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 some central nervous system (CNS) disorders, owing to the high docosahexaenoic acid (DHA) content enriched in their brains. However, whether this protective effect is connected to the blood–brain barrier (BBB) remains unclear. This study aims to investigate the mechanisms of the protective effect against hypoxic-ischemic brain damage (HIBD) of mfat-1 transgenic mice. mfat-1 mice not only demonstrated a significant amelioration of neurological dysfunction and neuronal damage but also partly maintained the physiological permeability of the BBB after HIBD. We initially showed this was associated with elevated major facilitator superfamily domain-containing 2a (Mfsd2a) expression on the BBB, resulting from more lysophosphatidylcholine (LPC)-DHA entering the brain. Wild-type (WT) mice showed a similar Mfsd2a expression trend after long-term feeding with an LPC-DHA-rich diet. 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. HIBD-induced BBB high permeability was attenuated by Mfsd2a, primarily through a transcellular pathway to decrease caveolae-like vesicle-mediated transcytosis. Taken together, these findings not only reveal that mfat-1 transgenic mice have higher expression of Mfsd2a on the BBB, which partly sustains BBB permeability via vesicular transcytosis to alleviate the severity 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.

Investigation of the Binding Interaction of Mfsd2a with NEDD4-2 via Molecular Dynamics Simulations

“…In CNS, Mfsd2a is mainly expressed in the brain microvascular endothelial cells of the BBB and has been shown to be abnormally degraded in the middle cerebral artery occlusion (MCAO) model of rats, which further aggravates brain damage. ,, Therefore, we utilized an oxygen-glucose deprivation (OGD) model of brain microvascular endothelial cells bEnd.3 to verify the protective effect of peptides a, b, and c on the degradation of Mfsd2a. bEnd.3 cells were exposed to OGD for several hours and then reoxygenated.…”

“…The normal expression level of Mfsd2a is particularly important in keeping the physiological function of the CNS, and its pathological degradation is associated with a variety of neurological diseases such as neurodegenerative diseases, brain metastases, , and poststroke neurological damage. ,, As described in the previous section, blocking the binding of NEDD4-2 and Mfsd2a is a potential strategy for protecting the normal level of Mfsd2a from degradation. However, due to the poor understanding of the ubiquitination process of Mfsd2a, there is no intervention method against pathological degradation of Mfsd2a so far.…”

“…It is highly expressed in endothelial cells, which are extensively distributed in the blood–brain and blood–retina barriers and have been recently demonstrated to be critical for BBB formation and function. , Abnormal degradation of Mfsd2a often results in dysfunction of BBB and subsequent neurological damage. − For example, the decrease of Mfsd2a induced by subarachnoid hemorrhage (SAH) significantly deteriorated brain edema in intracerebral hemorrhage (ICH) mice and aggravated the damage of BBB, while upregulation of Mfsd2a reversed this damage . A similar situation happened in ischemic stroke by regulating the expression level of Mfsd2a . Additionally, it is reported that the decreased level of Mfsd2a may be an early biomarker of Alzheimer’s disease progression .…”

“…17 A similar situation happened in ischemic stroke by regulating the expression level of Mfsd2a. 18 Additionally, it is reported that the decreased level of Mfsd2a may be an early biomarker of Alzheimer's disease progression. 19 Therefore, reversing an abnormal decrease of Mfsd2a is a highly potential strategy to protect the BBB and alleviate neurological damages.…”