title: MW151 Inhibited IL-1β Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses.
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.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.|Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, Kentucky, United States of America.|Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Zhengqiu
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, Kentucky, United States of America.|Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Rowe
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Xing
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Goulding
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Alyssa N
authors.initials: AN
authors.lastname: Conley
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Pradoldej
authors.initials: P
authors.lastname: Sompol
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Shelby
authors.initials: S
authors.lastname: Meier
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.|Department of Physiology, University of Kentucky, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Abisambra
authors.affiliation: Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, Kentucky, United States of America.|Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
authors.affiliation: Department of Pharmacology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.|Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, Kentucky, United States of America.|Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000032:analysis / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D011743:Pyrimidines