Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 273, Issue 2, Pages 355-364Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2013.09.011
Keywords
Microglia; Sodium Channel; Sodium hydrogen exchanger; Neurodegeneration; Lipopoysaccharide; NADPH oxidase
Categories
Funding
- National Institutes of Health [R01ES015991, P30ES005022, R21NS072097, U01NS079249]
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Persistent neuroinflammation and microglial activation play an integral role in the pathogenesis of many neurological disorders. We investigated the role of voltage-gated sodium channels (VGSC) and Na+/H+ exchangers (NHE) in the activation of immortalized microglial cells (BV-2) after lipopolysaccharide (LPS) exposure. LPS (10 and 100 ng/ml) caused a dose- and time-dependent accumulation of intracellular sodium [(Na+)(i)] in BV-2 cells. Pre-treatment of cells with the VGSC antagonist tetrodotoxin (TTX, 1 mu M) abolished short-term Na+ influx, but was unable to prevent the accumulation of (Na+)i observed at 6 and 24 h after LPS exposure. The NHE inhibitor cariporide (1 mu M) significantly reduced accumulation of (Na+)(i) 6 and 24 h after LPS exposure. Furthermore, LPS increased the mRNA expression and protein level of NHE-1 in a dose- and time-dependent manner, which was significantly reduced after co-treatment with TTX and/or cariporide. LPS increased production of TNF-alpha, ROS, and H2O2 and expression of gp91(phox), an active subunit of NADPH oxidase, in a dose- and time-dependent manner, which was significantly reduced by TTX or TTX + cariporide. Collectively, these data demonstrate a closely-linked temporal relationship between VGSC and NHE-1 in regulating function in activated microglia, which may provide avenues for therapeutic interventions aimed at reducing neuroinflammation. (C) 2013 Elsevier Inc. All rights reserved.
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