Skip to main content

Advertisement

SpringerLink
Log in

Simvastatin Ameliorates Cauda Equina Compression Injury in a Rat Model of Lumbar Spinal Stenosis

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Lumbar spinal stenosis (LSS) is the leading cause of morbidity and mortality worldwide. LSS pathology is associated with secondary injury caused by inflammation, oxidative damage and cell death. Apart from laminectomy, pharmacological therapy targeting secondary injury is limited. Statins are FDA-approved cholesterol-lowering drug. They also show pleiotropic anti-inflammatory, antioxidant and neuroprotective effects. To investigate the therapeutic efficacy of simvastatin in restoring normal locomotor function after cauda equina compression (CEC) in a rat model of LSS, CEC injury was induced in rats by implanting silicone gels into the epidural spaces of L4 and L6. Experimental group was treated with simvastatin (5 mg/kg body weight), while the injured (vehicle) and sham operated (sham) groups received vehicle solution. Locomotor function in terms of latency on rotarod was measured for 49 days and the threshold of pain was determined for 14 days. Rats were sacrificed on day 3 and 14 and the spinal cord and cauda equina fibers were extracted and studied by histology, immunofluorescence, electron microscopy (EM) and TUNEL assay. Simvastatin aided locomotor functional recovery and enhanced the threshold of pain after the CEC. Cellular Infiltration and demyelination decreased in the spinal cord from the simvastatin group. EM revealed enhanced myelination of cauda equina in the simvastatin group. TUNEL assay showed significantly decreased number of apoptotic neurons in spinal cord from the simvastatin group compared to the vehicle group. Simvastatin hastens the locomotor functional recovery and reduces pain after CEC. These outcomes are mediated through the neuroprotective and anti-inflammatory properties of simvastatin. The data indicate that simvastatin may be a promising drug candidate for LSS treatment in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Abrahamson EE, Ikonomovic MD, Dixon CE, DeKosky ST (2009) Simvastatin therapy prevents brain trauma-induced increases in beta-amyloid peptide levels. Ann Neurol 66(3):407–414. doi:10.1002/ana.21731

    Article  PubMed  CAS  Google Scholar 

  • Adamova B, Vohanka S, Dusek L (2003) Differential diagnostics in patients with mild lumbar spinal stenosis: the contributions and limits of various tests. Eur Spine J 12(2):190–196. doi:10.1007/s00586-002-0503-x

    PubMed  CAS  Google Scholar 

  • Bethea JR (2000) Spinal cord injury-induced inflammation: a dual-edged sword. Prog Brain Res 128:33–42. doi:10.1016/S0079-6123(00)28005-9

    Article  PubMed  CAS  Google Scholar 

  • Bresnahan L, Fessler RG, Natarajan RN (2010) Evaluation of change in muscle activity as a result of posterior lumbar spine surgery using a dynamic modeling system. Spine (Phila Pa 1976) 35(16):E761–E767. doi:10.1097/BRS.0b013e3181e45a6e

    Article  Google Scholar 

  • Brosamle C, Schwab ME (2000) Ipsilateral, ventral corticospinal tract of the adult rat: ultrastructure, myelination and synaptic connections. J Neurocytol 29(7):499–507

    Article  PubMed  CAS  Google Scholar 

  • Cahill KS, Wang MY (2012) Cost effectiveness of lumbar fusion improves with time. Neurosurgery 70(2):N21. doi:10.1227/01.neu.0000410938.46452.b600006123-201202000-00009

    Article  PubMed  Google Scholar 

  • Carloni S, Girelli S, Buonocore G, Longini M, Balduini W (2009) Simvastatin acutely reduces ischemic brain damage in the immature rat via Akt and CREB activation. Exp Neurol 220(1):82–89. doi:10.1016/j.expneurol.2009.07.026

    Article  PubMed  CAS  Google Scholar 

  • Chauhan NB, Gatto R (2011) Restoration of cognitive deficits after statin feeding in TBI. Restor Neurol Neurosci 29(1):23–34. doi:10.3233/RNN-2011-0573

    PubMed  CAS  Google Scholar 

  • Chen G, Zhang S, Shi J, Ai J, Qi M, Hang C (2009) Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/NF-kappaB pathway. Exp Neurol 216(2):398–406. doi:10.1016/j.expneurol.2008.12.019

    Article  PubMed  CAS  Google Scholar 

  • Chu LW, Chen JY, Yu KL, Cheng KI, Wu PC, Wu BN (2012) Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model. Int J Immunopathol Pharmacol 25(1):219–230

    PubMed  CAS  Google Scholar 

  • Cimino M, Balduini W, Carloni S, Gelosa P, Guerrini U, Tremoli E, Sironi L (2005) Neuroprotective effect of simvastatin in stroke: a comparison between adult and neonatal rat models of cerebral ischemia. Neurotoxicology 26(5):929–933. doi:10.1016/j.neuro.2005.03.009

    Article  PubMed  CAS  Google Scholar 

  • Dembowski E, Davidson MH (2009) A review of lipid management in primary and secondary prevention. J Cardiopulm Rehabil Prev 29(1):2–12. doi:10.1097/HCR.0b013e318192754e

    PubMed  Google Scholar 

  • Die J, Wang K, Fan L, Jiang Y, Shi Z (2010) Rosuvastatin preconditioning provides neuroprotection against spinal cord ischemia in rats through modulating nitric oxide synthase expressions. Brain Res 1346:251–261. doi:10.1016/j.brainres.2010.05.068

    Article  PubMed  CAS  Google Scholar 

  • Dommisse GF, Grobler L (1976) Arteries and veins of the lumbar nerve roots and cauda equina. Clin Orthop Relat Res 115:22–29

    PubMed  Google Scholar 

  • Eroglu H, Nemutlu E, Turkoglu OF, Nacar O, Bodur E, Sargon MF, Beskonakli E, Oner L (2010) A quadruped study on chitosan microspheres containing atorvastatin calcium: preparation, characterization, quantification and in-vivo application. Chem Pharm Bull 58(9):1161–1167

    Article  PubMed  CAS  Google Scholar 

  • Gibson JN, Waddell G (2005) Surgery for degenerative lumbar spondylosis: updated Cochrane Review. Spine (Phila Pa 1976) 30(20):2312–2320

    Article  Google Scholar 

  • Habtemariam A, Gronblad M, Virri J, Seitsalo S, Karaharju E (1998) A comparative immunohistochemical study of inflammatory cells in acute-stage and chronic-stage disc herniations. Spine (Phila Pa 1976) 23(20):2159–2165, discussion 2166

    Article  CAS  Google Scholar 

  • Han X, Yang N, Xu Y, Zhu J, Chen Z, Liu Z, Dang G, Song C (2011) Simvastatin treatment improves functional recovery after experimental spinal cord injury by upregulating the expression of BDNF and GDNF. Neurosci Lett 487(3):255–259. doi:10.1016/j.neulet.2010.09.007

    Article  PubMed  CAS  Google Scholar 

  • Hausmann ON (2003) Post-traumatic inflammation following spinal cord injury. Spinal Cord 41(7):369–378. doi:10.1038/sj.sc.31014833101483

    Article  PubMed  CAS  Google Scholar 

  • Igel M, Sudhop T, von Bergmann K (2002) Pharmacology of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin. J Clin Pharmacol 42(8):835–845

    Article  PubMed  CAS  Google Scholar 

  • Ito T, Ohtori S, Inoue G, Koshi T, Doya H, Ozawa T, Saito T, Moriya H, Takahashi K (2007) Glial phosphorylated p38 MAP kinase mediates pain in a rat model of lumbar disc herniation and induces motor dysfunction in a rat model of lumbar spinal canal stenosis. Spine (Phila Pa 1976) 32(2):159–167. doi:10.1097/01.brs.0000251437.10545.e900007632-200701150-00004

    Article  Google Scholar 

  • Kawaguchi S, Yamashita T, Yokogushi K, Murakami T, Ohwada O, Sato N (2001) Immunophenotypic analysis of the inflammatory infiltrates in herniated intervertebral discs. Spine (Phila Pa 1976) 26(11):1209–1214

    Article  CAS  Google Scholar 

  • Khan M, Im YB, Shunmugavel A, Gilg AG, Dhindsa RK, Singh AK, Singh I (2009) Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact. J Neuroinflammation 6:32. doi:10.1186/1742-2094-6-32

    Article  PubMed  Google Scholar 

  • Kiernan J (1990) Interactions between mast cells and nerves. Neurogenic inflammation. Trends Pharmacol Sci 11(8):316

    Article  PubMed  CAS  Google Scholar 

  • Kirkaldy-Willis WH, Wedge JH, Yong-Hing K, Tchang S, de Korompay V, Shannon R (1982) Lumbar spinal nerve lateral entrapment. Clin Orthop Relat Res 169:171–178

    PubMed  Google Scholar 

  • Koike Y, Uzuki M, Kokubun S, Sawai T (2003) Angiogenesis and inflammatory cell infiltration in lumbar disc herniation. Spine (Phila Pa 1976) 28(17):1928–1933. doi:10.1097/01.BRS.0000083324.65405.AE

    Article  Google Scholar 

  • Koyanagi I, Tator CH, Lea PJ (1993) Three-dimensional analysis of the vascular system in the rat spinal cord with scanning electron microscopy of vascular corrosion casts. Part 1: normal spinal cord. Neurosurgery 33(2):277–283, discussion 283–274

    Article  PubMed  CAS  Google Scholar 

  • Kwak B, Mulhaupt F, Myit S, Mach F (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6(12):1399–1402. doi:10.1038/82219

    Article  PubMed  CAS  Google Scholar 

  • Lassmann H, Wisniewski HM (1979) Chronic relapsing experimental allergic encephalomyelitis: clinicopathological comparison with multiple sclerosis. Arch Neurol 36(8):490–497

    Article  PubMed  CAS  Google Scholar 

  • Li B, Mahmood A, Lu D, Wu H, Xiong Y, Qu C, Chopp M (2009) Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury. Neurosurgery 65(1):179–185. doi:10.1227/01.NEU.0000346272.76537.DC, discussion 185–176

    Article  PubMed  Google Scholar 

  • Markovic-Plese S, Singh AK, Singh I (2008) Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair. Futur Neurol 3(2):153. doi:10.2217/14796708.3.2.153

    Article  CAS  Google Scholar 

  • Mascitelli L, Grant WB, Goldstein MR (2011) Statins, vitamin D, and neuropathic pain. Pain 152(7):1686–1687. doi:10.1016/j.pain.2011.04.022, author reply 1687

    Article  PubMed  Google Scholar 

  • Miranda HF, Noriega V, Olavarria L, Zepeda RJ, Sierralta F, Prieto JC (2011) Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice. Basic Clin Pharmacol Toxicol 109(6):438–442. doi:10.1111/j.1742-7843.2011.00746.x

    Article  PubMed  CAS  Google Scholar 

  • Ohtori S, Suzuki M, Koshi T, Takaso M, Yamashita M, Inoue G, Yamauchi K, Orita S, Eguchi Y, Kuniyoshi K, Ochiai N, Kishida S, Nakamura J, Aoki Y, Ishikawa T, Arai G, Miyagi M, Kamoda H, Toyone T, Takahashi K (2010) Proinflammatory cytokines in the cerebrospinal fluid of patients with lumbar radiculopathy. Eur Spine J. doi:10.1007/s00586-010-1595-3

  • Orendacova J, Cizkova D, Kafka J, Lukacova N, Marsala M, Sulla I, Marsala J, Katsube N (2001) Cauda equina syndrome. Prog Neurobiol 64(6):613–637

    Article  PubMed  CAS  Google Scholar 

  • Pahan K, Sheikh FG, Namboodiri AM, Singh I (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 100(11):2671–2679. doi:10.1172/JCI119812

    Article  PubMed  CAS  Google Scholar 

  • Paintlia AS, Paintlia MK, Singh AK, Stanislaus R, Gilg AG, Barbosa E, Singh I (2004) Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by Lovastatin. J Neurosci Res 77(1):63–81. doi:10.1002/jnr.20130

    Article  PubMed  CAS  Google Scholar 

  • Paintlia AS, Paintlia MK, Singh I, Skoff RB, Singh AK (2009) Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia 57(2):182–193. doi:10.1002/glia.20745

    Article  PubMed  Google Scholar 

  • Pan HC, Yang DY, Ou YC, Ho SP, Cheng FC, Chen CJ (2010) Neuroprotective effect of atorvastatin in an experimental model of nerve crush injury. Neurosurgery 67(2):376–388. doi:10.1227/01.NEU.0000371729.47895.A0, discussion 388–379

    Article  PubMed  Google Scholar 

  • Pannu R, Barbosa E, Singh AK, Singh I (2005) Attenuation of acute inflammatory response by atorvastatin after spinal cord injury in rats. J Neurosci Res 79(3):340–350. doi:10.1002/jnr.20345

    Article  PubMed  CAS  Google Scholar 

  • Pannu R, Christie DK, Barbosa E, Singh I, Singh AK (2007) Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem 101(1):182–200. doi:10.1111/j.1471-4159.2006.04354.x

    Article  PubMed  CAS  Google Scholar 

  • Porter RW, Ward D (1992) Cauda equina dysfunction. The significance of two-level pathology. Spine (Phila Pa 1976) 17(1):9–15

    Article  CAS  Google Scholar 

  • Qu C, Lu D, Goussev A, Schallert T, Mahmood A, Chopp M (2005) Effect of atorvastatin on spatial memory, neuronal survival, and vascular density in female rats after traumatic brain injury. J Neurosurg 103(4):695–701. doi:10.3171/jns.2005.103.4.0695

    Article  PubMed  CAS  Google Scholar 

  • Qu C, Xiong Y, Mahmood A, Kaplan DL, Goussev A, Ning R, Chopp M (2009) Treatment of traumatic brain injury in mice with bone marrow stromal cell-impregnated collagen scaffolds. J Neurosurg 111(4):658–665. doi:10.3171/2009.4.JNS081681

    Article  PubMed  Google Scholar 

  • Reichert F, Levitzky R, Rotshenker S (1996) Interleukin 6 in intact and injured mouse peripheral nerves. Eur J Neurosci 8(3):530–535

    Article  PubMed  CAS  Google Scholar 

  • Schonbeck U, Libby P (2004) Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation 109(21 Suppl 1):II18–II26. doi:10.1161/01.CIR.0000129505.34151.23

    PubMed  Google Scholar 

  • Schwab ME, Bartholdi D (1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 76(2):319–370

    PubMed  CAS  Google Scholar 

  • Schwab JM, Brechtel K, Mueller CA, Failli V, Kaps HP, Tuli SK, Schluesener HJ (2006) Experimental strategies to promote spinal cord regeneration–an integrative perspective. Prog Neurobiol 78(2):91–116. doi:10.1016/j.pneurobio.2005.12.004

    Article  PubMed  CAS  Google Scholar 

  • Seichi A, Takeshita K, Kawaguchi H, Nakajima S, Akune T, Nakamura K (2004) Postoperative expansion of intramedullary high-intensity areas on T2-weighted magnetic resonance imaging after cervical laminoplasty. Spine (Phila Pa 1976) 29(13):1478–1482, discussion 1482

    Article  Google Scholar 

  • Sekiguchi M, Kikuchi S, Myers RR (2004) Experimental spinal stenosis: relationship between degree of cauda equina compression, neuropathology, and pain. Spine (Phila Pa 1976) 29(10):1105–1111

    Article  Google Scholar 

  • Shi XQ, Lim TK, Lee S, Zhao YQ, Zhang J (2011) Statins alleviate experimental nerve injury-induced neuropathic pain. Pain 152(5):1033–1043. doi:10.1016/j.pain.2011.01.006

    Article  PubMed  CAS  Google Scholar 

  • Shunmugavel A, Khan M, Te Chou PC, Dhindsa RK, Martin MM, Copay AG, Subach BR, Schuler TC, Bilgen M, Orak JK, Singh I (2010) Simvastatin protects bladder and renal functions following spinal cord injury in rats. J Inflamm (Lond) 7:17. doi:10.1186/1476-9255-7-17

    Article  Google Scholar 

  • Shunmugavel A, Khan M, Chou PC, Singh I (2012a) Spinal cord injury induced arrest in estrous cycle of rats is ameliorated by S-nitrosoglutathione: novel therapeutic agent to treat amenorrhea. J Sex Med 9(1):148–158. doi:10.1111/j.1743-6109.2011.02526.x

    Article  CAS  Google Scholar 

  • Shunmugavel A, Khan M, Martin MM, Copay AG, Subach BR, Schuler TC, Singh I (2012b) S-Nitrosoglutathione administration amelioratescauda equina compression injury in rats. Neurosci Med 3(3):294–305. doi:10.4236/nm.2012.33034

    Article  Google Scholar 

  • Siebert E, Pruss H, Klingebiel R, Failli V, Einhaupl KM, Schwab JM (2009) Lumbar spinal stenosis: syndrome, diagnostics and treatment. Nat Rev Neurol 5(7):392–403. doi:10.1038/nrneurol.2009.90

    Article  PubMed  Google Scholar 

  • Stanislaus R, Singh AK, Singh I (2001) Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis. J Neurosci Res 66(2):155–162. doi:10.1002/jnr.1207

    Article  PubMed  CAS  Google Scholar 

  • Takenobu Y, Katsube N, Marsala M, Kondo K (2001) Model of neuropathic intermittent claudication in the rat: methodology and application. J Neurosci Methods 104(2):191–198

    Article  PubMed  CAS  Google Scholar 

  • Tator CH, Fehlings MG (1991) Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75(1):15–26. doi:10.3171/jns.1991.75.1.0015

    Article  PubMed  CAS  Google Scholar 

  • Walker KM, Urban L, Medhurst SJ, Patel S, Panesar M, Fox AJ, McIntyre P (2003) The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 304(1):56–62. doi:10.1124/jpet.102.042010

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Hashizume Y, Yoshida M, Inagaki T, Kameyama T (1999) Pathological changes of the spinal cord in centenarians. Pathol Int 49(2):118–124

    Article  PubMed  CAS  Google Scholar 

  • Watanabe K, Konno S, Sekiguchi M, Kikuchi S (2007) Spinal stenosis: assessment of motor function, VEGF expression and angiogenesis in an experimental model in the rat. Eur Spine J 16(11):1913–1918. doi:10.1007/s00586-007-0394-y

    Article  PubMed  Google Scholar 

  • Weber MS, Youssef S, Dunn SE, Prod'homme T, Neuhaus O, Stuve O, Greenwood J, Steinman L, Zamvil SS (2006) Statins in the treatment of central nervous system autoimmune disease. J Neuroimmunol 178(1–2):140–148. doi:10.1016/j.jneuroim.2006.06.006

    Article  PubMed  CAS  Google Scholar 

  • Wong AP, Smith ZA, Lall RR, Bresnahan LE, Fessler RG (2012) The microendoscopic decompression of lumbar stenosis: a review of the current literature and clinical results. Minim Invasive Surg 2012:325095. doi:10.1155/2012/325095

    PubMed  Google Scholar 

  • Wu H, Mahmood A, Lu D, Jiang H, Xiong Y, Zhou D, Chopp M (2010) Attenuation of astrogliosis and modulation of endothelial growth factor receptor in lipid rafts by simvastatin after traumatic brain injury. J Neurosurg 113(3):591–597. doi:10.3171/2009.9.JNS09859

    Article  PubMed  CAS  Google Scholar 

  • Yagi M, Okada E, Ninomiya K, Kihara M (2009) Postoperative outcome after modified unilateral-approach microendoscopic midline decompression for degenerative spinal stenosis. J Neurosurg Spine 10(4):293–299. doi:10.3171/2009.1.SPINE08288

    Article  PubMed  Google Scholar 

  • Zhou Y, Wang Y, Abdelhady M, Mourad MS, Hassouna MM (2002) Change of vanilloid receptor 1 following neuromodulation in rats with spinal cord injury. J Surg Res 107(1):140–144

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from The Spinal Research Foundation VA and by grants from Betty L. Beatty and Guy E. Beatty Foundations. The work was also supported in part by grants NS-72511,NS-22576, and NS-37766 and DC00422; 07506 from the NIH, CO6 RR018823 and CO6 RR0015455 from the Extramural Research Facilities Program of the National Center for Research Resources. The authors thank Dr. Hainan Lang, Ph.D., Department of Pathology and Laboratory Medicine for help in histology, Ms. Danielle Clark Lowe for help in proof reading and Ms. Joyce Bryan and Ms. Chara Williams for help in animal and reagents procurement.

Conflict of Interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA

    Anandakumar Shunmugavel, Mushfiquddin Khan & Inderjit Singh

  2. The Virginia Spine Institute, 1831 Wiehle Avenue, Reston, VA, 20190, USA

    Marcus M. Martin, Anne G. Copay, Brian R. Subach & Thomas C. Schuler

Authors
  1. Anandakumar Shunmugavel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus M. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mushfiquddin Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne G. Copay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brian R. Subach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas C. Schuler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Inderjit Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Inderjit Singh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shunmugavel, A., Martin, M.M., Khan, M. et al. Simvastatin Ameliorates Cauda Equina Compression Injury in a Rat Model of Lumbar Spinal Stenosis. J Neuroimmune Pharmacol 8, 274–286 (2013). https://doi.org/10.1007/s11481-012-9419-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-012-9419-3

Keywords

Search

Navigation