Neurological, Cognitive, and Molecular Effects of Mitoquinone in Open Head Traumatic Brain Injury Mouse Model at Chronic Time-point

Abstract

Traumatic brain injury (TBI) is a heterogeneous disease in terms of its origin, pathology, and prognosis. Globally, it is one of the leading causes of death and long-lasting disability. TBI is classified according to the mechanism of injury and its severity. TBI can be either an open head injury where the skull is fractured, also known as penetrating brain injury (PBI), or a closed head injury where the skull remains intact. TBI exerts its effects through two major, dynamic, and overlapping events denoted as the primary and the secondary injuries. The primary injury is the result of the mechanical force exerted, leading to the disruption and necrosis of neural tissue, hemorrhage, and axonal damage. Pathological changes trigger then the secondary injury, initiating a cascade of metabolic events that include further excitotoxicity, neuroinflammation, disruption of the blood-brain barrier (BBB), and cell death. Notably, mitochondria play an important role in the pathology of TBI via reactive oxygen species (ROS) overproduction creating a state of oxidative stress and via apoptosis induction. Finding therapies for TBI, and PBI specifically, remains one major challenge since there are currently no FDA-approved drugs. Some suggested treatments target oxidative stress since antioxidants have been shown to ameliorate the pathology of TBI. An example of this, is the mitochondria-targeted drug called Mitoquinone (MitoQ). It is synthesized by conjugating a ubiquinone moiety to a triphenylphosphonium cation (TPP+). Previous studies from our lab have shown that MitoQ improves behavioral and cognitive impairments, oxidative stress, and neuro-inflammation in a model of repetitive mild TBI at acute, subacute and chronic time-points. So, this study aimed at investigating the effect of MitoQ supplementation on neurological, behavioral, and molecular functions 30 days post-open head TBI mouse model. It found that MitoQ reduces long-term effects of open head TBI by decreasing the state of oxidative stress and enhancing neurological and behavioral sequences. This is along with dampening the chronic activation of astrocytes and microglia, leading to a reduced inflammatory state.