Abstract
Mitogen-activated protein kinase (MAPK) signaling pathways involve two closely related MAPKs, known as extracellular signal-regulated kinase (ERK)1 and ERK2. The aim of the present study was to evaluate the contribution of MAPK3/MAPK1 in the secondary damage in experimental spinal cord injury (SCI) in mice. To this purpose, we used 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059), which is an inhibitor of MAPK3/MAPK1. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. PD98059 treatment (10 mg/kg i.p.) at 1 and 6 h after the SCI significantly reduced 1) the degree of spinal cord inflammation and tissue injury (histological score), 2) neutrophil infiltration (myeloperoxidase activity), 3) nitrotyrosine formation, 4) proinflammatory cytokines expression, 5) nuclear factor-κB activation, 6) phospho-ERK1/2 expression, and 6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, Fas ligand, Bax, and Bcl-2 expression). Moreover, PD98059 significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. Taken together, our results clearly demonstrate that PD98059 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.
Footnotes
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T.G. and E.E. contributed equally to this work.
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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.107.131060.
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ABBREVIATIONS: SCI, spinal cord injury; CNS, central nervous system; iNOS, inducible nitric-oxide synthase; ONOO–, peroxynitrite; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; TNF, tumor necrosis factor; JNK, c-Jun NH2-terminal kinase; IL, interleukin; PD98059, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; NF-κB, nuclear factor-κB; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; MPO, myeloperoxidase activity; FasL, Fas ligand; IκB, inhibitor of nuclear factor-κB; SAPK, stress-activated protein kinase; PMSF, phenylmethylsulfonyl fluoride; p, phosphorylated; MDA, malondialdehyde-bis-(dimethylacetal)1,1,3,3-tetramethoxypropan; BBB, Basso, Beattie, and Bresnahan; IKK, IκB kinase complex; wm, white matter; gm, gray matter.
- Received August 31, 2007.
- Accepted January 4, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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