A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a closed head injury model of mild TBI suppressed acute cytokine up-regulation and downstream cognitive impairment. Here, we report results from a diffuse brain injury model in mice using midline fluid percussion. Low dose (0.5–5.0 mg/kg) administration of MW151 suppresses interleukin-1 beta (IL-1β) levels in the cortex while sparing reactive microglia and astrocyte responses. To probe molecular mechanisms, we used live cell imaging of the BV-2 microglia cell line to demonstrate that MW151 does not affect proliferation, migration, or phagocytosis of the cells. Our results provide insight into the roles of glial responses to brain injury and indicate the feasibility of using appropriate dosing for selective therapeutic modulation of injurious IL-1β increases while sparing other glial responses to injury.
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This research was supported in part by NIH/NIA (K99 AG044445 to ADB, and U01 AG050636 to LVE and DMW), and the Kentucky Spinal Cord and Head Injury Research Trust (12-20A to LVE).
Bachstetter, Adam D.; Zhou, Zhengqiu; Rowe, Rachel K.; Xing, Bin; Goulding, Danielle S.; Conley, Alyssa N.; Sompol, Pradoldej; Meier, Shelby; Abisambra, Jose F.; Lifshitz, Jonathan; Watterson, D. Martin; and Van Eldik, Linda J., "MW151 Inhibited IL-1β Levels After Traumatic Brain Injury with No Effect on Microglia Physiological Responses" (2016). Sanders-Brown Center on Aging Faculty Publications. 71.