TT-301 hydrochloride

C57BL/6J mice (closed-skull impact traumatic brain injury model)^[2]

1 mg/kg

i.p.; twice daily; 5 days; i.p.; twice daily; 28 days; i.v. (first dose at 30 min, 3 h, or 6 h post-injury), then i.p.; twice daily; 5 days

Reduced F4/80-positive microglial cell counts at 1 and 10 days post-injury.
Reduced Fluoro Jade B-positive degenerating neurons in the hippocampus at 24 h post-injury.
Increased NeuN-positive surviving neurons in the hippocampus to 63025 neurons/mm³ at 28 days post-injury.
Improved Rotorod latency by 52.7% by day 7 post-injury.
Improved Morris water maze latencies by 232.5% at 4 weeks post-injury, and increased time spent in target quadrant to 62.3 seconds during probe testing.
Showed prolonged 28-day treatment did not enhance functional outcomes beyond 5-day treatment.
Retained significant functional benefits with delayed treatment initiation up to 6 h post-injury, with mice spending 56.8 seconds in the target quadrant during probe testing.
Identified 18 genes with ≥ 2-fold differential expression between treated and vehicle groups, with 12 genes directly involved in the Janus kinase-Signal Transducer and Activator of Transcription pathway.

C57BL/6J mice (collagenase-induced intracerebral hemorrhage model)^[2]

1 mg/kg

i.p.; twice daily; 5 days

Did not alter hematoma volume (0.689 mm³ vs. vehicle control).
Reduced cerebral edema to 61.52% brain water vs. vehicle control.
Improved Rotorod performance by 39.6% over the 7-day testing period.

C57BL/6 J (male, 10-12 weeks old, subarachnoid hemorrhage induced by endovascular filament perforation of the anterior and middle cerebral arteries)^[5]

5 mg/kg

i.p.; every 12 hours; 7 days (starting 30 minutes post-SAH)

Improved rotarod latency across the 35-day testing period, with no delayed performance deficit seen on days 6-7.
Improved overall neuroseverity score across the 35-day period.
Increased CatWalk gait speed at days 7 and 35 post-injury, and reduced CatWalk run duration at days 7 and 35.
Reduced number of TMEM119-positive microglia in the caudal cortex at 35 days post-SAH.
Reduced brain levels of proinflammatory KC/GRO/CXCL1 and TARC/CCL1 at 24 hours post-SAH.
Increased brain levels of SDF1/CXCL1 at 24 hours post-SAH.

C57BL/6 J (female, 10 weeks old, subarachnoid hemorrhage induced by endovascular filament perforation of the anterior and middle cerebral arteries)^[5]

5 mg/kg

i.p.; every 12 hours; 7 days (starting 30 minutes post-SAH)

Achieved 73% survival rate over the 35-day period.
Improved rotarod latency throughout the 35-day testing period.
Showed trends toward improvement in neuroseverity score and CatWalk gait speed.
Reduced CatWalk run duration at days 7 and 35.
Reduced number of fluoro-jade C-positive injured hippocampal neurons.