Inhibition of tyrosine kinase-mediated cellular signalling by Tyrphostins AG126 and AG556 modulates secondary damage in experimental spinal cord trauma

Tiziana Genovese, Emanuela Mazzon, Emanuela Esposito, Carmelo Muià, Rosanna Di Paola, Concetta Crisafulli, Placido Bramanti, Salvatore Cuzzocrea

Research output: Contribution to journalArticle

Abstract

Protein tyrosine kinases help to regulate the expression of many genes, which play an important role in the pathophysiology of a number of diseases. Here we investigate the effects of the tyrosine kinase inhibitors, AG126 and AG556 on the degree of experimental spinal cord trauma induced by the application of vascular clips to the dura via a four-level T4-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by oedema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with AG126 and AG556 significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) iNOS, nitrotyrosine, and PARP expression and (4) apoptosis (TUNEL staining and Bax and Bcl-2 expression). In a separate set of experiments, AG126 and AG556 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). This study provides an experimental evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of inflammation and tissue injury associated with spinal cord trauma, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of spinal cord trauma.

Original languageEnglish
Pages (from-to)1454-1471
Number of pages18
JournalNeuropharmacology
Volume52
Issue number7
DOIs
Publication statusPublished - Jun 2007

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Keywords

  • COX-2
  • iNOS
  • Myeloperoxidase activity
  • NF-κB expression
  • Nitrotyrosine
  • Spinal cord injury
  • Tyrosine-kinase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

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