Mitochondrial Dysfunction After Repeated Mild Blast Traumatic Brain Injury Is Attenuated by a Mild Mitochondrial Uncoupling Prodrug

Journal of Neurotrauma · 8 authors, 5 centres

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TL;DR

The central result was that oral MP201 treatment, particularly at 80 mg/kg, rescued impairments in synaptic mitochondrial respiration and reduced oxidative damage in glia-enriched mitochondria in specific brain regions at 2 days post-injury.

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Rats received repeated blast overpressure (11 psi) and were treated with vehicle or MP201 (8 or 80 mg/kg). Mitochondria were isolated from the prefrontal cortex (PFC), amygdala/entorhinal/piriform cortex (AEP), and hippocampus 2 days post-injury. The central finding was that rmbTBI caused impairments in synaptic mitochondrial respiration in the PFC and AEP, which were rescued by MP201 treatment. Specifically, 80 mg/kg MP201 increased synaptic mitochondrial function in the PFC and AEP. Additionally, rmbTBI increased oxidative damage (HNE, 3NT) in glia-enriched mitochondria in the PFC and hippocampus, which was attenuated by MP201. The study demonstrates that mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance after rmbTBI in a region-specific manner.

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other

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preclinical research

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ORIGINAL PAPER

PMC10653072

Mitochondrial Dysfunction After Repeated Mild Blast Traumatic Brain Injury Is Attenuated by a Mild Mitochondrial Uncoupling Prodrug

Journal of Neurotrauma

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ABSTRACT

Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11 psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2 days post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared with its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated a mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. Although there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.

CITATION EXPORT

W. Brad Hubbard, Hemendra J. Vekaria, Gopal V. Velmurugan et al.. Mitochondrial Dysfunction After Repeated Mild Blast Traumatic Brain Injury Is Attenuated by a Mild Mitochondrial Uncoupling Prodrug. Journal of Neurotrauma. (2023). https://doi.org/10.1089/neu.2023.0102

AUTHORS

8 · 5 CENTRES

W. Brad Hubbard, Hemendra J. Vekaria, Gopal V. Velmurugan, Olivia J. Kalimon, Paresh Prajapati, Emily Brown, John G. Geisler, Patrick G. Sullivan

1Lexington Veterans' Affairs Healthcare System, Lexington, Kentucky, USA.
2Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
3Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky, USA.
4Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA.
5Mitochon Pharmaceuticals, Inc., Blue Bell, Pennsylvania, USA.