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-1ß 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.

Catalpol Exerts an Anti-Epilepticus Effect, Possibly by Regulating the Nrf2-Keap1-ARE Signaling Pathway.

BACKGROUND Status epilepticus (SE) is a refractory neurological disease with high mortality and morbidity rates. SE can be induced by numerous factors, including oxidative stress. Catalpol has several biological activities, including regulating the oxidative stress response. However, the role of catapol in SE has not been fully elucidated. MATERIAL AND METHODS Thirty Wistar rats were randomly and equally divided into 3 groups: a control group, an SE group established by LiCl-pilocarpine intraperitoneal injection, and an SE+catalpol group established administering catalpol to SE rats. Epileptic seizure level and after-discharge duration (ADD) were analyzed. Cognitive function was assessed by Morris water maze. Myeloperoxidase (MPO) and superoxide dismutase (SOD) activities were tested. Keap1 and ARE mRNA expressions were detected by real-time PCR. Nrf2 protein expression was determined by Western blot. RESULTS Catalpol significantly decreased epileptic seizure level, extended ADD, and improved cognitive function compared with the SE group (P<0.05). MPO was increased, SOD was reduced, Keap1 mRNA was upregulated, and Nrf2 protein and ARE mRNA were reduced in the SE group compared with the control group (P<0.05). Catalpol markedly decreased MPO, enhanced SOD activity, decreased Keap1 mRNA level, and elevated Nrf2 protein and ARE mRNA expressions compared with the SE group (P<0.05). CONCLUSIONS Catalpol plays an anti-epileptic role and improves cognitive function by regulating the Nrf2-Keap1-ARE signaling pathway to inhibit oxidative stress response.