HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/H1893    most recent 01110.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Sharp, C. D. Articles by Alexander, J. S. Search for Related Content PubMed PubMed Citation Articles by Sharp, C. D. Articles by Alexander, J. S.

N-methyl-D-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress

Departments of ¹Molecular and Cellular Physiology, ²Neurosurgery, and ³Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana

Submitted 20 November 2003 ; accepted in final form 29 November 2004

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 the cerebral endothelial barrier via activation of N-methyl-D-aspartate (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 dihydrorhodamine were used to measure intracellular reactive oxygen species (ROS) formation in response to glutamate receptor agonists, antagonists, and second message blockers. Glutamate (1 mM) significantly increased ROS formation compared with sham controls (30 min). This ROS response was significantly reduced by 1) MK-801, a noncompetitive NMDA receptor antagonist; 2) 8-(N,N-diethylamino)-n-octyl-3,4,5-trimethoxybenzoate, an intracellular Ca²⁺ antagonist; 3) LaCl₃, an extracellular Ca²⁺ channel blocker; 4) diphenyleiodonium, a heme-ferryl-containing protein inhibitor; 5) itraconazole, a cytochrome P-450 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 reduced nicotinamide adenine dinucleotide oxidase, cytochrome P-450, and the mitochondria.

reactive oxygen species; mitochondria; reduced nicotinamide adenine dinucleotide oxidase; arachidonic acid; human; brain

This article has been cited by other articles:

				K. S. McCully Chemical Pathology of Homocysteine. IV. Excitotoxicity, Oxidative Stress, Endothelial Dysfunction, and Inflammation Ann. Clin. Lab. Sci., January 1, 2009; 39(3): 219 - 232. [Abstract] [Full Text] [PDF]

				F. Domoki, B. Kis, T. Gaspar, F. Bari, and D. W. Busija Cerebromicrovascular endothelial cells are resistant to L-glutamate Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1099 - R1108. [Abstract] [Full Text] [PDF]

				S. Mohan, K. Koyoma, A. Thangasamy, H. Nakano, R. D. Glickman, and N. Mohan Low shear stress preferentially enhances IKK activity through selective sources of ROS for persistent activation of NF-{kappa}B in endothelial cells Am J Physiol Cell Physiol, January 1, 2007; 292(1): C362 - C371. [Abstract] [Full Text] [PDF]

				H. Parfenova, S. Basuroy, S. Bhattacharya, D. Tcheranova, Y. Qu, R. F. Regan, and C. W. Leffler Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection Am J Physiol Cell Physiol, May 1, 2006; 290(5): C1399 - C1410. [Abstract] [Full Text] [PDF]

				C. W. Leffler, H. Parfenova, J. H. Jaggar, and R. Wang Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation J Appl Physiol, March 1, 2006; 100(3): 1065 - 1076. [Abstract] [Full Text] [PDF]

				C. W. Leffler, L. Balabanova, A. L. Fedinec, and H. Parfenova Nitric oxide increases carbon monoxide production by piglet cerebral microvessels Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1442 - H1447. [Abstract] [Full Text] [PDF]