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1 Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA
* To whom correspondence should be addressed. E-mail: jalexa{at}lsuhsc.edu.
Cerebral endothelial cells in the rat, pig, and most recently human, have been shown to express several types of receptors specific for glutamate. High levels of glutamate disrupt cerebral endothelial barrier via activation of NMDA receptors we have previously suggested that this glutamate induced barrier dysfunction was oxidant dependent. Here we provide evidence that human cerebral endothelial cells respond to glutamate by generating an intracellular oxidant stress via NMDA receptor activation. Cerebral endothelial cells loaded with the oxidant sensitive probe dihydro-rhodamine (DHR) were used to measure intracellular ROS formation in response to glutamate receptor agonists, antagonists and 2nd message blockers. 1mM Glutamate significantly increased ROS formation compared to sham controls (30 min). This ROS response was significantly reduced by: 1) MK-801 (a non-competitive NMDA receptor antagonist), 2) TMB-8 (an intracellular Ca2+ antagonist), 3) LaCl3 (an extracellular Ca2+ channel blocker), 4) DPI (a heme-ferryl containing protein inhibitor), 5) Itraconazole (a cytochrome P450 3A4 inhibitor) and 6) cyclosporine A (which prevents mitochondrial membrane pore transition required for mitochondrial dependent ROS generation). Our results suggest that the cerebral endothelial barrier dysfunction seen in response to glutamate is Ca2+-dependent and may require several intracellular signaling events mediated by oxidants derived from NAD(P)H oxidase, cytochrome P450, and the mitochondria.
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