RT Journal Article
SR Electronic
T1 Glycogen Synthase Kinase-3β Inhibition Reduces Secondary Damage in Experimental Spinal Cord Trauma
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 79
OP 89
DO 10.1124/jpet.106.102863
VO 318
IS 1
A1 Salvatore Cuzzocrea
A1 Tiziana Genovese
A1 Emanuela Mazzon
A1 Concetta Crisafulli
A1 Rosanna Di Paola
A1 Carmelo Muià
A1 Marika Collin
A1 Emanuela Esposito
A1 Placido Bramanti
A1 Christoph Thiemermann
YR 2006
UL http://jpet.aspetjournals.org/content/318/1/79.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics