Abstract
Secondary impairment of blood-brain barrier (BBB) occurs in the remote thalamus after ischemic stroke. Netrin-1, an axonal guidance molecule, presents bifunctional effects on blood vessels through receptor-dependent pathways. This study investigates whether netrin-1 protects BBB against secondary injury. Netrin-1 (600 ng/d for 7 days) was intracerebroventricularly infused 24 h after middle cerebral artery occlusion (MCAO) in hypertensive rats. Neurological function was assessed 8 and 14 days after MCAO, and the permeability of BBB in the ipsilateral thalamus was detected. The viability of brain microvascular endothelial cells was determined after being disposed with netrin-1 (50 ng/mL) before oxygen-glucose deprivation (OGD). The role of netrin-1 was further explored by examining its receptors and their function. We found that netrin-1 infusion improved neurological function, attenuated secondary impairment of BBB by up-regulating the levels of tight junction proteins and diminishing extravasation of albumin, with autophagy activation 14 days after MCAO. Netrin-1 also enhanced cell survival and autophagy activity in OGD-treated cells, inhibited by UNC5H2 siRNA transfection. Furthermore, the beneficial effects of netrin-1 were suppressed by PI3K inhibitors 3-Methyladenine and LY294002. Our results showed that netrin-1 ameliorated BBB impairment secondary to ischemic stroke by promoting tight junction function and endothelial survival. PI3K-mediated autophagy activation depending on UNC5H2 receptor could be an underlying mechanism.
Highlights
Vascular impairment and cellular damage take place in primary lesion, and in remote loci connected to the cerebral infarction by synapses, which could be responsible for poor neurological recovery after stroke or injury (Ling et al, 2009; Zhang et al, 2012; Duering et al, 2015)
Extravasation of erythrocyte by H&E staining and damaged tight junctions by transmission electron microscopy were exhibited in the ipsilateral thalamus after middle cerebral artery occlusion (MCAO), indicating the secondary impairment of blood-brain barrier (BBB) (Figure 2)
With exogenous netrin-1 protein continuously infused to the ventricle for 7 days after MCAO, we found the expression of endothelial cells (ECs) in the ipsilateral thalamus remained unchanged compared to the vehicle control, but neurological function was improved
Summary
Vascular impairment and cellular damage take place in primary lesion, and in remote loci connected to the cerebral infarction by synapses, which could be responsible for poor neurological recovery after stroke or injury (Ling et al, 2009; Zhang et al, 2012; Duering et al, 2015). Our previous study in hypertension, a well-known risk factor of stroke, has revealed vascular impairment in the ipsilateral thalamus at acute stage of focal cerebral infarction (Li et al, 2011). Local newly-formed blood vessels with immature blood-brain barrier (BBB), which are characterized by high permeability, could spark off neuronal loss due to the injury of extravasation of serum macromolecules and inflammatory factors to brain parenchyma (Abraham et al, 2002; Krueger et al, 2015; Prakash and Carmichael, 2015).
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