF-α level (P≤0.05).

Conclusions: Atorvastatin showed analgesic properties, which might be acting through NMDA receptors and reduction of inflammatory cytokines.

 

https://doi.org/10.32592/ircmj.2021.23.1.454
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References

  1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124-36. doi: 10.1016/S0140-6736(09)62124-3. [PubMed: 20580421].
  2. Hosseinzadeh A, Juybari KB, Kamarul T, Sharifi AM. Protective effects of atorvastatin on high glucose-induced oxidative stress and mitochondrial apoptotic signaling pathways in cultured chondrocytes. J Physiol Biochem. 2019;75(2):153-62. doi: 10.1007/s13105-019-00666-8. [PubMed: 30796627].
  3. Caporale JE, Elgart JF, Gagliardino JJ. Diabetes in Argentina: cost and management of diabetes and its complications and challenges for health policy. Global Health. 2013;9(54). doi: 10.1186/1744-8603-9-54. [PubMed: 24168330].
  4. Agarwal AS, Fuladi AB, Mishra G, Tayade BO. Spirometry and diffusion studies in patients with type-2 diabetes mellitus and their association with microvascular complications. Indian J Chest Dis Allied Sci. 2010;52(4):213-6. [PubMed: 21302598].
  5. Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J. 2006;82(964):95-100. doi: 10.1136/pgmj.2005.036137. [PubMed: 16461471].
  6. Vinik AI, Strotmeyer ES, Nakave AA, Patel CV. Diabetic neuropathy in older adults. Clin Geriatr Med. 2008;24(3):407-35,v. doi: 10.1016/j.cger.2008.03.011. [PubMed: 18672180].
  7. Yagihashi S, Yamagishi SI, Wada R. Pathology and pathogenetic mechanisms of diabetic neuropathy: correlation with clinical signs and symptoms. Diabetes Res Clin Pract. 2007;77Suppl 1:S184-9. doi: 10.1016/j.diabres.2007.01.054. [PubMed: 17462777].
  8. Lai AK, Lo AC. Animal models of diabetic retinopathy: summary and comparison. J Diabetes Res. 2013;2013:106594. doi: 10.1155/2013/106594. [PubMed: 24286086].
  9. El-Asrar AM. Role of inflammation in the pathogenesis of diabetic retinopathy. Middle East Afr J Ophthalmol. 2012;19(1):70-4. doi: 10.4103/0974-9233.92118. [PubMed: 22346117].
  10. Zhu S, Stein RA, Yoshioka C, Lee CH, Goehring A, Mchaourab HS, et al. Mechanism of NMDA receptor inhibition and activation. Cell. 2016;165(3):704-14. doi: 10.1016/j.cell.2016.03.028. [PubMed: 27062927].
  11. Zhou HY, Chen SR, Pan HL. Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2011;4(3):379-88. doi: 10.1586/ecp.11.17. [PubMed: 21686074].
  12. Collins S, Sigtermans MJ, Dahan A, Zuurmond WWA, Perez RSGM. NMDA receptor antagonists for the treatment of neuropathic pain. Pain Med. 2010;11(11):1726-42. doi: 10.1111/j.1526-4637.2010.00981.x. [PubMed: 21044263].
  13. Aiyer R, Mehta N, Gungor S, Gulati A. A systematic review of nmda receptor antagonists for treatment of neuropathic pain in clinical practice. Clin J Pain. 2018;34(5):450-67. doi: 10.1097/AJP.0000000000000547. [PubMed: 28877137].
  14. Chen SR, Samoriski G, Pan HL. Antinociceptive effects of chronic administration of uncompetitive NMDA receptor antagonists in a rat model of diabetic neuropathic pain. Neuropharmacology. 2009;57(2):121-6. doi: 10.1016/j.neuropharm.2009.04.010. [PubMed: 19422840].
  15. Wu QJ, Tymianski M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain. 2018;11(1):15. doi: 10.1186/s13041-018-0357-8. [PubMed: 29534733].
  16. Bösel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC, et al. Neuroprotective effects of atorvastatin against glutamate‐induced excitotoxicity in primary cortical neurones. J Neurochem. 2005;92(6):1386-98. doi: 10.1111/j.1471-4159.2004.02980.x. [PubMed: 15748157].
  17. Ghaisas MM, Dandawate PR, Zawar SA, Ahire YS, Gandhi SP. Antioxidant, antinociceptive and anti-inflammatory activities of atorvastatin and rosuvastatin in various experimental models. Inflammopharmacology. 2010;18(4):169-77. doi: 10.1007/s10787-010-0044-6. [PubMed: 20532641].
  18. Rayegan S, Dehpour AR, Sharifi AM. Studying neuroprotective effect of Atorvastatin as a small molecule drug on high glucose-induced neurotoxicity in undifferentiated PC12 cells: role of NADPH oxidase. Metab Brain Dis. 2017;32(1):41-9. doi: 10.1007/s11011-016-9883-1. [PubMed: 27476541].
  19. Ludka FK, Constantino LC, Dal-Cim T, Binder LB, Zomkowski A, Rodrigues ALS, et al. Involvement of PI3K/Akt/GSK-3β and mTOR in the antidepressant-like effect of atorvastatin in mice. J Psychiatr Res. 2016;82:50-7. doi: 10.1016/j.jpsychires.2016.07.004. [PubMed: 27468164].
  20. Sattar NA, Ginsberg H, Ray K, Chapman MJ, Arca M, Averna M, et al. The use of statins in people at risk of developing diabetes mellitus: evidence and guidance for clinical practice. Atherosclerosis Suppl. 2014;15(1):1-15. doi: 10.1016/j.atherosclerosissup.2014.04.001. [PubMed: 24840509].
  21. Park Y. Chapter 1 - Oxidative Stress and Diabetic Neuropathy. In: Preedy VR, editor. Diabetes: Oxidative Stress and Dietary Antioxidants. San Diego: Academic Press; 2014. p. 3-13.
  22. Hosseini A, Abdollahi M. Diabetic neuropathy and oxidative stress: therapeutic perspectives. Oxid Med Cell Longev. 2013;2013:168039. doi: 10.1155/2013/168039. [PubMed: 23738033].
  23. Sun G, Li Y, Ji Z. Atorvastatin attenuates inflammation and oxidative stress induced by ischemia/reperfusion in rat heart via the Nrf2 transcription factor. Int J Clin Exp Med. 2015;8(9):14837-45. [PubMed: 26628965].
  24. Pathak NN, Balaganur V, Lingaraju MC, Kant V, Latief N, More AS, et al. Atorvastatin attenuates neuropathic pain in rat neuropathy model by down-regulating oxidative damage at peripheral, spinal and supraspinal levels. Neurochem Int. 2014;68:1-9. doi: 10.1016/j.neuint.2014.01.014. [PubMed: 24513038].
  25. Massari CM, Castro AA, Dal-Cim T, Lanznaster D, Tasca CI. In vitro 6-hydroxydopamine-induced toxicity in striatal, cerebrocortical and hippocampal slices is attenuated by atorvastatin and MK-801. Toxicol Vitro. 2016;37:162-8. doi: 10.1016/j.tiv.2016.09.015. [PubMed: 27647473].
  26. Pergolizzi JV, Magnusson P, LeQuang JA, Razmi R, Zampogna G, Taylor R. Statins and neuropathic pain: a narrative review. Pain Ther. 2020;9(1):97-111. doi: 10.1007/s40122-020-00153-9. [PubMed: 32020545].
  27. Snow WM, Albensi BC. Neuronal gene targets of NF-κB and their dysregulation in Alzheimer's disease. Front Mol Neurosci. 2016;9:118. doi: 10.3389/fnmol.2016.00118. [PubMed: 27881951].
  28. Barsante MM, Roffê E, Yokoro CM, Tafuri WL, Souza DG, Pinho V, et al. Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis. Eur J Pharmacol. 2005;516(3):282-9. doi: 10.1016/j.ejphar.2005.05.005. [PubMed: 15970284].
  29. Dichtl W, Dulak J, Frick M, Alber HF, Schwarzacher SP, Ares MP, et al. HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003;23(1):58-63. doi: 10.1161/01.atv.0000043456.48735.20. [PubMed: 12524225].