Effect of Fasudil, a Selective Inhibitor of Rho Kinase Activity, in the Secondary Injury Associated with the Experimental Model of Spinal Cord Trauma

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-B (NF-B) 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-1␤ (IL-1␤); 7) neutrophil infiltration; 8) nitrotyrosine and poly-ADPribose formation; 9) glial fibrillary acidic protein expression; 10) apoptosis (terminal deoxynucleotidyl transferase dUTP nickend 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 NH 2 -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.

Activation and Regulation of NLRP3 Inflammasome by Intrathecal Application of SDF-1a in a Spinal Cord Injury Model

“…Further, SCI promoted the assembly and activity of this inflammasome complex, and neuronal purinergic P2X receptor subtypes are involved in SCI-mediated NALP1 activation [6]. Another report showed that the inhibition of Rho kinase signaling pathways after SCI reduced the secondary neural injury in conjunction with attenuated inflammasome activation [43]. In a recent study, we could demonstrate that polyunsaturated fatty acids such as omega-3 fish oil components are neuroprotective agents in another acute brain damaging model, i.e., ischemic stroke in rats [19].…”

Role of Rho Kinase Inhibition in the Protective Effect of Fasudil and Simvastatin Against 3-Nitropropionic Acid-Induced Striatal Neurodegeneration and Mitochondrial Dysfunction in Rats

“…Herein, 3 NP-induced ROCK activation was significantly suppressed following fasudil and simvastatin administration. Beforehand, experimental spinal cord injury was associated with increase in ROCK activity which was markedly attenuated by fasudil treatment [48]. It is worthy to note that the potent ROCK inhibition by fasudil could be mediated via competition for ATP binding site in the ROCK catalytic domain [49].…”

O papel da farmacoterapia na modificação do estado neurológico de traumatizados vértebro‐medulares

“…25 Vários fármacos inibem a apoptose por diversos mecanismos, entre os quais a inibição das caspases, 25 a inibição de diversas vias de sinalização intracelular 26,27 e a redução do estresse oxidativo. 28 Um vasto grupo de fármacos inibe a calpaína, uma endoprotease que promove a apoptose em vários tipos de células através da proteólise de proteínas do citoesqueleto, da membrana e da mielina. 29…”