Glycogen synthase kinase-3β inhibition reduces secondary damage in experimental spinal cord trauma

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

Research output: Contribution to journalArticle

Abstract

Glycogen synthase kinase-3 (GSK-3) has recently been identified as an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3β inhibition on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury (SCI) in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a potent and selective GSK-3β inhibitor, significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score); 2) neutrophil infiltration (myeloperoxidase activity); 3) inducible nitric-oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression; and 4) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and Bax and Bcl-2 expression). In a separate set of experiments, TDZD-8 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with TDZD-8 reduces the development of inflammation and tissue injury associated with spinal cord trauma.

Original languageEnglish
Pages (from-to)79-89
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume318
Issue number1
DOIs
Publication statusPublished - 2006

ASJC Scopus subject areas

  • Pharmacology

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