Mfsd2a attenuated hypoxic-ischemic brain damage via protection of the blood-brain barrier in mfat-1 transgenic mice

Abstract

Previous studies have shown that mfat-1 transgenic mice have protective effects against certain central nervous system (CNS) disorders, mainly through the high docosahexaenoic acid (DHA) content enriched in the brain without mentioning the blood - brain barrier (BBB). This study aimed to investigate the underlying mechanisms of the protective effect against hypoxic-ischemic brain damage (HIBD) of mfat-1 transgenic mice. We first found the mfat-1 mice showed a significant amelioration of neurological dysfunction and neuronal damage associated with elevated major facilitator superfamily domain-containing 2a (Mfsd2a) expression on the BBB after HIBD. Knockdown of Mfsd2a by siRNA intra-cerebroventricular (ICV) injection neutralized the protective effect against HIBD-induced BBB disruption in mfat-1 mice, further validating the protective function of Mfsd2a on BBB. Mfsd2a attenuated BBB high-permeability caused by HIBD through inhibiting caveolae-like vesicles-mediated transcytosis. Taken together, these results not only reveal mfat-1 transgenic mice have higher expression of Mfsd2a on the BBB, which partly sustains BBB permeability via vesicular transcytosis to alleviate the degree of HIBD but also suggest that dietary intake of LPC-DHA may upregulate Mfsd2a expression as a novel therapeutic strategy for BBB dysfunction and survival in HIBD patients.