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.
Footnotes
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This study was supported by Programmi di Ricerca di Interesse Nazionale 2003.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.102863.
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ABBREVIATIONS: SCI, spinal cord injury; GSK-3β, glycogen synthase kinase-3β; PI-3K, phosphatidyl-inositol-3-kinase; TDZD-8, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; NF-κB, nuclear factor-κB; iNOS, inducible nitric-oxide synthase; COX, cyclooxygenase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; DMSO, dimethyl sulfoxide; SB415286, 3-[(3-chloro-4-hydroxyphenyl)amino]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione; PBS, phosphate-buffered saline; MPO, myeloperoxidase; EMSA, electrophoretic mobility shift assay; BBB, Basso, Beattie, and Bresnahan; TNF, tumor necrosis factor.
- Received February 13, 2006.
- Accepted April 5, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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