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.
| Original language | English |
|---|---|
| Pages (from-to) | 79-89 |
| Number of pages | 11 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 318 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2006 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Glycogen synthase kinase-3β inhibition reduces secondary damage in experimental spinal cord trauma. / Cuzzocrea, Salvatore; Genovese, Tiziana; Mazzon, Emanuela; Crisafulli, Concetta; Di Paola, Rosanna; Muià, Carmelo; Collin, Marika; Esposito, Emanuela; Bramanti, Placido; Thiemermann, Christoph.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 318, No. 1, 2006, p. 79-89.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glycogen synthase kinase-3β inhibition reduces secondary damage in experimental spinal cord trauma
AU - Cuzzocrea, Salvatore
AU - Genovese, Tiziana
AU - Mazzon, Emanuela
AU - Crisafulli, Concetta
AU - Di Paola, Rosanna
AU - Muià, Carmelo
AU - Collin, Marika
AU - Esposito, Emanuela
AU - Bramanti, Placido
AU - Thiemermann, Christoph
PY - 2006
Y1 - 2006
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=33745241901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745241901&partnerID=8YFLogxK
U2 - 10.1124/jpet.106.102863
DO - 10.1124/jpet.106.102863
M3 - Article
C2 - 16601144
AN - SCOPUS:33745241901
VL - 318
SP - 79
EP - 89
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 1
ER -