Tamoxifen reduces infiltration of inflammatory cells, apoptosis and inhibits IKK/NF-kB pathway after spinal cord injury in rats
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Abstract
In this study, neuroprotective effect of tamoxifen has been explored in spinal cord injury (SCI) in rats by examining factors influencing IKK/NF-kB pathway in SCI in rats. It has been shown in several studies that IKK/NF-kB signaling pathway plays a key role in pathophysiology of SCI. In this study, three groups of rats (n = 17 each) were selected that included, tamoxifen group (here tamoxifen was injected after SCI in rats), SCI group (here only dimethylsulfoxide was administered after inducing SCI in rats) and sham group (here only laminectomy was performed). The effect of tamoxifen (5 mg/kg) on various factors responsible for activation of IKK/NF-kB signaling pathway including NF-kB p65, phosphorylated I-kBα was studied through Western blotting as well as densitometry. The examination of expression of active caspase-3 and myeloperoxidase activity was also carried out through Western blot analysis and densitometry. A comparison of three groups of rats showed that administration of tamoxifen significantly reduced the expression of NF-kB p65 and phosphorylated I-kBα (P < 0.05) compared to control. It also attenuated the expression of active caspase-3 resulting in the reduction of apoptosis, and infiltration of leukocytes to the injury site was also greatly reduced in the group where tamoxifen was administered. Statistical analysis through SPSS 13.0 software showed a significant decrease in the expression of inflammatory factors in groups where tamoxifen was administered. We conclude that tamoxifen possesses the potential neuroprotective effects that can be explored further for future therapeutic techniques in treating spinal cord injuries.
Keywords
Spinal cord injury IKK/NF-kB pathway NF-kB p65 Active caspase-3 MPO activityReferences
- 1.Tian DS, Liu JL, Xie MJ et al (2009) Tamoxifen attenuates inflammatory-mediated damage and improves functional outcome after spinal cord injury in rats. J Neurochem 109:1658–1667PubMedCrossRefGoogle Scholar
- 2.Xie Q, Guan J, Wu G, Xi G, Keep RF, Hua Y (2011) Tamoxifen treatment for intracerebral hemorrhage. Acta Neurochir Suppl 1 11:271–275CrossRefGoogle Scholar
- 3.Feng Y, Fratkins JD, LeBlanc MH (2004) Treatment with tamoxifen reduces hypoxic–ischemic brain injury in neonatal rats. Eur J Pharmacol 484:65–74PubMedCrossRefGoogle Scholar
- 4.Kimelberg HK, Feustel PJ, Jin Y, Paquette J, Boulos A, Keller RW Jr, Tranmer BI (2000) Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion. Neuro Report 11:2675–2679Google Scholar
- 5.Kimelberg HK, Jin Y, Charniga C, Feustel PJ (2003) Neuroprotective activity of tamoxifen in permanent focal ischemia. J Neurosurg 99:138–142PubMedCrossRefGoogle Scholar
- 6.Rutledge EM, Aschner M, Kimelberg HK (1998) Pharmacological characterization of swelling-induced D-[3H]aspartate released from primary astrocyte cultures. Am J Physiol 274:C1511–C1520PubMedGoogle Scholar
- 7.Wiseman H, Cannon M, Arnstein HR, Halliwell B (1993) Tamoxifen inhibits lipid peroxidation in cardiac microsomes. Comparison with liver microsomes and potential relevance to the cardiovascular benefits associated with cancer prevention and treatment by tamoxifen. Biochem Pharmacol 45:1851–1855PubMedCrossRefGoogle Scholar
- 8.Osuka K, Feustel PJ, Mongin AA, Tranmer BI, Kimelberg HK (2001) Tamoxifen inhibits nitrotyrosine formation after reversible middle cerebral artery occlusion in the rat. J Neurochem 76:1842–1850PubMedCrossRefGoogle Scholar
- 9.Suuronen T, Nuutinen T, Huuskonen J, Ojala J, Thornell A, Salminen A (2005) Anti-inflammatory effect of selective estrogen receptor modulators (SERMs) in microglial cells. Inflamm Res 54:194–203PubMedCrossRefGoogle Scholar
- 10.Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS (2001) Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 24:254–264PubMedCrossRefGoogle Scholar
- 11.Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR (2004) Pathophysiology and pharmacologic treatment of acute spinal cord injury. J Spine 4:451–464CrossRefGoogle Scholar
- 12.Fehlings MG, Baptiste DC (2005) Current status of clinical trials for acute spinal cord injury. Injury 36(Suppl. 2):B113–B122PubMedCrossRefGoogle Scholar
- 13.Rowland JW, Hawryluk GW, Kwon B, Fehlings MG (2008) Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus 25(5):E2PubMedCrossRefGoogle Scholar
- 14.Beattie MS (2004) Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. Trends Mol Med 10:580–583PubMedCrossRefGoogle Scholar
- 15.Hu X, Nesic-Taylor O, Qiu J, Rea HC, Fabian R, Rassin DK, Perez-Polo JR (2005) Activation of nuclear factor-kB signaling pathway by interleukin-1 after hypoxia/ischemia in neonatal rat hippocampus and cortex. J Neurochem 93:26–37PubMedCrossRefGoogle Scholar
- 16.Karin M, Yamamoto Y, Wang QM (2004) The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3:17–26PubMedCrossRefGoogle Scholar
- 17.Brambilla R, Bracchi-Ricard V, Hu WH et al (2005) Inhibition of astroglial nuclear factor kB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202:145–156PubMedCentralPubMedCrossRefGoogle Scholar
- 18.Han X, Lu M, Wang S, Lv DC (2012) Targeting IKK/NF-kappa B pathway reduces infiltration of inflammatory cells and apoptosis after spinal cord injury in rats. Neurosci Lett 511:28–32PubMedCrossRefGoogle Scholar
- 19.Panter SS, Yum SW, Faden AI (1990) Alteration in extracellular amino acids after traumatic spinal cord injury. Ann Neurol 27:96–99PubMedCrossRefGoogle Scholar
- 20.Blesch A, Tuszynski MH (1997) Robust growth of chronically injured spinal cord axons induced by grafts of genetically modified NGF secreting cells. Exp Neurol 148:444–452PubMedCrossRefGoogle Scholar
- 21.Bregman BS, Broude E, McAtee M, Kelley MS (1998) Transplants and neurotrophic factors prevent atrophy of mature CNS neurons after spinal cord injury. Exp Neurol 149:13–27PubMedCrossRefGoogle Scholar
- 22.Xuebo S, Chengyuan J, Tong H, Zhong W, Gang C (2013) Tamoxifen as an effective neuroprotectant against early brain injury and learning deficits induced by subarachnoid hemorrhage: possible involvement of inflammatory signaling. J Neuroinflamm 10:157CrossRefGoogle Scholar
- 23.Han X, Wang SY, Zhang Z, Lü DC, Liu HR (2011) BMS-345541 inhibited nuclear factor kappa B expression and improved locomotor function recovery in rats after acute spinal cord injury. Neural Regen Res 6:1775–1779Google Scholar
- 24.Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ (2010) Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 133:433–447PubMedCentralPubMedCrossRefGoogle Scholar
- 25.Pandey MK, Sandur SK, Sung B, Sethi G, Kunnumakkara AB, Aggarwal BB (2007) Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaBand NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue. J Biol Chem 282:17340–17350PubMedCrossRefGoogle Scholar
- 26.Niederberger E, Geisslinger G (2008) The IKK-NF-kappa B pathway: a source for novel molecular drug targets in pain therapy. J FASEB 22:3432–3442CrossRefGoogle Scholar
- 27.Huxford T, Huang DB, Malek S, Ghosh G (1998) The crystal structure of the IkappaBalpha/NF-kappa B complex reveals mechanisms of NF-kappa B inactivation. Cell 95:759–770PubMedCrossRefGoogle Scholar
- 28.Bao F, Liu D (2003) Peroxynitrite generated in the rat spinal cord induces apoptotic cell death and activates caspase-3. Neuroscience 116:59–70PubMedCrossRefGoogle Scholar
- 29.Bao F, Liu D (2004) Hydroxyl radicals generated in the rat spinal cord at the level produced by impact injury induce cell death by necrosis and apoptosis: protection by a metalloporphyrin. Neuroscience 126:285–295PubMedCrossRefGoogle Scholar
- 30.Bethea JR (2000) Spinal cord injury-induced inflammation: a dual-edged sword. Prog Brain Res 128:33–42PubMedCrossRefGoogle Scholar
- 31.Chatzipanteli K, Yanagawa Y, Marcillo AE, Kraydieh S, Yezierski RP, Dietrich WD (2000) Posttraumatic hypothermia reduces polymorphonuclear leukocyte accumulation following spinal cord injury in rats. J Neurotrauma 17:321–332PubMedCrossRefGoogle Scholar
- 32.Trivedi A, Olivas AD, Noble-Haeusslein LJ (2006) Inflammation and spinal cord injury: infiltrating leukocytes as determinants of injury and repair processes. Clin Neurosci Res 6:283–292PubMedCentralPubMedCrossRefGoogle Scholar
- 33.Grossman SD, Rosenberg LJ, Wrathall JR (2001) Temporal-spatial pattern of acute neuronal and glial loss after spinal cord contusion. Exp Neurol 168:273–282PubMedCrossRefGoogle Scholar
- 34.Hagg T, Oudega M (2006) Degenerative and spontaneous regenerative processes after spinal cord injury. J Neurotrauma 23:264–280PubMedGoogle Scholar
- 35.Jiang SC, Bendjelloul F, Ballerini Iolanda P, D’Alimonte I, Nargi E, Jiang C, Huang XJ, Rathbone MP (2007) Guanosine reduces apoptosis and inflammation associated with restoration of function in rats with acute spinal cord injury. Purinergic Signal 3:411–421PubMedCentralPubMedCrossRefGoogle Scholar