SEW2871 Attenuates Blood-Brain Barrier Damage and Neuropathological Outcomes Related to Cerebral Small Vessel Disease

Abstract

Background: Blood-brain barrier (BBB) dysfunction contributes to the pathogenesis of cerebral small vessel disease. This study assessed SEW2871, a selective agonist of sphingosine-1-phosphate receptor 1, as a potential novel therapy for small vessel disease by targeting BBB damage using a rat model of small vessel disease.

Methods: Twelve-week male and female spontaneously hypertensive rat stroke-prones were subjected to unilateral carotid artery occlusion (UCAO) and Japanese permissive diet (JPD). Three doses of SEW2871 (0.5, 1.0, and 5.0 mg/kg, delivered every other day up to 5 weeks) were tested. Dynamic body weight, oxygen saturation, and SEW2871 plasma concentration were evaluated. BBB permeability, white matter lesions and gray matter lesions, and cerebral blood flow (CBF) were assessed with preclinical magnetic resonance imaging at 2 and 5 weeks after UCAO/JPD onset. Cognitive outcomes were evaluated using Morris Water Maze during week 5 of UCAO/JPD.

Results: We found that SEW2871 delayed the occurrence of UCAO/JPD-induced chronic hypoxic hypoperfusion in the spontaneously hypertensive rat stroke-prones. Magnetic resonance imaging showed increased BBB permeability, white matter lesions and gray matter lesions, and decreased CBF at 2 and 5 weeks after UCAO/JPD onset. T₂-weighted and fractional anisotropy magnetic resonance imaging showed that all doses of SEW2871 demonstrated a protective effect on white matter lesions and gray matter lesions with the most significant improvements in the 1.0 mg/kg group. Dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling maps showed significantly reduced BBB leakage and improved CBF in 0.5 and 1.0 mg/kg groups. Immunohistochemical analysis for serum IgG extravasation and microglia/macrophage activation in rat brains verified the protective effects of SEW2871 on BBB leakage and neuroinflammation. Morris Water Maze test revealed a significant improvement in spatial memory in 0.5 and 1.0 mg/kg groups compared with the vehicle animals.

Conclusions: Long-term treatment with SEW2871 mitigated BBB leakage and brain injury, improved CBF and cognitive impairment in the spontaneously hypertensive rat stroke-prone model of small vessel disease. SEW2871 is effective at all doses, while 1.0 mg/kg dose demonstrated exceptional protection against the neuropathological cascades associated with small vessel disease.

Keywords: blood-brain barrier; cerebral small vessel disease; gray matter; hypoxic brain damage; magnetic resonance imaging; phingosine-1-phosphate receptor 1; white matter.