Metformin Reduces Repeat Mild Concussive Injury Pathophysiology

Abstract

Mild traumatic brain injury (mTBI) can initiate complex pathophysiological changes in the brain. Numerous cellular and molecular mechanisms underlying these pathologic changes are altered after injury, including those involved in energy utilization, excitotoxicity, ionic disturbances, and inflammation. It is thought that targeting multiple mechanisms may be necessary to produce meaningful reductions in brain pathology and to improve outcome. Previous studies have reported that the anti-diabetic drug metformin can also affect inflammatory, cell survival, and metabolic outcomes, possibly by acting on multiple targets and/or pathways. We therefore questioned whether metformin treatment can reduce pathology after repeat mild closed head injury (rmCHI) in male C57Bl/6 mice. We found that metformin, administered acutely after each head impact, resulted in markedly reduced white matter damage, astrogliosis, loss of hippocampal parvalbumin neurons, and improved mitochondrial function. In addition, both motor and cognitive functions were significantly improved when tested after discontinuation of the treatment. These studies suggest that metformin may be beneficial as a treatment for repeat concussion.

Significance Statement

Repeat concussions (or repeat mild traumatic brain injury; rmTBI) can occur in persons participating in contact sports, and in military personnel. Unfortunately, there are no approved treatments to lessen the consequences of rmTBI. It is thought that outcome from rmTBI is influenced by several secondary events, including altered brain metabolism, inflammation, and damage to brain cells. Here, we show that the anti-diabetes drug metformin reduces repeat concussion brain pathology and improves motor and cognitive functions.