Plasma Feeding Protects the Blood-Brain Barrier Post-Asphyxia While the Blood-CSF Barrier Remains Spared

Metabolic and neurovascular disturbances contribute to brain injury after birth asphyxia. We previously showed that plasma feeding attenuated neuropathology after transient umbilical cord occlusion in piglets. This study explored the metabolic and molecular consequences of birth asphyxia and whether plasma feeding preserves metabolic homeostasis and brain barrier integrity.

Piglets (n=89) delivered by cesarean section on gestational day 113 underwent umbilical cord occlusion (asphyxia) or remained nonasphyxiated (control). Asphyxia and control piglets were randomly assigned to receive formula reconstituted with either water (vehicle-treated group) or sow plasma (plasma-treated group). Animals were euthanized at 1 hour, 24 hours, or day 4 after insult. Cerebrospinal fluid metabolites were profiled by untargeted liquid chromatography-mass spectrometry metabolomics at 24 hours. Expression of metabolite transporters and structural components of the blood-brain barrier in the caudate nucleus and the blood-cerebrospinal fluid barrier at the choroid plexus was assessed by reverse transcription quantitative polymerase chain reaction and Western blotting. The CSF/plasma Na⁺ ratio was assessed, and cell-specific AQP4 expression was confirmed with RNAscope. Data were analyzed using linear and linear mixed-effects models.

Birth asphyxia dysregulated the CSF metabolic profile, with reductions in multiple metabolites and increases in a smaller subset, consistent with impaired amino acid and lipid metabolism. This was accompanied by reduced expression of substrate transporters, including xCT, LAT1, ASCT2, FATP1, CAV1, and MCTs. In the caudate nucleus, expression of blood-brain barrier structural proteins and ion transporters, including Na⁺/K⁺-ATPase, was reduced, whereas the choroid plexus blood-CSF barrier remained largely preserved. Plasma feeding partially restored transporter expression at both brain interfaces and increased AQP4 and ion transporter expression at the blood-brain barrier by day 4. Increased VE-cadherin (vascular endothelial cadherin) and ZO-1 (zonula occludens-1) expression and elevated CSF Na⁺ concentrations suggested early modulation of the integrity of the 2 brain barriers.

Plasma feeding preserves metabolic homeostasis and supports brain barrier integrity after birth asphyxia, highlighting plasma-derived factors as potential therapeutic targets to reduce neurodevelopmental impairment after perinatal asphyxia.