ABSTRACT
There are no drugs to manage traumatic brain injury (TBI) presently. A major problem in developing therapeutics is that drugs to manage TBI lack sufficient potency when dosed within a clinically relevant time window. Previous studies have shown that minocycline (MINO, 45 mg/kg) plus N-acetylcysteine (NAC, 150 mg/kg) synergistically improved cognition and memory, modulated inflammation, and prevented loss of oligodendrocytes that remyelinated damaged white matter when first dosed 1 h after controlled cortical impact (CCI) in rats. We show that MINO (45 mg/kg) plus NAC (150 mg/kg) also prevent brain injury in a mouse closed head injury (CHI) TBI model. Using the CHI model, the concentrations of MINO and NAC were titrated to determine that MINO (22.5 mg/kg) plus NAC (75 mg/kg) was more potent than the original formulation. MINO (22.5 mg/kg) plus NAC (75 mg/kg) also limited injury in the rat CCI model. The therapeutic time window of MINO plus NAC was then tested in the CHI and CCI models. Mice and rats could acquire an active place avoidance task when MINO plus NAC was first dosed at 12 h post-injury. A first dose at 12 h also limited gray matter injury in the hippocampus and preserved myelin in multiple white matter tracts. Mice and rats acquired Barnes maze when MINO plus NAC was first dosed at 24 h post-injury. These data suggest that MINO (22.5 mg/kg) plus NAC (75 mg/kg) remain potent when dosed at clinically useful time windows. Both MINO and NAC are drugs approved by the Food and Drug Administration and have been administered safely to patients in clinical trials at the doses in the new formulation. This suggests that the drug combination of MINO plus NAC may be effective in treating patients with TBI.
