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.