Immediate Anti-Tumor Necrosis Factor-Alpha (Etanercept) Therapy Enhances Axonal Regeneration After Sciatic Nerve Crush

J Neurosci Res. 2010 Feb 1;88(2):360-8. doi: 10.1002/jnr.22202.

Abstract

Peripheral nerve regeneration begins immediately after injury. Understanding the mechanisms by which early modulators of axonal degeneration regulate neurite outgrowth may affect the development of new strategies to promote nerve repair. Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the initiation of degenerative cascades after peripheral nerve injury. Here we demonstrate using real-time Taqman quantitative RT-PCR that, during the time course (days 1-60) of sciatic nerve crush, TNF-alpha mRNA expression is induced at 1 day and returned to baseline at 5 days after injury in nerve and the corresponding dorsal root ganglia (DRG). Immediate therapy with the TNF-alpha antagonist etanercept (fusion protein of TNFRII and human IgG), administered systemically (i.p.) and locally (epineurially) after nerve crush injury, enhanced the rate of axonal regeneration, as determined by nerve pinch test and increased number of characteristic clusters of regenerating nerve fibers distal to nerve crush segments. These fibers were immunoreactive for growth associated protein-43 (GAP-43) and etanercept, detected by anti-human IgG immunofluorescence. Increased GAP-43 expression was found in the injured nerve and in the corresponding DRG and ventral spinal cord after systemic etanercept compared with vehicle treatments. This study established that immediate therapy with TNF-alpha antagonist supports axonal regeneration after peripheral nerve injury.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Axons / drug effects*
  • Axons / physiology
  • Etanercept
  • Female
  • Fluorescent Antibody Technique
  • GAP-43 Protein / metabolism
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiopathology
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / metabolism
  • Immunoglobulin G / pharmacology*
  • Nerve Crush
  • Nerve Regeneration / drug effects*
  • Nerve Regeneration / physiology
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Tumor Necrosis Factor / administration & dosage
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / physiopathology
  • Sciatic Neuropathy / drug therapy*
  • Sciatic Neuropathy / physiopathology
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • GAP-43 Protein
  • Immunoglobulin G
  • Neuroprotective Agents
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept