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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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 and Christoph Thiemermann
Journal of Pharmacology and Experimental Therapeutics July 2006, 318 (1) 79-89; DOI: https://doi.org/10.1124/jpet.106.102863
Salvatore Cuzzocrea
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Tiziana Genovese
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Emanuela Mazzon
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Concetta Crisafulli
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Rosanna Di Paola
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Carmelo Muià
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Marika Collin
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Emanuela Esposito
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Placido Bramanti
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Christoph Thiemermann
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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

  • This study was supported by Programmi di Ricerca di Interesse Nazionale 2003.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.102863.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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 and Christoph Thiemermann
Journal of Pharmacology and Experimental Therapeutics July 1, 2006, 318 (1) 79-89; DOI: https://doi.org/10.1124/jpet.106.102863

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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 and Christoph Thiemermann
Journal of Pharmacology and Experimental Therapeutics July 1, 2006, 318 (1) 79-89; DOI: https://doi.org/10.1124/jpet.106.102863
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