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

• Published in: Neurobiology of disease 2016-07, Vol.91, p.37-46
• Main Authors: Zhang, Wenting, Zhang, Hui, Mu, Hongfeng, Zhu, Wen, Jiang, Xiaoyan, Hu, Xiaoming, Shi, Yejie, Leak, Rehana K, Dong, Qiang, Chen, Jun, Gao, Yanqin
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Blood brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Disease Models, Animal; Fatty Acids, Omega-3 - metabolism; Fatty Acids, Omega-3 - pharmacology; Female; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - metabolism; Hypoxia/ischemia; MMP-2; MMP-9; Neurology; Rats, Sprague-Dawley; Tight junction
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2016.02.020

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 14 days after parturition. H/I was introduced in 7 day-old offspring. We observed relatively rapid BBB penetration of the small molecule cadaverine (640 Da) at 4 h post-H/I and a delayed penetration of larger dextrans (3 kD–40 kD) 24–48 h after injury. Surprisingly, the neonatal BBB was impermeable to Evans Blue or 70 kD dextran leakage for up to 48 h 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.