Nafamostat Mesilate Improves Neurological Outcome and Axonal Regeneration after Stroke in Rats

Disability including deficiency in sensorimotor and cognition functions is a dominant consequence after stroke. Evidence suggests that serine proteases play an important role in the physiology and pathology of the brain. Previous studies reported that nafamostat mesilate (NM), a synthetic serine protease inhibitor, attenuates neuronal damage in the acute phase after stroke. However, its efficacy in the chronic phase and the mechanism underlying its beneficial effect are not fully known. Here, we have studied whether NM improves long-term functional recovery after ischemic stroke. Experimental ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO). NM treatment attenuated the brain infarct volume and the loss of body weight and improved the recovery of sensorimotor and cognitive functions. One month after tMCAO, neuronal axons and dendrites were preserved in the NM group, accompanied by increasedsynaptic proteins and structures in the ipsilateral hippocampus. The expression of brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 was increased in the contralateral sensorimotor cortex and ipsilateral hippocampus by the administration of NM. Furthermore, NM activated tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinas1/2(ERK1/2) and cAMP-response element binding protein (CREB) and inhibited the activity of Cyclin-dependent Kinase 5 (Cdk5) in the contralateral sensorimotor cortex and ipsilateral hippocampus. These results demonstrated that NM treatment could improve neurological outcome and axonal regeneration, which might be correlated with down-regulating Cdk5 activity and up-regulating TrkB-ERK1/2-CREB pathway.