title: Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse.
abstract: Traumatic brain injury (TBI) is induced by mechanical forces which initiate a cascade of secondary injury processes, including inflammation. Therapies which resolve the inflammatory response may promote neural repair without exacerbating the primary injury. Specific derivatives of omega-3 fatty acids loosely grouped as specialized pro-resolving lipid mediators (SPMs) and termed resolvins promote the active resolution of inflammation. In the current study, we investigate the effect of two resolvin molecules, RvE1 and AT-RvD1, on post-traumatic sleep and functional outcome following diffuse TBI through modulation of the inflammatory response. Adult, male C57BL/6 mice were injured using a midline fluid percussion injury (mFPI) model (6-10min righting reflex time for brain-injured mice). Experimental groups included mFPI administered RvE1 (100ng daily), AT-RvD1 (100ng daily), or vehicle (sterile saline) and counterbalanced with uninjured sham mice. Resolvins or saline were administered daily for seven consecutive days beginning 3days prior to TBI to evaluate proof-of-principle to improve outcome. Immediately following diffuse TBI, post-traumatic sleep was recorded for 24h post-injury. For days 1-7 post-injury, motor outcome was assessed by rotarod. Cognitive function was measured at 6days post-injury using novel object recognition (NOR). At 7days post-injury, microglial activation was quantified using immunohistochemistry for Iba-1. In the diffuse brain-injured mouse, AT-RvD1 treatment, but not RvE1, mitigated motor and cognitive deficits. RvE1 treatment significantly increased post-traumatic sleep in brain-injured mice compared to all other groups. RvE1 treated mice displayed a higher proportion of ramified microglia and lower proportion of activated rod microglia in the cortex compared to saline or AT-RvD1 treated brain-injured mice. Thus, RvE1 treatment modulated post-traumatic sleep and the inflammatory response to TBI, albeit independently of improvement in motor and cognitive outcome as seen in AT-RvD1-treated mice. This suggests AT-RvD1 may impart functional benefit through mechanisms other than resolution of inflammation alone.
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; Interdisciplinary Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA.
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Harrison
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; Phoenix Veteran Affairs Healthcare System, Phoenix, AZ, USA.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Rowe
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Ellis
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Yee
authors.affiliation: Department of Biology, University of Kentucky College of Arts and Sciences, Lexington, KY, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Bruce F
authors.initials: BF
authors.lastname: O'Hara
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; Interdisciplinary Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA.
authors.forename: P David
authors.initials: PD
authors.lastname: Adelson
authors.affiliation: BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; Interdisciplinary Graduate Program in Neuroscience, Arizona State University, Tempe, AZ, USA; Phoenix Veteran Affairs Healthcare System, Phoenix, AZ, USA. Electronic address: jlifshitz@email.arizona.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D012890:Sleep / Q000187:drug effects / Q000502:physiology*
chemical_list: C518399:resolvin D1; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
keywords: Aspirin-triggered resolvin; Behavior; Inflammation; Mouse; Protectins; Resolvins; Sleep; TBI