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Title: Coordinated role of voltage-gated sodium channels and the Na+/H+ exchanger in sustaining microglial activation during inflammation.

Authors: Hossain, Muhammad M; Sonsalla, Patricia K; Richardson, Jason R

Published In Toxicol Appl Pharmacol, (2013 Dec 01)

Abstract: 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 μM) abolished short-term Na(+) influx, but was unable to prevent the accumulation of (Na(+))i observed at 6 and 24h after LPS exposure. The NHE inhibitor cariporide (1 μM) significantly reduced accumulation of (Na(+))i 6 and 24h 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-α, 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.

PubMed ID: 24070585 Exiting the NIEHS site

MeSH Terms: Animals; Cell Line, Transformed; Dose-Response Relationship, Drug; Inflammation/chemically induced; Inflammation/metabolism*; Inflammation/pathology*; Lipopolysaccharides/toxicity; Mice; Mice, Inbred C57BL; Microglia/drug effects; Microglia/metabolism*; Microglia/pathology; Sodium-Hydrogen Exchangers/physiology*; Voltage-Gated Sodium Channel Blockers/pharmacology; Voltage-Gated Sodium Channels/physiology*

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