Anti-inflammatory Signalling Molecule Improved Peripheral Nerve Repair

Fatemeh Basiri Basiri, Abbass Ali Imani Fooladi, Masoumeh Foroutan Koudehi, Babak Farzam, Shahnaz Shekarforoush, Mohammad Reza Nourani


Early inflammatory procedures may inhibit functional recovery after nerve injury. Tumor necrosis factor-α (TNF) plays a crucial role in the initiation of degenerative cascades after peripheral nerve injury.The aim of this study was to test the effects of TNF antagonist etanerceptonnerve regeneration in a rat model of sciatic nerve crush injury. 15 adult Wistar rats underwent a surgical procedure involving right sciatic nerve crush injury. Etanercept(6 mg/kg) was administered intra-peritoneally (IP)once immediately after nerve crush in the experimental group. Rats in the control group received saline IP post surgery. Genomic and immune-histochemical tests were done at 1, 3, 7, 21 and 42 days after injury. Functional and electromyography (EMG) assessments of nerves were performed at 7, 21 and 42 days after injury. Functional recovery was analyzed using hot plate test, a walking track assessment and quantified using the sciatic functional index (SFI). TNF mRNA expression was induced at 1 day and returned to baseline at the end of 1 week after injury in nerve. Etanerceptprevented increase of TNF in the crush site and enhanced the rate of axonal regeneration, as determined by increased number of characteristic clusters of regenerating nerve fibers distal to nerve crush segments, but it was not significant statistically with control group on 42 days. The statistical analyses of EMG studies showed that the latency and the amplitude in experimental group of 21 and 42 days were significantly different from the control group. SFI in the experimental group on 21 and 42 days was significantly higher than that of the control group. This study established that immediate therapy with etanercept promotes the regeneration of peripheral nerve injuries in a rat model.


Tumor necrosis factor-α, Nerve Regeneration

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Arslan E, Milcan A, Unal S, Demirkan F, Polat A, Bagdatoglu O and others (2003), The effects of carnitine on distally burned dorsal skin flap: an experimental study in rats. Burns 29:221-227.

Boivin A, Pineau I, Barrette B, Filali M, Vallieres N, Rivest S and others (2007a), Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci 27(46):12565-76.

Boivin A, Pineau I, Barrette B, Filali M, Vallieres N, Rivest S and others (2007b), Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci 27:12565-12576.

Campbell JN (2001) Nerve lesions and the generation of pain. Muscle Nerve 24:1261-1273.

Campbell SJ, Jiang Y, Davis AE, Farrands R, Holbrook J, Leppert D and others (2007), Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response. J Neurochem 103:2245-2255.

Chio C, Lin J, Chang M, Wang C, Kuo J, Yang C and others (2010), Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem 115:921-929.

Di Paola R, Mazzon E, Muià C, Crisafulli C, Terrana D, Greco S (2007), Effects of etanercept, a tumour necrosis factor-alpha antagonist, in an experimental model of periodontitis in rats. Br J Pharmacol 2007;150:286-97 150:286-97.

Frisen J (1997), Determinants of axonal regeneration. Histol Histopathol 12:867-868.

Gao X, Wang Y, Chen J, Peng J (2013).The role of peripheral nerve ECM components in the tissue engineering nerve construction.Rev Neurosci. 2013;24(4):443-53

Genovese T, Mazzon E, Crisafulli C, Di Paola R, Muia C, Bramanti P and others (2006) Immunomodulatory effects of etanercept in an experimental model of spinal cord injury. J Pharmacol Exp Ther 316:1006-4016.

Gudemez E, Ozer K, Cunningham B, Siemionow K, Browne E, Siemionow M (2002) Dehydro epiandrosterone as an enhancer of functional recovery following crush injury to rat sciatic nerve. Microsurgery 22:234-241.

Hall, S., The response to injury in the peripheral nervous system. The bone and joint J., 2014 96-B(6)

Kalender AM, Dogan A, Bakan V, Yildiz H, Gokalp MA, Kalender M (2009), Effect of Zofenopril on regeneration of sciatic nerve crush injury in a rat model. J. Brachial Plexus and Peripheral Injury 4(6):1-7.

Kato K, Kikuchi S, Shubayev VI, Myers RR (2009), Distribution and tumor necrosis factor-alpha isoform binding specificity of locally administered etanercept into injured and uninjured rat sciatic nerve. Neuroscience 160:492-500.

Kato K, Liu H, Kikuchi S, Myers RR, Shubayev VI (2010), Immediate Anti-tumor Necrosis Factor-a (Etanercept) Therapy Enhances Axonal Regeneration After Sciatic Nerve Crush. J. Neuroscience Research 88:360-368.

Koudehi MF, Fooladi AA, Mansoori K, Jamalpoor Z, Amiri A, Nourani MR (2013), Preparation and evaluation of novel nano-bioglass/gelatin conduit for peripheral nerve regeneration. J Mater Sci Mater Med.

Le Prell CG, Hughes LF, Miller JM (2007), Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma. Free Radic Biol Med 42:1454-1463.

Otoshi K, Kikuchi S, Konno S, Sekiguchi M (2010), The reactions of glial cells and endoneurial macrophages in the dorsal root ganglion and their contribution to pain-related behavior after application of nucleus pulposus onto the nerve root in rats. Spine 35:264-271.

Rotshenker S (2011), Wallerian degeneration: the innate-immune response to traumatic nerve injury. J NeuroInflammation 8(109):1-14.

Scha¨ fers M, Christian Geis C, Brors R, Yaksh T, Sommer C (2002), Anterograde Transport of Tumor Necrosis Factor- in the Intact and Injured Rat Sciatic Nerve. J. Nauroscience 22(2):536-545.

Sehirli O, Unlu B, Cetinel S, Tetik S, Sener E, Sener G (2011), Etanercept protectsremote organ damage in a rat model of thermal injury. Marmara Pharmaceutical J 15:118-124.

Sekiguchi M, Sekiguchi Y, Konno S, Kobayashi H, Homma Y, Kikuchi S (2009), Comparison of neuropathic pain and neuronal apoptosis following nerve root or spinal nerve compression. Eur Spine J 18:1978-1985.

Shamash S, Reichert F, Rotshenker S (2002), The Cytokine Network of Wallerian Degeneration: Tumor Necrosis Factor-α, Interleukin-1α, and Interleukin-1β. J Neuroscience 22(8):3052-3060.

Sunderland S (1990), The anatomy and physiology of nerve injury. Muscle Nerve 13:771-784.

Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP (2008), Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 117:244-279.

Zanella JM, Burright EN, Hildebrand K, Hobot C, Cox M, Christoferson L and others (2008), Effect of etanercept, a tumor necrosis factoralpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine 33:227-234.


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