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Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury
Wenting Zhang1, Hui Zhang2, Hongfeng Mu3
1State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Insights
Omega-3 fatty acids protect the neonatal brain by maintaining blood-brain barrier integrity after hypoxic-ischemic injury. These essential fats reduce damage by inhibiting matrix metalloproteinases, crucial for barrier function.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Neonatal hypoxic-ischemic (H/I) injury poses a significant threat to brain development.
- Omega-3 polyunsaturated fatty acids (n-3 PUFAs) show neuroprotective potential, but mechanisms remain unclear.
- Blood-brain barrier (BBB) integrity is a critical factor in H/I vulnerability.
Purpose of the Study:
- To investigate the impact of n-3 PUFAs on blood-brain barrier (BBB) integrity following neonatal H/I.
- To elucidate the role of BBB permeability in H/I-induced brain injury in neonates.
Main Methods:
- Female rats received diets with or without n-3 PUFA enrichment during gestation and lactation.
- Neonatal offspring (7 days old) were subjected to H/I injury.
- BBB integrity was assessed using tracer molecules (cadaverine, dextrans, Evans Blue, IgG) and electron microscopy.
Main Results:
- H/I induced BBB damage, evidenced by tracer extravasation and IgG leakage, particularly at later time points.
- n-3 PUFA supplementation significantly ameliorated H/I-induced BBB damage, reducing tracer efflux and IgG extravasation.
- n-3 PUFAs preserved BBB ultrastructure and enhanced tight junction protein expression, while preventing increased matrix metalloproteinase (MMP) activity.
Conclusions:
- n-3 PUFAs protect the neonatal brain against H/I injury by preserving blood-brain barrier integrity.
- The neuroprotective effect of n-3 PUFAs is associated with the inhibition of MMP activation following H/I.
- Maintaining BBB function is a key mechanism through which n-3 PUFAs confer neuroprotection in neonates.
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.
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