Minocycline plus N-acetylcysteine repairs the injured brain by modulating neuroinflammation and inducing remyelination.

Abstract

Mild traumatic brain injury (mTBI) occurs to 1.3 million people every year. While symptoms of mTBI can be treated, little can be done for the underlying injury. The FDA-approved drugs Minocycline plus N-acetylcysteine (MINO plus NAC) synergistically improved cognition and memory in an animal model of traumatic brain injury, moderate controlled cortical impact. Mechanisms underlying the synergistic action of MINO plus NAC are unknown nor is it known whether the drug combination improves mild controlled cortical impact (mCCI). This thesis addresses these issues via 3 specific aims: 1) Does MINO plus NAC improve cognition and memory after mCCI?, 2) Does MINO plus NAC promote remyelination following mCCI?, and 3) How are microglia modulated by MINO plus NAC? The effect of the drug combination on white matter damage and neuroinflammation were examined during time points when behavioral deficits arise after mCCI. MINO plus NAC synergistically improved memory and cognition following mCCI. Additional synergies of MINO plus NAC were seen in protecting resident oligodendrocytes and modulating microglial activation. Synergistic drug effects are uncommon suggesting that modulation of inflammation protects oligodendrocytes leading to remyelination and improved cognition and memory. These findings provide new and important insights into how drug treatments can repair the brain after traumatic brain injury.