PMID- 35065054 OWN - NLM STAT- MEDLINE DCOM- 20220504 LR - 20220504 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 351 DP - 2022 May TI - Mitoquinone supplementation alleviates oxidative stress and pathologic outcomes following repetitive mild traumatic brain injury at a chronic time point. PG - 113987 LID - S0014-4886(22)00012-7 [pii] LID - 10.1016/j.expneurol.2022.113987 [doi] AB - Traumatic brain injury (TBI) is a major cause of disability and death. Mild TBI (mTBI) constitutes ~75% of all TBI cases. Repeated exposure to mTBI (rmTBI), leads to the exacerbation of the symptoms compared to single mTBI. To date, there is no FDA-approved drug for TBI or rmTBI. This research aims to investigate possible rmTBI neurotherapy by targeting TBI pathology-related mechanisms. Oxidative stress is partly responsible for TBI/rmTBI neuropathologic outcomes. Thus, targeting oxidative stress may ameliorate TBI/rmTBI consequences. In this study, we hypothesized that mitoquinone (MitoQ), a mitochondria-targeted antioxidant, would ameliorate TBI/rmTBI associated pathologic features by mitigating rmTBI-induced oxidative stress. To model rmTBI, C57BL/6 mice were subjected to three concussive head injuries. MitoQ (5 mg/kg) was administered intraperitoneally to rmTBI+MitoQ mice twice per week over one month. Behavioral and cognitive outcomes were assessed, 30 days following the first head injury, using a battery of behavioral tests. Immunofluorescence was used to assess neuroinflammation and neuronal integrity. Also, qRT-PCR was used to evaluate the expression levels of antioxidant enzymes. Our findings indicated that MitoQ alleviated fine motor function and learning impairments caused by rmTBI. Mechanistically, MitoQ reduced astrocytosis, microgliosis, dendritic and axonal shearing, and increased the expression of antioxidant enzymes. MitoQ administration following rmTBI may represent an efficient approach to ameliorate rmTBI neurological and cellular outcomes with no observable side effects. CI - Copyright (c) 2022. Published by Elsevier Inc. FAU - Tabet, Maha AU - Tabet M AD - Faculty of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon; Molecular, Cellular, and Developmental biology department (MCD), Centre de Biologie Integrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France. Electronic address: maha.tabet@univ-tlse3.fr. FAU - El-Kurdi, Marya AU - El-Kurdi M AD - Faculty of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon. Electronic address: mbe12@mail.aub.edu. FAU - Haidar, Muhammad Ali AU - Haidar MA AD - Faculty of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon. FAU - Nasrallah, Leila AU - Nasrallah L AD - Faculty of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon. Electronic address: ln23@aub.edu.lb. FAU - Reslan, Mohammad Amine AU - Reslan MA AD - Faculty of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon. FAU - Shear, Deborah AU - Shear D AD - Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States. Electronic address: deborah.a.shear@us.army.mil. FAU - Pandya, Jignesh D AU - Pandya JD AD - Brain Trauma Neuroprotection (BTN) Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States. Electronic address: jignesh.d.pandya.civ@mail.mil. FAU - El-Yazbi, Ahmed F AU - El-Yazbi AF AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; Faculty of Pharmacy, Alalamein International University, Alalamein, Egypt. Electronic address: ayazbi@aiu.edu.eg. FAU - Sabra, Mirna AU - Sabra M AD - Faculty of Medicine, Lebanese University, Neuroscience Research Center (NRC), Beirut, Lebanon. Electronic address: sabram@students.iarc.fr. FAU - Mondello, Stefania AU - Mondello S AD - Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy. Electronic address: smondello@unime.it. FAU - Mechref, Yehia AU - Mechref Y AD - Texas Tech University, Lubbock, TX, USA. Electronic address: yehia.mechref@ttu.edu. FAU - Shaito, Abdullah AU - Shaito A AD - Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar. FAU - Wang, Kevin K AU - Wang KK AD - Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, Psychiatry, Neuroscience and Chemistry, University of Florida, Gainesville, FL, USA. Electronic address: kwang@ufl.edu. FAU - El-Khoury, Riyad AU - El-Khoury R AD - Department of Pathology and Laboratory Medicine, Neuromuscular Diagnostic Laboratory, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon. Electronic address: re70@aub.edu.lb. FAU - Kobeissy, Firas AU - Kobeissy F AD - Faculty of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon; Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, Psychiatry, Neuroscience and Chemistry, University of Florida, Gainesville, FL, USA. Electronic address: firasko@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220119 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Antioxidants) RN - 0 (Organophosphorus Compounds) RN - 1339-63-5 (Ubiquinone) RN - 47BYS17IY0 (mitoquinone) SB - IM MH - Animals MH - Antioxidants/metabolism/pharmacology/therapeutic use MH - *Brain Concussion/complications/drug therapy/pathology MH - *Brain Injuries, Traumatic/complications/drug therapy MH - Dietary Supplements MH - Disease Models, Animal MH - Mice MH - Mice, Inbred C57BL MH - Organophosphorus Compounds MH - Oxidative Stress MH - Ubiquinone/analogs & derivatives OTO - NOTNLM OT - Antioxidants OT - Concussions OT - Mitochondria OT - Mitoquinone OT - Oxidative stress OT - Repeated mild TBI EDAT- 2022/01/23 06:00 MHDA- 2022/05/06 06:00 CRDT- 2022/01/22 20:09 PHST- 2021/05/27 00:00 [received] PHST- 2021/11/23 00:00 [revised] PHST- 2022/01/13 00:00 [accepted] PHST- 2022/01/23 06:00 [pubmed] PHST- 2022/05/06 06:00 [medline] PHST- 2022/01/22 20:09 [entrez] AID - S0014-4886(22)00012-7 [pii] AID - 10.1016/j.expneurol.2022.113987 [doi] PST - ppublish SO - Exp Neurol. 2022 May;351:113987. doi: 10.1016/j.expneurol.2022.113987. Epub 2022 Jan 19.