Hydrogen alleviated cognitive impairment and blood‒brain barrier damage in sepsis-associated encephalopathy by regulating ABC efflux transporters in a PPARα-dependent manner

Hydrogen (H₂) can protect against blood‒brain barrier (BBB) damage in sepsis-associated encephalopathy (SAE), but the mechanism is still unclear. We examined whether it is related to PPARα and its regulatory targets, ABC efflux transporters. After injection with DMSO/GW6471 (a PPARα Inhibitor), the mice subjected to sham/caecal ligation and puncture (CLP) surgery were treated with H₂ for 60 min postoperation. Additionally, bEnd.3 cells were grown in DMSO/GW6471-containing or saline medium with LPS. In addition to the survival rates, cognitive function was assessed using the Y-maze and fear conditioning tests. Brain tissues were stained with TUNEL and Nissl staining. Additionally, inflammatory mediators (TNF-α, IL-6, HMGB1, and IL-1β) were evaluated with ELISA, and PPARα, ZO-1, occludin, VE-cadherin, P-gp, BCRP and MRP2 were detected using Western blotting. BBB destruction was assessed by brain water content and Evans blue (EB) extravasation. Finally, we found that H₂ improved survival rates and brain dysfunction and decreased inflammatory cytokines. Furthermore, H₂ decreased water content in the brain and EB extravasation and increased ZO-1, occludin, VE-cadherin and ABC efflux transporters regulated by PPARα. Thus, we concluded that H₂ decreases BBB permeability to protect against brain dysfunction in sepsis; this effect is mediated by PPARα and its regulation of ABC efflux transporters.

ABC efflux transporters; Blood‒brain barrier; Peroxisome proliferator-activated receptors; Sepsis-associated encephalopathy.