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TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice.

Publication ,  Journal Article
James, ML; Wang, H; Cantillana, V; Lei, B; Kernagis, DN; Dawson, HN; Klaman, LD; Laskowitz, DT
Published in: Anesthesiology
June 2012

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.

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Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

June 2012

Volume

116

Issue

6

Start / End Page

1299 / 1311

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Real-Time Polymerase Chain Reaction
  • Pyridines
  • Pyridazines
  • Psychomotor Performance
  • Postural Balance
  • Piperazines
  • Microglia
  • Mice, Inbred C57BL
  • Mice
 

Citation

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James, M. L., Wang, H., Cantillana, V., Lei, B., Kernagis, D. N., Dawson, H. N., … Laskowitz, D. T. (2012). TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice. Anesthesiology, 116(6), 1299–1311. https://doi.org/10.1097/ALN.0b013e318253a02a
James, Michael L., Haichen Wang, Viviana Cantillana, Beilei Lei, Dawn N. Kernagis, Hana N. Dawson, Lori D. Klaman, and Daniel T. Laskowitz. “TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice.Anesthesiology 116, no. 6 (June 2012): 1299–1311. https://doi.org/10.1097/ALN.0b013e318253a02a.
James ML, Wang H, Cantillana V, Lei B, Kernagis DN, Dawson HN, et al. TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice. Anesthesiology. 2012 Jun;116(6):1299–311.
James, Michael L., et al. “TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice.Anesthesiology, vol. 116, no. 6, June 2012, pp. 1299–311. Pubmed, doi:10.1097/ALN.0b013e318253a02a.
James ML, Wang H, Cantillana V, Lei B, Kernagis DN, Dawson HN, Klaman LD, Laskowitz DT. TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice. Anesthesiology. 2012 Jun;116(6):1299–1311.

Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

June 2012

Volume

116

Issue

6

Start / End Page

1299 / 1311

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Real-Time Polymerase Chain Reaction
  • Pyridines
  • Pyridazines
  • Psychomotor Performance
  • Postural Balance
  • Piperazines
  • Microglia
  • Mice, Inbred C57BL
  • Mice