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Background  Strategies to maintain BBB integrity in diseases with a hypoxia/reoxygenation (H/R) component involve preventing glutathione (GSH) loss from endothelial cells. GSH efflux transporters include multidrug resistance proteins (Mrps). Therefore, characterization of Mrp regulation at the BBB during H/R is required to advance these transporters as therapeutic targets. Our goal was to investigate, in vivo, regulation of  Abcc1 ,  Abcc2 , and  Abcc4  mRNA expression (i.e., genes encoding Mrp isoforms that transport GSH) by nuclear factor E2-related factor (Nrf2) using a well-established H/R model.    Methods  Female Sprague–Dawley rats (200–250 g) were subjected to normoxia (Nx, 21% O 2 , 60 min), hypoxia (Hx, 6% O 2 , 60 min) or H/R (6% O 2 , 60 min followed by 21% O 2 , 10 min, 30 min, or 1 h) or were treated with the Nrf2 activator sulforaphane (25 mg/kg, i.p.) for 3 h.  Abcc  mRNA expression in brain microvessels was determined using quantitative real-time PCR. Nrf2 signaling activation was examined using an electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) respectively. Data were expressed as mean ± SD and analyzed via ANOVA followed by the post hoc Bonferroni  t  test.    Results  We observed increased microvascular expression of  Abcc1, Abcc2,  and  Abcc4  mRNA following H/R treatment with reoxygenation times of 10 min, 30 min, and 1 h and in animals treated with sulforaphane. Using a biotinylated Nrf2 probe, we observed an upward band shift in brain microvessels isolated from H/R animals or animals administered sulforaphane. ChIP studies showed increased Nrf2 binding to antioxidant response elements on  Abcc1, Abcc2,  and  Abcc4  promoters following H/R or sulforaphane treatment, suggesting a role for Nrf2 signaling in  Abcc  gene regulation.    Conclusions  Our data show increased  Abcc1, Abcc2,  and  Abcc4  mRNA expression at the BBB in response to H/R stress and that  Abcc  gene expression is regulated by Nrf2 signaling. Since these Mrp isoforms transport GSH, these results may point to endogenous transporters that can be targeted for BBB protection during H/R stress. Experiments are ongoing to examine functional implications of Nrf2-mediated increases in  Abcc  transcript expression. Such studies will determine utility of targeting Mrp isoforms for BBB protection in diseases with an H/R component.

fluids and barriers of the cns

Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood–brain barrier following hypoxia-reoxygenation stress