Abstract
Rho kinase (ROK) may play an important role in regulating the biological events of cells, including proliferation, differentiation, and survival/death. Blockade of ROK promotes axonal regeneration and neuron survival in vivo and in vitro, thereby exhibiting potential clinical applications in spinal cord damage and stroke. The aim of this experimental study was to determine the role of ROK signaling pathways in the inflammatory response, in particular in the secondary injury associated with the experimental model of spinal cord trauma. The injury was induced by application of vascular clips to the dura via a four-level T5 to T8 laminectomy in mice. Fasudil was administered in mice (10 mg/kg i.p.) 1 and 6 h after the trauma. The treatment with fasudil significantly decreased 1) histological damage; 2) motor recovery; 3) nuclear factor-κB (NF-κB) expression; 4) ROK activity; 5) inflammasome activation (caspase-1 and NOD-like receptor family, pyrin domain-containing 3 expression); 6) production of proinflammatory cytokine such as tumor necrosis factor and interleukin-1β (IL-1β); 7) neutrophil infiltration; 8) nitrotyrosine and poly-ADP-ribose formation; 9) glial fibrillary acidic protein expression; 10) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, FAS ligand expression, and Bax and Bcl-2 expression); and 11) mitogen-activated protein kinase activation (phospho-extracellular signal-regulated kinase and phospho-c-Jun NH2-terminal kinase expression). Our results indicate that inhibition of ROK by fasudil may represent a useful therapeutic perspective in the treatment of inflammation associated with spinal cord trauma.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- SCI
- spinal cord injury
- NO
- nitric oxide
- ROS
- reactive oxygen species
- IκB
- inhibitor of nuclear factor-κB
- NF-κB
- nuclear factor-κB
- MAPK
- mitogen-activated protein kinase
- NLRP3
- NOD-like receptor family, pyrin domain-containing 3
- ROK
- Rho kinase
- TNF-α
- tumor necrosis factor-α
- IL-1β
- interleukin-1β
- PBS
- phosphate-buffered saline
- PMSF
- phenylmethylsulfonyl fluoride
- MPO
- myeloperoxidase
- BMS
- Basso Mouse Scale
- PAR
- poly-ADP-ribose
- GFAP
- glial fibrillary acidic protein
- P-JNK
- phospho-c-Jun NH2-terminal kinase
- CNS
- central nervous system
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- P-ERK
- phospho-extracellular signal-regulated kinase
- π-MYPT1
- myosin phosphate target subunit-1
- Y27632
- (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride
- ONOO−
- peroxynitrate
- PARP
- poly-ADP-ribose polymerase.
- Received December 22, 2011.
- Accepted June 22, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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