Minocycline plus N-acetylcysteine synergize to modulate inflammation and prevent cognitive and memory deficits in a rat model of mild traumatic brain injury

Abstract Traumatic brain injury (TBI) differs in severity from severe to mild. This study examined whether a combination of the drugs minocycline (MINO) plus N-acetylcysteine (NAC) produces behavioral and histological improvements in a mild version of the controlled cortical impact model of TBI (mCCI). Following mCCI, rats acquired an active place avoidance task by learning the location of a stationary shock zone on a rotating arena. Rats acquired this task with a training protocol using a 10-minute intertrial interval. Mildly injured rats had an apparent deficit in long-term memory since they did not acquire the task when the intertrial interval was increased to 24 h. Mildly injured rats also had an apparent deficit in set shifting since, after successfully learning one shock zone location they did not learn the location of a second shock zone. MINO plus NAC synergistically limited these behavioral deficits in long-term memory and set shifting. mCCI also produced neuroinflammation at the impact site and at distal white matter tracts including the corpus callosum. At the impact site, MINO plus NAC attenuated CD68-expressing phagocytic microglia without altering neutrophil infiltration or astrocyte activation. The drugs had no effect on astrocyte activation in the corpus callosum or hippocampus. In the corpus callosum, MINO plus NAC decreased CD68 expression yet increased overall microglial activation as measured by Iba-1. MINO plus NAC acted synergistically to increase Iba-1 expression since MINO alone suppressed expression and NAC alone had no effect. Despite the known anti-inflammatory actions of the individual drugs, MINO plus NAC appeared to modulate, rather than suppress neuroinflammation. This modulation of neuroinflammation may underlie the synergistic improvement in memory and set-shifting by the drug combination after mCCI.