Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury.
MRI
Seahorse
controlled cortical impact
mitochondria
synapse
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
31 12 2021
31 12 2021
Historique:
received:
10
02
2021
revised:
28
07
2021
accepted:
04
08
2021
entrez:
31
12
2021
pubmed:
1
1
2022
medline:
23
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34972207
pii: 6491314
doi: 10.1093/brain/awab341
pmc: PMC8719838
doi:
Substances chimiques
Iron-Binding Proteins
0
Membrane Proteins
0
Neuroprotective Agents
0
mitoNEET protein, mouse
0
Pioglitazone
X4OV71U42S
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3788-3807Subventions
Organisme : NINDS NIH HHS
ID : R01 NS112693
Pays : United States
Organisme : BLRD VA
ID : IK2 BX004618
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG058171
Pays : United States
Organisme : BLRD VA
ID : I01 BX003405
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA177558
Pays : United States
Organisme : NIH HHS
ID : S10 OD023573
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY026584
Pays : United States
Informations de copyright
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
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