In this study, we report that ischemic stroke in C57BL/6J mice induced by transient middle cerebral artery occlusion triggers time-dependent changes in the blood-CSF barrier permeability, tight-junction damage and dynamic changes of SPAK-NKCC1 complex pathway at 1–7 days post-stroke, which is featured by an elevation of albumin permeability, phosphorylatory stimulation of SPAK-NKCC1 protein complex, elevation of proinflammatory lipocalin-2 (Lcn2) mRNA and protein expression, and elevation of CD11b+/CD45+/CD206+ macrophages in the ChP. This evidence concerns the gene SLC12A2 and stroke disorder.