PT  - JOURNAL ARTICLE
AU  - Asit Kumar
AU  - Rebecca J. Henry
AU  - Bogdan A. Stoica
AU  - David J. Loane
AU  - Gelareh Abulwerdi
AU  - Shahnawaz A. Bhat
AU  - Alan I. Faden
TI  - Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury
AID  - 10.1124/jpet.118.253955
DP  - 2019 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 338--352
VI  - 368
IP  - 3
4099  - http://jpet.aspetjournals.org/content/368/3/338.short
4100  - http://jpet.aspetjournals.org/content/368/3/338.full
SO  - J Pharmacol Exp Ther2019 Mar 01; 368
AB  - Neuroinflammation is one of the key secondary injury mechanisms triggered by traumatic brain injury (TBI). Microglial activation, a hallmark of brain neuroinflammation, plays a critical role in regulating immune responses after TBI and contributes to progressive neurodegeneration and neurologic deficits following brain trauma. Here we evaluated the role of neutral sphingomyelinase (nSMase) in microglial activation by examining the effects of the nSMase inhibitors altenusin and GW4869 in vitro (using BV2 microglia cells and primary microglia), as well as in a controlled cortical injury (CCI) model in adult male C57BL/6 mice. Pretreatment of altenusin or GW4869 prior to lipopolysaccharide (LPS) stimulation for 4 or 24 hours, significantly downregulated gene expression of the pro-inflammatory mediators TNF-α, IL-1β, IL-6, iNOS, and CCL2 in microglia and reduced the release of nitric oxide and TNF-α. These nSMase inhibitors also attenuated the release of microparticles and phosphorylation of p38 MAPK and ERK1/2. In addition, altenusin pretreatment also reduced the gene expression of multiple inflammatory markers associated with microglial activation after experimental TBI, including TNF-α, IL-1β, IL-6, iNOS, CCL2, CD68, NOX2, and p22phox. Overall, our data demonstrate that nSMase inhibitors attenuate multiple inflammatory pathways associated with microglial activation in vitro and after experimental TBI. Thus, nSMase inhibitors may represent promising therapeutics agents targeting neuroinflammation.