The Noncompetitive AMPAR Antagonist Perampanel Abrogates Brain Endothelial Cell Permeability in Response to Ischemia: Involvement of Claudin-5

Abstract

The blood-brain barrier (BBB) is formed by brain endothelial cells, and decreased BBB integrity contributes to vasogenic cerebral edema and increased mortality after stroke. In the present study, we investigated the protective effect of perampanel, an orally active noncompetitive AMPA receptor antagonist, on BBB permeability in an in vitro ischemia model in murine brain endothelial cells (mBECs). The results showed that perampanel significantly attenuated oxygen glucose deprivation (OGD)-induced loss of cell viability, release of lactate dehydrogenase, and apoptotic cell death in a dose-dependent manner. Perampanel treatment did not alter the expression and surface distribution of various glutamate receptors. Furthermore, the results of calcium imaging showed that perampanel had no effect on OGD-induced increase in intracellular Ca(2+) concentrations. Treatment with perampanel markedly reduced the paracellular permeability of mBECs after OGD in different time points, as measured by transepithelial electrical resistance assay. In addition, the expression of claudin-5 at protein level, but not at mRNA level, was increased by perampanel treatment after OGD. Knockdown of claudin-5 partially prevented perampanel-induced protection in cell viability and BBB integrity in OGD-injured mBECs. These data show that the noncompetitive AMPA receptor antagonist perampanel affords protection against ischemic stroke through caludin-5 mediated regulation of BBB permeability.

Otopathogenic Pseudomonas aeruginosa Enters and Survives Inside Macrophages

“…In this study, we observed that otopathogenic P. aeruginosa induces death of human MDMs and mouse BMMϕ as determined by LDH release in the cell culture supernatants and ethidium homodimer-I staining. LDH is the most acceptable and reliable marker for determining host cell death (Kwon et al, 2015; Park et al, 2015; Lv et al, 2016) . Ethidium homodimer-I is a fluorescent nuclear stain that penetrates dead cells due to disrupted plasma membrane and increases intensity after binding to DNA (Eidet et al, 2015; McCanna et al, 2015; Yoeruek et al, 2016).…”

The Role of Endothelial Ca2+ Signaling in Neurovascular Coupling: A View from the Lumen

“…As described elsewhere [ 50 ], synaptically-activated neurons and/or astrocytes could directly stimulate brain microvessels by releasing mediators that traverse the VSMC or pericyte layers and bind to receptors located on the abluminal side of endothelium. Interestingly, brain microvascular endothelial cells may also express NMDARs [ 55 , 56 ] and mGluR1 [ 57 , 58 , 59 , 60 ], although their potential contribution to NVC has been barely appreciated [ 4 ]. Accordingly, recent studies demonstrated that endothelial NMDARs participate in glutamate-induced vasodilation of intraparenchymal arterioles by mediating Ca 2+ entry and subsequent eNOS activation [ 55 , 56 ].…”

The Novel Direct Modulatory Effects of Perampanel, an Antagonist of AMPA Receptors, on Voltage-Gated Sodium and M-type Potassium Currents

“…In addition, PER has also been reported to be beneficial for patients with Parkinson’s disease and motor neuron diseases [12,13,14,15] and also in treating glioma-associated epilepsy [16,17,18,19]. However, several reports have shown that some of the actions of PER may not be closely linked to its blocking effect on AMPA receptors [11,20].…”