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

Muhammad Ali Haidar,Jignesh D Pandya,Kevin Wang,Firas Kobeissy,Riyad El Khoury,Mona Goli,Maha Tabet,Hala Darwish,Sarin Mekhjian,Chloe Barsa,Yehia Mechref,Deborah Shear,Zaynab Shakkour

doi:10.3390/biomedicines10020250

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.

Highlights

Traumatic brain injury (TBI) is one of the leading causes of death and long-lasting disability
We investigated the general neurological function of TBI mice using the modified Garcia neurological score test
The experiment was first conducted 3 days before the injury to make sure that all animals (n = 10 per group) had a similar basal score and no prior neurological dysfunction was present (Figure 2A)

Summary

Introduction

The incidence of TBI is estimated to be 939 in 10,000 worldwide, with major causes being falls, Biomedicines 2022, 10, 250. TBI leads to neurological complications through two major events, dynamic and overlapping, denoted as primary and secondary injuries. The resultant excitotoxicity leads to an energetic crisis and oxidative stress by increasing reactive oxygen species (ROS) [5]. These can directly stimulate the release of cytokines and pro-inflammatory factors, contributing to an elevated inflammatory state [6,7]. Mitochondrial dysfunction, characterized by their membrane disruption and fission/fusion imbalance, plays an important role in the pathology of TBI via the excessive production of ROS, eventually leading to apoptotic cell death [9]

Methods

Results

Discussion

Conclusion