Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice
| Autor: | Patrick G. Sullivan, W. Brad Hubbard, Hemendra J. Vekaria, John G. Geisler, Christopher L. Harwood |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Traumatic brain injury Hippocampus Oxidative phosphorylation Pharmacology medicine.disease_cause Neuroprotection Article Lesion Mice 03 medical and health sciences Cellular and Molecular Neuroscience Oxygen Consumption 0302 clinical medicine Memory Brain Injuries Traumatic medicine Animals Prodrugs Neurons chemistry.chemical_classification Reactive oxygen species Uncoupling Agents business.industry Recognition Psychology medicine.disease Mitochondria Mice Inbred C57BL Disease Models Animal Oxidative Stress Neuroprotective Agents 030104 developmental biology medicine.anatomical_structure chemistry Neuron medicine.symptom 2 4-Dinitrophenol Energy Metabolism business 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Journal of Neuroscience Research. 96:1677-1688 |
| ISSN: | 1097-4547 0360-4012 |
| DOI: | 10.1002/jnr.24271 |
| Popis: | Traumatic brain injury (TBI) results in cognitive impairment, which can be long-lasting after moderate to severe TBI. Currently, there are no FDA-approved therapeutics to treat the devastating consequences of TBI and improve recovery. This study utilizes a prodrug of 2,4-dinitrophenol (DNP), MP201, a mitochondrial uncoupler with extended elimination time, that was administered after TBI to target mitochondrial dysfunction, a hallmark of TBI. Using a model of cortical impact in male C57/BL6 mice, MP201 (80 mg/kg) was provided via oral gavage 2-hours post-injury and daily afterwards. At 25-hours post-injury, mice were euthanized and the acute rescue of mitochondrial bioenergetics was assessed demonstrating a significant improvement in both the ipsilateral cortex and ipsilateral hippocampus after treatment with MP201. Additionally, oxidative markers, 4- hydroxyneneal and protein carbonyls, were reduced compared to vehicle animals after MP201 administration. At 2-weeks post-injury, mice treated with MP201 post-injury (80mg/kg; q.d.) displayed significantly increased cortical sparing (p = 0.0059; 38% lesion spared) and improved cognitive outcome (p = 0.0133) compared to vehicle-treated mice. Additionally, vehicle-treated mice had significantly lower (p = 0.0019) CA3 neuron count compared to sham while MP201-treated mice were not significantly different from sham levels. These results suggest that acute mitochondrial dysfunction can be targeted to impart neuroprotection from reactive oxygen species, but chronic administration may have an added benefit in recovery. This study highlights the potential for safe, effective therapy by MP201 to alleviate negative outcomes of TBI. |
| Databáze: | OpenAIRE |
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