Effect of simvastatin on sensorial, motor, and morphological parameters in sciatic nerve crush induced-neuropathic pain in rats

  • Claudia Rita Corso
  • Daniel Fernandes Martins
  • Stephanie Carvalho Borges
  • Olair Carlos Beltrame
  • José Ederaldo Queiroz Telles
  • Nilza Cristina Buttow
  • Maria Fernanda de Paula Werner
Original Article
  • 13 Downloads

Abstract

The present study compares the effects of a low and high doses of simvastatin in a model of peripheral neuropathy by evaluating sensorial, motor, and morphological parameters. First, male Wistar rats were orally treated with vehicle (saline, 1 mL/kg), simvastatin (2 and 80 mg/kg) or morphine (2 mg/kg, s.c.), 1 h before 2.5% formalin injection. Neuropathic pain was induced by crushing the sciatic nerve, and mechanical and cold allodynia, nerve function, histology, MPO and NAG concentrations, as well as mevalonate induced-nociception were evaluated. Animals were orally treated with vehicle, simvastatin, or gabapentin (30 mg/kg) for 18 days. Simvastatin (2 and 80 mg/kg) reduced the inflammatory pain induced by formalin, but failed to decrease the paw edema. Mechanical allodynia was reduced by the simvastatin (2 mg/kg) until the 12th day after injury and until the 18th day by gabapentin. However, both simvastatin and gabapentin treatments failed in attenuated cold allodynia or improved motor function. Interestingly, both doses of simvastatin showed a neuroprotective effect and inhibited MPO activity without altering kidney and hepatic parameters. Additionally, only the higher dose of simvastatin reduced the cholesterol levels and the nociception induced by mevalonate. Our results reinforce the antinociceptive, antiallodynic, and anti-inflammatory effects of oral simvastatin administration, which can strongly contribute to the sciatic nerve morphology preservation. Furthermore, our data suggest that lower and higher doses of simvastatin present beneficial effects that are dependent and independent of the mevalonate pathway, respectively, without causing signs of nerve damage.

Keywords

Simvastatin Neuropathic pain Sciatic nerve Neuroprotection Mevalonate 

Notes

Acknowledgements

This work was supported by Grants from Fundação Araucária (672/2014). C.R. Corso thanks the master’s scholarship of CAPES.

Compliance with ethical standards

Conflict of interest

The authors declare that there was no conflict of interest.

References

  1. Aikawa M, Rabkin E, Sugiyama S et al (2001) An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 103:276–283. https://doi.org/10.1161/01.CIR.103.2.276 CrossRefPubMedGoogle Scholar
  2. Bailey PJ (1988) Sponge implants as models. Methods Enzym 162:327–334CrossRefGoogle Scholar
  3. Baron R (2009) Neuropathic pain: a clinical perspective. Handb Exp Pharmacol. https://doi.org/10.1007/978-3-540-79090-7_1 PubMedGoogle Scholar
  4. Bhalla S, Singh N, Jaggi AS (2015) Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats. Food Chem Toxicol 80:32–40. https://doi.org/10.1016/j.fct.2015.02.016 CrossRefPubMedGoogle Scholar
  5. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  6. Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78:206–209CrossRefPubMedGoogle Scholar
  7. Brown WV (2008) Safety of statins. Curr Opin Lipidol 19:558–562. https://doi.org/10.1097/MOL.0b013e328319baba CrossRefPubMedGoogle Scholar
  8. Chase AJ, Bond M, Crook MF, Newby AC (2002) Role of nuclear factor-kB activation in metalloproteinase-1, -3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo. Arterioscler Thromb Vasc Biol 22:765–771. https://doi.org/10.1161/01.ATV.0000015078.09208.92 CrossRefPubMedGoogle Scholar
  9. de Medinaceli L (1995) Interpreting nerve morphometry data after experimental traumatic lesions. J Neurosci Methods 58:29–37CrossRefPubMedGoogle Scholar
  10. De Young LM, Kheifets JB, Ballaron SJ, Young JM (1989) Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions 26:335–341CrossRefPubMedGoogle Scholar
  11. Dias QM, Rossaneis AC, Fais RS, Prado WA (2013) An improved experimental model for peripheral neuropathy in rats. Brazilian J Med Biol Res 46:253–256. https://doi.org/10.1590/1414-431X20122462 CrossRefGoogle Scholar
  12. Fernandez G, Spatz ES, Jablecki C, Phillips PS (2011) Statin myopathy: a common dilemma not reflected in clinical trials. Cleve Clin J Med 78:393–403. https://doi.org/10.3949/ccjm.78a.10073 CrossRefPubMedGoogle Scholar
  13. Gaist D, Jeppesen U, Andersen M et al (2002) Statins and risk of polyneuropathy: a case-control study. Neurology 58:1333–1337CrossRefPubMedGoogle Scholar
  14. Garcia GG, Miranda HF, Noriega V et al (2011) Antinociception induced by atorvastatin in different pain models. Pharmacol Biochem Behav 100:125–129. https://doi.org/10.1016/j.pbb.2011.08.007 CrossRefPubMedGoogle Scholar
  15. Ghaisas MM, Dandawate PR, Zawar SA et al (2010) Antioxidant, antinociceptive and anti-inflammatory activities of atorvastatin and rosuvastatin in various experimental models. Inflammopharmacology 18:169–177. https://doi.org/10.1007/s10787-010-0044-6 CrossRefPubMedGoogle Scholar
  16. Ikeda U, Shimpo M, Ohki R et al (2000) Fluvastatin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells. Hypertension 36:325–329. https://doi.org/10.1161/01.HYP.36.3.325 CrossRefPubMedGoogle Scholar
  17. Jaiswal SR, Sontakke SD (2012) Experimental evaluation of analgesic and anti-inflammatory activity of simvastatin and atorvastatin. Indian J Pharmacol 44:475–479. https://doi.org/10.4103/0253-7613.99311 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Kukkar A, Bali A, Singh N, Jaggi AS (2013) Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res 36:237–251. https://doi.org/10.1007/s12272-013-0057-y CrossRefPubMedGoogle Scholar
  19. Kukkar A, Singh N, Jaggi AS (2014) Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats. J Formos Med Assoc. https://doi.org/10.1016/j.jfma.2013.05.013 PubMedGoogle Scholar
  20. Lee I, Jeong Y (2002) Effects of different concentrations of formalin on paw edema and pain behaviors in rats. J Korean Med Sci 17:81–85CrossRefPubMedPubMedCentralGoogle Scholar
  21. Loeser JD, Treede R-D (2008) The Kyoto protocol of IASP basic pain terminology. Pain 137:473–477. https://doi.org/10.1016/j.pain.2008.04.025 CrossRefPubMedGoogle Scholar
  22. Mahmood A, Goussev A, Kazmi H et al (2009) Long-term benefits after treatment of traumatic brains injury with simvastatin in rats. Neurosurgery 65:187–192. https://doi.org/10.1227/01.NEU.0000343540.24780.D6.LONG-TERM CrossRefPubMedPubMedCentralGoogle Scholar
  23. Mansouri MT, Naghizadeh B, Ghorbanzadeh B, Alboghobeish S (2017) Systemic and local anti-nociceptive effects of simvastatin in the rat formalin assay: role of peroxisome proliferator-activated receptor γ and nitric oxide. J Neurosci Res 95:1776–1785. https://doi.org/10.1002/jnr.24008 CrossRefPubMedGoogle Scholar
  24. Martins DF, Mazzardo-Martins L, Gadotti VM et al (2011) Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats. Pain 152:2653–2661. https://doi.org/10.1016/j.pain.2011.08.014 CrossRefPubMedGoogle Scholar
  25. Mendell JR, Sahenk Z (2003) Clinical practice: painful sensory neuropathy. N Engl J Med 348:1243–1255. https://doi.org/10.1056/NEJMcp022282 CrossRefPubMedGoogle Scholar
  26. Miranda HF, Noriega V, Olavarria L et al (2011) Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice. Basic Clin Pharmacol Toxicol 109:438–442. https://doi.org/10.1111/j.1742-7843.2011.00746.x CrossRefPubMedGoogle Scholar
  27. Miron VE, Zehntner SP, Kuhlmann T et al (2009) Statin therapy inhibits remyelination in the central nervous system. Am J Pathol 174:1880–1890. https://doi.org/10.2353/ajpath.2009.080947 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Ohsawa M, Mutoh J, Hisa H (2008) Mevalonate sensitizes the nociceptive transmission in the mouse spinal cord. Pain 134:285–292. https://doi.org/10.1016/j.pain.2007.04.031 CrossRefPubMedGoogle Scholar
  29. Ohsawa M, Aasato M, Hayashi S-S, Kamei J (2011) RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice. Pain 152:114–122. https://doi.org/10.1016/j.pain.2010.10.005 CrossRefPubMedGoogle Scholar
  30. Ohsawa M, Mutoh J, Yamamoto S et al (2012) Effect of spinally administered simvastatin on the formalin-induced nociceptive response in mice. J Pharmacol Sci 119:102–106. https://doi.org/10.1254/jphs.12007SC CrossRefPubMedGoogle Scholar
  31. Ohsawa M, Otake S, Murakami T et al (2014) Gabapentin prevents oxaliplatin-induced mechanical hyperalgesia in mice. J Pharmacol Sci 125:292–299. https://doi.org/10.1254/jphs.14058FP CrossRefPubMedGoogle Scholar
  32. Pan HC, Yang DY, Ou YC et al (2010) Neuroprotective effect of atorvastatin in an experimental model of nerve crush injury. Neurosurgery 67:376–388. https://doi.org/10.1227/01.NEU.0000371729.47895.A0 CrossRefPubMedGoogle Scholar
  33. Pannu R, Christie DK, Barbosa E et al (2007) Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem 101:182–200. https://doi.org/10.1111/j.1471-4159.2006.04354.x CrossRefPubMedGoogle Scholar
  34. Pathak NN, Balaganur V, Lingaraju MC et al (2013) Antihyperalgesic and anti-inflammatory effects of atorvastatin in chronic constriction injury-induced neuropathic pain in rats. Inflammation 36:1468–1478. https://doi.org/10.1007/s10753-013-9688-x CrossRefPubMedGoogle Scholar
  35. Phan T, McLeod JG, Pollard JD et al (1995) Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatry 58:625–628. https://doi.org/10.1136/jnnp.58.5.625 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Roglio I, Bianchi R, Gotti S et al (2008) Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury. Neuroscience 155:673–685. https://doi.org/10.1016/j.neuroscience.2008.06.034 CrossRefPubMedGoogle Scholar
  37. Schmalbruch H (1986) Fiber composition of the rat sciatic nerve. Anat Rec 215:71–81. https://doi.org/10.1002/ar.1092150111 CrossRefPubMedGoogle Scholar
  38. Shi XQ, Lim TKY, Lee S et al (2011) Statins alleviate experimental nerve injury-induced neuropathic pain. Pain 152:1033–1043. https://doi.org/10.1016/j.pain.2011.01.006 CrossRefPubMedGoogle Scholar
  39. Shubayev VI, Myers RR (2000) Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury. Brain Res 855:83–89CrossRefPubMedGoogle Scholar
  40. Sirtori CR (2014) The pharmacology of statins. Pharmacol Res. https://doi.org/10.1016/j.phrs.2014.03.002 PubMedGoogle Scholar
  41. Varejão ASP, Cabrita AM, Meek MF et al (2004) Functional and morphological assessment of a standardized rat sciatic nerve crush injury with a non-serrated clamp. J Neurotrauma 21:1652–1670CrossRefPubMedGoogle Scholar
  42. Watson JC, Sandroni P (2016) Central neuropathic pain syndromes. Mayo Clin Proc 91:372–385. https://doi.org/10.1016/j.mayocp.2016.01.017 CrossRefPubMedGoogle Scholar
  43. Werner MFP, Kassuya CAL, Ferreira J et al (2007) Peripheral kinin B(1) and B(2) receptor-operated mechanisms are implicated in neuropathic nociception induced by spinal nerve ligation in rats. Neuropharmacology 53:48–57. https://doi.org/10.1016/j.neuropharm.2007.04.013 CrossRefPubMedGoogle Scholar
  44. West B, Williams CM, Jilbert E et al (2014) Statin use and peripheral sensory perception: a pilot study. Somatosens Mot Res 31:57–61. https://doi.org/10.3109/08990220.2013.840281 CrossRefPubMedGoogle Scholar
  45. Wong B, Lumma WC, Smith AM et al (2001) Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation. J Leukoc Biol 69:959–962PubMedGoogle Scholar
  46. Wu H, Lu D, Jiang H et al (2008) Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3 K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J Neurotrauma 25:130–139. https://doi.org/10.1089/neu.2007.0369 CrossRefPubMedGoogle Scholar
  47. Xavier AM, Serafim KGG, Higashi DT et al (2012) Simvastatin improves morphological and functional recovery of sciatic nerve injury in Wistar rats. Injury 43:284–289. https://doi.org/10.1016/j.injury.2011.05.036 CrossRefPubMedGoogle Scholar
  48. Zhao Y, Feng Q, Huang Z et al (2014) Simvastatin inhibits inflammation in ischemia-reperfusion injury. Inflammation 37:1865–1875. https://doi.org/10.1007/s10753-014-9918-x CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Claudia Rita Corso
    • 1
  • Daniel Fernandes Martins
    • 2
  • Stephanie Carvalho Borges
    • 3
  • Olair Carlos Beltrame
    • 4
  • José Ederaldo Queiroz Telles
    • 5
  • Nilza Cristina Buttow
    • 3
  • Maria Fernanda de Paula Werner
    • 1
  1. 1.Department of Pharmacology, (UFPR), Biological Science SectorFederal University of ParanaCuritibaBrazil
  2. 2.Post-Graduate Program in Health ScienceUNISULPalhoçaBrazil
  3. 3.Department of Morphological SciencesState University of MaringaMaringaBrazil
  4. 4.Department of Veterinary MedicineFederal University of ParanaCuritibaBrazil
  5. 5.Department of Medical PathologyFederal University of ParanaCuritibaBrazil

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