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- Title
Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury.
- Authors
Hubbard, W Brad; Spry, Malinda L; Gooch, Jennifer L; Cloud, Amber L; Vekaria, Hemendra J; Burden, Shawn; Powell, David K; Berkowitz, Bruce A; Geldenhuys, Werner J; Harris, Neil G; Sullivan, Patrick G
- Abstract
Pioglitazone, an FDA-approved compound, has been shown to target the novel mitochondrial protein mitoNEET and produce short-term neuroprotection and functional benefits following traumatic brain injury. To expand on these findings, we now investigate the dose- and time-dependent effects of pioglitazone administration on mitochondrial function after experimental traumatic brain injury. We then hypothesize that optimal pioglitazone dosing will lead to ongoing neuroprotection and cognitive benefits that are dependent on pioglitazone-mitoNEET signalling pathways. We show that delayed intervention is significantly more effective than early intervention at improving acute mitochondrial bioenergetics in the brain after traumatic brain injury. In corroboration, we demonstrate that mitoNEET is more heavily expressed, especially near the cortical contusion, in the 18 h following traumatic brain injury. To explore whether these findings relate to ongoing pathological and behavioural outcomes, mice received controlled cortical impact followed by initiation of pioglitazone treatment at either 3 or 18 h post-injury. Mice with treatment initiation at 18 h post-injury exhibited significantly improved behaviour and tissue sparing compared to mice with pioglitazone initiated at 3 h post-injury. Further using mitoNEET knockout mice, we show that this therapeutic effect is dependent on mitoNEET. Finally, we demonstrate that delayed pioglitazone treatment improves serial motor and cognitive performance in conjunction with attenuated brain atrophy after traumatic brain injury. This study illustrates that mitoNEET is the critical target for delayed pioglitazone intervention after traumatic brain injury, mitochondrial-targeting is highly time-dependent after injury and there is an extended therapeutic window to effectively treat mitochondrial dysfunction after brain injury.
- Subjects
UNITED States. Food &; Drug Administration; BRAIN injuries; MITOCHONDRIAL pathology; CEREBRAL atrophy; MITOCHONDRIAL proteins; KNOCKOUT mice; CELLULAR signal transduction; RESEARCH; ANIMAL experimentation; RESEARCH methodology; EVALUATION research; MITOCHONDRIA; COMPARATIVE studies; METALLOPROTEINS; NEUROPROTECTIVE agents; RESEARCH funding; MEMBRANE proteins; MICE; PHARMACODYNAMICS
- Publication
Brain: A Journal of Neurology, 2021, Vol 144, Issue 12, p3788
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awab341