title: TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice.
abstract: BACKGROUND
  Microglial inhibition may reduce secondary tissue injury and improve functional outcome following acute brain injury. Utilizing clinically relevant murine models of traumatic brain injury and intracerebral hemorrhage, neuroinflammatory responses and functional outcome were examined in the presence of a potential microglial inhibitor, TT-301.
  
  
  METHODS
  TT-301 or saline was administered following traumatic brain injury or intracerebral hemorrhage, and then for four subsequent days. The effect of TT-301 on neuroinflammatory responses and neuronal viability was assessed, as well as short-term vestibulomotor deficit (Rotorod) and long-term neurocognitive impairment (Morris water maze). Finally differential gene expression profiles of mice treated with TT-301 were compared with those of vehicle.
  
  
  RESULTS
  Reduction in F4/80+ staining was demonstrated at 1 and 10 days, but not 28 days, after injury in mice treated with TT-301 (n = 6). These histologic findings were associated with improved neurologic function as assessed by Rotorod, which improved by 52.7% in the treated group by day 7, and Morris water maze latencies, which improved by 232.5% as a function of treatment (n = 12; P < 0.05). Similar benefit was demonstrated following intracerebral hemorrhage, in which treatment with TT-301 was associated with functional neurologic improvement of 39.6% improvement in Rotorod and a reduction in cerebral edema that was independent of hematoma volume (n = 12; P < 0.05). Differential gene expression was evaluated following treatment with TT-301, and hierarchical cluster analysis implicated involvement of the Janus kinase-Signal Transducer and Activator of Transcription pathway after administration of TT-301 (n = 3/group).
  
  
  CONCLUSIONS
  Modulation of neuroinflammatory responses through TT-301 administration improved histologic and functional parameters in murine models of acute neurologic injury.
authors.affiliation: Department of Anesthesiology, Duke University, Durham, NC 27710, USA. michael.james@duke.edu
authors.forename: Michael L
authors.initials: ML
authors.lastname: James
authors.forename: Haichen
authors.initials: H
authors.lastname: Wang
authors.forename: Viviana
authors.initials: V
authors.lastname: Cantillana
authors.forename: Beilei
authors.initials: B
authors.lastname: Lei
authors.forename: Dawn N
authors.initials: DN
authors.lastname: Kernagis
authors.forename: Hana N
authors.initials: HN
authors.lastname: Dawson
authors.forename: Lori D
authors.initials: LD
authors.lastname: Klaman
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001786:Blood Glucose / Q000378:metabolism; D001834:Body Water / Q000378:metabolism; D001923:Brain Chemistry; D001930:Brain Injuries / Q000188:drug therapy; D002452:Cell Count; D002460:Cell Line; D002490:Central Nervous System / Q000293:injuries*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D008070:Lipopolysaccharides; D010879:Piperazines; D011724:Pyridazines; D011725:Pyridines; C573580:TT-301