Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury.

Autor:	Hubbard WB; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA.; Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA.; Department of Physiology, University of Kentucky, Lexington, KY 40508, USA.; Lexington VA Healthcare System, Lexington, KY 40502, USA., Spry ML; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA., Gooch JL; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA., Cloud AL; College of Medicine, University of Kentucky, Lexington, KY 40508, USA., Vekaria HJ; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA., Burden S; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA., Powell DK; Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA., Berkowitz BA; Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48202, USA., Geldenhuys WJ; Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA., Harris NG; UCLA Brain Injury Research Center, Department of Neurosurgery, and Intellectual Development and Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA., Sullivan PG; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA.; Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA.; Lexington VA Healthcare System, Lexington, KY 40502, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2021 Dec 31; Vol. 144 (12), pp. 3788-3807.
DOI:	10.1093/brain/awab341
Abstrakt:	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. (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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