Omega-3 polyunsaturated fatty acids mitigate blood–brain barrier disruption after hypoxic–ischemic brain injury

Abstract

Omega-3 polyunsaturated fatty acids (n‐3 PUFAs) have been shown to protect the neonatal brain against hypoxic/ischemic (H/I) injury. However, the mechanism of n‐3 PUFA-afforded neuroprotection is not well understood. One major determinant of H/I vulnerability is the permeability of the blood–brain barrier (BBB). Therefore, we examined the effects of n‐3 PUFAs on BBB integrity after neonatal H/I. Female rats were fed a diet with or without n‐3 PUFA enrichment from day 2 of pregnancy to 14days after parturition. H/I was introduced in 7day-old offspring. We observed relatively rapid BBB penetration of the small molecule cadaverine (640Da) at 4h post-H/I and a delayed penetration of larger dextrans (3kD–40kD) 24–48h after injury. Surprisingly, the neonatal BBB was impermeable to Evans Blue or 70kD dextran leakage for up to 48h post-H/I, despite evidence of IgG extravasation at this time. As expected, n‐3 PUFAs ameliorated H/I-induced BBB damage, as shown by reductions in tracer efflux and IgG extravasation, preservation of BBB ultrastructure, and enhanced tight junction protein expression. Furthermore, n‐3 PUFAs prevented the elevation in matrix metalloproteinase (MMP) activity in the brain and blood after H/I. Thus, n‐3 PUFAs may protect neonates against BBB damage by blunting MMPs activation after H/I.