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

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-3beta 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-3beta 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.

• Authors: Salvatore Cuzzocrea, Tiziana Genovese, Emanuela Mazzon, Concetta Crisafulli, Rosanna Di Paola, Carmelo Muià, Marika Collin, Emanuela Esposito, Placido Bramanti, Christoph Thiemermann
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 318 Issue 1 Pg. 79-89 (Jul 2006) ISSN: 0022-3565 [Print] United States
• PMID: 16601144 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Thiadiazoles
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Animals
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 beta
• Male
• Mice
• Motor Skills (drug effects, physiology)
• Spinal Cord Injuries (drug therapy, enzymology, pathology)
• Thiadiazoles (pharmacology, therapeutic use)