Grants and Contracts Details
Description
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. A wealth of experimental evidence shows that mitochondrial dysfunction is poised to be a
pivotal link in the neuropathology of brain injury. We previously have targeted bioenergetic impairment with
mitochondria-directed therapeutics, including mild mitochondrial uncouplers, which have shown to be
neuroprotective. These uncouplers facilitate the movement of protons from the mitochondrial inner-membrane
space into the mitochondrial matrix, thereby reducing the mitochondrial membrane potential (Äø). While
complete uncoupling of mitochondria would be detrimental, we have published data showing that transient or
“mild uncoupling” confers neuroprotection in preclinical models of TBI. Recently, we demonstrated that a prodrug
of 2,4-dinitrophenol (DNP), MP201, a mitochondrial uncoupler with better pharmacodynamic properties including
higher tolerability and extended elimination time, rescues acute mitochondrial bioenergetics, reduces oxidative
damage, increases brain-derived neurotropic factor (BDNF) and is neuroprotective. We hypothesize that the
optimal dosage and timing of therapeutic intervention of MP201 is neuroprotective across species following focal
contusion brain injury. Our proposed studies will explore how MP201 administration can improve acute,
longitudinal, and chronic outcomes, paired with critical biomarkers, including platelet physiology and
neurochemical profiles. To achieve this, we will use innovative techniques across multiple institutions to assess
synaptic and non-synaptic mitochondria in both porcine and murine models of TBI. Additionally, we will extend
our findings to examine therapeutic efficacy, measuring longitudinal cortical morphology (T2/DTI scanning),
neurometabolite profiles (MRS scanning), platelet signature (as a novel biomarker), and cognitive behavior.
Finally, we will explore the underlying mechanism behind the long-term neuroprotection imparted by MP201 after
TBI, examining BDNF levels and mitochondrial restoration. With strong preliminary data and utilizing many
innovative and clinically-relevant techniques, we anticipate this proposal will generate ground-breaking data.
Overall, this proposal will highlight highly translatable therapy by MP201 to alleviate negative outcomes of TBI.
Status | Active |
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Effective start/end date | 3/15/20 → 1/31/27 |
Funding
- National Institute of Neurological Disorders & Stroke: $2,567,139.00
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