Mitoquinone Helps Combat the Neurological, Cognitive, and Molecular Consequences of Open Head Traumatic Brain Injury at Chronic Time Point

Abstract

Traumatic brain injury (TBI) is a heterogeneous disease in its origin, neuropathology, and prognosis, with no FDA-approved treatments. The pathology of TBI is complicated and not sufficiently understood, which is the reason why more than 30 clinical trials in the past three decades turned out unsuccessful in phase III. The multifaceted pathophysiology of TBI involves a cascade of metabolic and molecular events including inflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction. In this study, an open head TBI mouse model, induced by controlled cortical impact (CCI), was used to investigate the chronic protective effects of mitoquinone (MitoQ) administration 30 days post-injury. Neurological functions were assessed with the Garcia neuroscore, pole climbing, grip strength, and adhesive removal tests, whereas cognitive and behavioral functions were assessed using the object recognition, Morris water maze, and forced swim tests. As for molecular effects, immunofluorescence staining was conducted to investigate microgliosis, astrocytosis, neuronal cell count, and axonal integrity. The results show that MitoQ enhanced neurological and cognitive functions 30 days post-injury. MitoQ also decreased the activation of astrocytes and microglia, which was accompanied by improved axonal integrity and neuronal cell count in the cortex. Therefore, we conclude that MitoQ has neuroprotective effects in a moderate open head CCI mouse model by decreasing oxidative stress, neuroinflammation, and axonal injury.

Neurological Outcomes Following Mitoquinone Supplementation in Mice, 3 and 7 Days Post Repeated Mild Traumatic Brain Injury

“…Mitochondrial impairment as well as oxidative damage represent integral parts of the pathophysiological process associated with rmTBI therein. The observed neuroprotective effects of MitoQ are also in line with previous studies that demonstrated the safe profile of MitoQ and its efficacy in alleviating cognitive impairments and motor deficiencies [23,27,45].…”

“…We have recently shown that MitoQ alleviated fine motor function and learning impairments, reduced reactive astrogliosis, microgliosis, dendritic and axonal shearing, and increased the expression of antioxidant enzymes in a mouse model of rmTBI at a chronic time point defined as 30 days post-injury [22]. Moreover, we have shown that MitoQ enhanced neurological and cognitive functions, (2) decreased the activation of astrocytes and microglia, and improved axonal integrity and neuronal cell count in the cortex 30 days post-injury in a mouse model of moderate open head injury [23].…”

“…The Institutional Animal Care and Use Committees (IACUC) at AUB authorized all experimental procedures performed on the animals under the approval number 17-01-458. Based on previous published studies, we did not observe differences in male/female outcomes; thus, this current work involved male mice [23,26,27].…”

TRAP1 Chaperones the Metabolic Switch in Cancer

“…TPP-Mitoquinone has shown utility and specificity by targeting the client-binding middle domain of TRAP1 [ 117 ]. Mitoquinone has been demonstrated to have protective properties in various animal models of neurological maladies, such as traumatic brain injury [ 131 ], Huntington’s disease [ 132 ], amyotrophic lateral sclerosis (ALS) [ 133 ], and Alzheimer’s disease [ 134 ]. This finding is contradictory to the working model of TRAP1 function, especially considering that TRAP1 downregulation is observed in Alzheimer’s disease patients [ 135 ] and its overexpression is protective against oxidative stress in ALS [ 62 ].…”

Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach

“…This review aimed to explore neuroprotective activities of histone deacetylase inhibitors in ischemic stroke. In line with neuroprotection, Haider et al [27] investigated the role of mitoquinone in chronic neuroprotection post-TBI, and found that mitoquinone reduced gliosis, decreased oxidative stress, limited neuroinflamamtion, and improved axonal integrity and neuronal survival in an open-head CCI mouse model of moderate TBI.…”