The histone deacetylase inhibitor SAHA restores blood-brain barrier integrity in a human stem cell-based model of ischemic stroke

Background and Purpose: Ischemic stroke is characterised by acute cerebrovascular occlusion, blood-brain barrier (BBB) breakdown and narrow therapeutic window. Its treatment is a clinical challenge due to the risk of reperfusion injury and limited efficacy of thrombolytic therapies, therefore, novel therapeutic approaches are needed. Histone deacetylase inhibitors (HDACi) have emerged as neuroprotective agents in stroke models, but their effect on preserving BBB integrity is still unexplored. Our aim was to investigate the effects of the HDACi suberoylanilide hydroxamic acid (SAHA) on BBB changes in a cell culture model of ischemic stroke.Experimental Approach: The effects of SAHA were tested on a human BBB co-culture model under normoxia and during a 24-hour reoxygenation (OGD/R) following a 6-hour oxygen-glucose deprivation (OGD).Key Results: SAHA treatment ameliorated the OGD/R-induced loss of BBB integrity, as shown by an increase in transendothelial electrical resistance and reduced BBB permeability. The expression of genes involved in cell proliferation decreased, while an increase was measured for basement membrane protein, glycocalyx-synthesis enzyme and Wnt signaling related genes. SAHA treatment elevated the claudin-5 protein expression and a metabolic shift from glycolysis to aerobic respiration was observed.Conclusion and Implications: Our results suggest that SAHA could be a potential adjunctive therapeutic drug for the treatment of ischemia-reperfusion injury via BBB protection. Since SAHA has already been approved for human use as the anticancer drug vorinostat, its repurposing to restore BBB functions and prevent post-stroke damages may be greatly facilitated.