Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats

Abstract

<jats:p content-type="fine-print"><jats:italic>Object.</jats:italic> In Japan fasudil hydrochloride (HA1077), a protein kinase inhibitor, is widely administered to prevent vasospasm in patients after subarachnoid hemorrhage. The effects of fasudil on experimental spinal cord injury (SCI) were investigated and compared with those obtained using methylprednisolone.</jats:p> <jats:p content-type="fine-print"><jats:italic>Methods.</jats:italic> Spinal cord contusion was induced in rats by applying an aneurysm clip extradurally to the spinal cord at T-3 for 1 minute. After injury three groups of rats were treated with intravenously administered saline (control), intraperitoneally administered fasudil (10 mg/kg), or intravenously administered methylprednisolone (four 30 mg/kg injections). Neurological recovery was evaluated periodically over 1 month by using a modified combined behavioral scale and histopathological examination. Leukocyte infiltration near the injury site was evaluated by measuring myeloperoxidase (MPO) activity at 24 hours. Spinal cord blood flow was measured at intervals up to 3 hours after injury by using laser Doppler flowmetry.</jats:p> <jats:p content-type="fine-print">In rats in the fasudil-treated group significant improvement in modified combined behavioral score was demonstrated at each time point, whereas in the methylprednisolone-treated rats no beneficial effects were shown. In the fasudil-treated group, reduction of traumatic spinal cord damage was evident histologically in the caudal portion of the injured areas, and tissue MPO activity in tissue samples was reduced. Spinal cord blood flow was not significantly different between fasudiltreated and control group rats.</jats:p> <jats:p content-type="fine-print"><jats:italic>Conclusions.</jats:italic> Fasudil hydrochloride showed promise of effectiveness in promoting neurological recovery after traumatic SCI. Possible mechanisms of this effect include protein kinase inhibition and decreased infiltration by neutrophils.</jats:p>

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…RhoA/ ROCK signaling activation downstream of Nogo receptor family members or chondroitin sulfate proteoglycan receptors promotes axon growth inhibition, thus suggesting that inhibition of this pathway may be a promising strategy for axon regeneration (Fujita and Yamashita, 2014). Indeed, treatment with the ROCK inhibitors fasudil or Y-27632 stimulates axonal regrowth and functional recovery in animal spinal cord injury models (Hara et al, 2000;Dergham et al, 2002;Fournier et al, 2003;Sung et al, 2003). A recent metaanalysis of 30 preclinical studies reposted that RhoA/ ROCK inhibition improves by 15% locomotor recovery after experiment spinal cord injury (Watzlawick et al, 2014).…”

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