Abstract
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.
Highlights
Traumatic brain injury (TBI), a common cause of morbidity and mortality, initiates a cascade of pathophysiological events that can exacerbate the primary injury and worsen long-term outcome, including an increased potential for neurodegenerative complications
In order to extend the significance of the dose-dependent modulation of brain injury induced increases in IL-1β levels we have previously reported following closed head injury (CHI) [3, 4, 20], we examined MW151 treatment in a Midline Fluid Percussion Injury (mFPI) model (Fig 1A)
We administered MW151 at 1h and 3h post-injury in order to target IL-1β as its brain cortex levels are increasing after injury
Summary
Traumatic brain injury (TBI), a common cause of morbidity and mortality, initiates a cascade of pathophysiological events that can exacerbate the primary injury and worsen long-term outcome, including an increased potential for neurodegenerative complications. The extended time window, and the contribution to pathophysiology progression, renders attenuation of proinflammatory cytokine overproduction a viable aspect of the neuroinflammation process amenable to therapeutic intervention. To address the need for small molecule CNS therapeutics for TBI and neurodegenerative disease, we developed CNS-penetrant, small molecule experimental therapeutics targeting neuroinflammation [12,13,14,15]. One of these compounds, MW01-2-151WH (= MW151) is a unique chemical entity that is a potential first-in-class candidate for addressing the challenge of selective modulation of glia responses [13]. MW151 has high potential for safety, with no detectable histological liver toxicity at chronic low doses or acute high doses and no evidence of cardiovascular toxicity as assessed by prolongation of QTc interval
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