Memantine protects against ischemia/reperfusion-induced brain endothelial permeability

Increased transendothelial permeability and subsequent blood-brain barrier damage play a key role in the pathological progression of human brain ischemia and secondary reperfusion. Memantine is a licensed drug providing clinically relevant efficacy in patients with Alzheimer's disease. However, little information is known regarding its effects on brain endothelial permeability. In this study, we investigated the effects of memantine on endothelial permeability and the underlying mechanisms in an ischemia-reperfusion (I/R) injury model in primary human brain microvascular endothelial cells. First, we found that memantine treatment prevented I/R-induced expression of tumor necrosis factor-α and interleukin-1β at both the mRNA and the protein levels. Additionally, our results indicate that memantine treatment significantly reduced endothelial monolayer permeability after I/R by increasing the expression of tight junction protein occludin and the adherens junction protein VE-cadherin. In addition, we found that memantine reduced the expression and activity of matrix metalloproteinase (MMP)-2 but not MMP-9 after I/R. Memantine also elevated the expression of tissue inhibitors of metalloproteinase-2. Mechanistically, we found that memantine increased the expression of the transcriptional factor Krueppel-like factor 2 (KFL2) through activating extracellular signal regulated kinase (ERK5). In conclusion, our results identified a novel function of memantine in maintaining brain vascular barrier function and suggested that memantine might be a potential therapeutic agent for the treatment of stroke. © 2018 IUBMB Life, 70(4):336-343, 2018.