• Atsushi Mizuma, Jong Youl Kim, Rachid Kacimi, Ken Stauderman, Michael Dunn, Sudarshan Hebbar, and Midori A Yenari.
• 1 Department of Neurology, University of California, San Francisco; the San Francisco VA Medical Center, San Francisco, California.
• J. Neurotrauma. 2019 Apr 1; 36 (7): 996-1007.

AbstractStore-operated Ca2+ entry (SOCE) mediated by calcium release-activated calcium (CRAC) channels contributes to calcium signaling. The resulting intracellular calcium increases activate calcineurin, which in turn activates immune transcription factor nuclear factor of activated T cells (NFAT). Microglia contain CRAC channels, but little is known whether these channels play a role in acute brain insults. We studied a novel CRAC channel inhibitor to explore the therapeutic potential of this compound in microglia-mediated injury. Cultured microglial BV2 cells were activated by Toll-like receptor agonists or IFNγ. Some cultures were treated with a novel CRAC channel inhibitor (CM-EX-137). Western blots revealed the presence of CRAC channel proteins STIM1 and Orai1 in BV2 cells. CM-EX-137 decreased nitric oxide (NO) release and inducible nitric oxide synthase (iNOS) expression in activated microglia and reduced agonist-induced intracellular calcium accumulation in microglia, while suppressing inflammatory transcription factors nuclear factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT). Male C57/BL6 mice exposed to experimental brain trauma and treated with CM-EX-137 had decreased lesion size, brain hemorrhage, and improved neurological deficits with decreased microglial activation, iNOS and Orai1 and STIM1 levels. We suggest a novel anti-inflammatory approach for managing acute brain injury. Our observations also shed light on new calcium signaling pathways not described previously in brain injury models.

33 keywords...

hide…