TY - JOUR 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 SP - 79 LP - 89 DO - 10.1124/jpet.106.102863 VL - 318 IS - 1 AU - Salvatore Cuzzocrea AU - Tiziana Genovese AU - Emanuela Mazzon AU - Concetta Crisafulli AU - Rosanna Di Paola AU - Carmelo Muià AU - Marika Collin AU - Emanuela Esposito AU - Placido Bramanti AU - Christoph Thiemermann Y1 - 2006/07/01 UR - http://jpet.aspetjournals.org/content/318/1/79.abstract N2 - 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 ER -