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Neutral Sphingomyelinase Inhibition Alleviates LPS Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury.

Research paper by Asit A Kumar, Rebecca R Henry, Bogdan B Stoica, David D Loane, Gelareh G Abulwerdi, Shahnawaz S Bhat, Alan A Faden

Indexed on: 20 Dec '18Published on: 20 Dec '18Published in: The Journal of pharmacology and experimental therapeutics



Abstract

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 neurological 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. Pre-treatment of Altenusin or GW4869 prior to lipopolysaccharide (LPS) stimulation for 4 h or 24 h, significantly downregulated gene expression of the pro-inflammatory mediators TNFα, IL-1β, IL-6, iNOS and CCL2 in microglia and reduced the release of Nitric Oxide and TNFα. These nSMase inhibitors also attenuated the release of microparticles and phosphorylation of p38 MAPK and ERK1/2. In addition, Altenusin pre-treatment also reduced the gene expression of multiple inflammatory markers associated with microglial activation after experimental TBI - including TNFα, 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. The American Society for Pharmacology and Experimental Therapeutics.