PDE5 inhibition restores mitochondrial function and improves neurobehavioral outcomes after repeated mild blast TBI
6 affiliations
- 1Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, 40536, USA
- 2Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, 40536, USA; Lexington Veterans' Affairs Healthcare System, Lexington, KY, 40502, USA
- 3Department of Toxicology and Cancer Biology, Lexington, KY, 40536, USA
- 4Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA; Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA
- 5Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, 40536, USA; Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA
- 6Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, 40536, USA; Lexington Veterans' Affairs Healthcare System, Lexington, KY, 40502, USA; Corresponding author.
Abstract
Repeated mild traumatic brain injury (rmbTBI) is associated with persistent neurological deficits in military personnel arising from secondary cerebrovascular and metabolic impairments. Critically, there are no FDA-approved therapeutics for rmbTBI. Phosphodiesterase 5 (PDE5) inhibition has been explored in preclinical and clinical TBI studies; however, its exact therapeutic mechanism remains unclear. Recent data demonstrate that PDE5 inhibition can rescue mitochondrial dysfunction. As such, we hypothesized that PDE5 inhibition with sildenafil restores mitochondrial health following rmbTBI, conferring neurobehavioral improvement after rmbTBI. To model rmbTBI, male rats were exposed to two 11 psi blast waves 24 h apart, and daily sildenafil was initiated either 15 min or 8 weeks post-blast to assess subacute and delayed treatment effects. At 7 d post-injury, sildenafil restored rmbTBI-induced reductions in hippocampal expression of PGC-1α, a master regulator of mitochondrial biogenesis. Transcriptomic analysis revealed enrichment of oxidative phosphorylation pathways in sildenafil-treated animals, and metabolomic profiling indicated that rmbTBI results in cortical accumulation of glycolytic intermediates and altered NAD + redox balance, both attenuated by sildenafil. To assess the mitochondrial signature of brain capillaries after PDE5 inhibition, we show that sildenafil restored mitochondrial bioenergetics in brain capillaries following AAPH-induced oxidative stress and rmbTBI. rmbTBI increased anxiety-like behavior at 3 d and 7 d post-injury, which was partially normalized by sildenafil. At 20 weeks, rmbTBI animals exhibited persistent fear-conditioned behavior, whereas sildenafil facilitated fear extinction. These findings demonstrate that rmbTBI disrupts mitochondrial function and behavior, and that PDE5 inhibition with sildenafil restores these alterations, supporting its potential as a therapeutic intervention for blast-induced TBI.
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BibTeX
@article{kilgore2026pde5,
title = {{PDE5 inhibition restores mitochondrial function and improves neurobehavioral outcomes after repeated mild blast TBI}},
author = {Madison O. Kilgore and Shaojing Ye and Felix Oyelami and Alaa Alareidi and Jaycie Gard and Lance A. Johnson and Gopal V. Velmurugan and W. Brad Hubbard},
journal = {Neurotherapeutics},
year = {2026},
month = oct,
doi = {10.1016/j.neurot.2026.e01076},
url = {https://doi.org/10.1016/j.neurot.2026.e01076},
note = {CC BY},
}
RIS
TY - JOUR
TI - PDE5 inhibition restores mitochondrial function and improves neurobehavioral outcomes after repeated mild blast TBI
AU - Madison O. Kilgore
AU - Shaojing Ye
AU - Felix Oyelami
AU - Alaa Alareidi
AU - Jaycie Gard
AU - Lance A. Johnson
AU - Gopal V. Velmurugan
AU - W. Brad Hubbard
PY - 2026
DA - 2026/10/24
JO - Neurotherapeutics
DO - 10.1016/j.neurot.2026.e01076
UR - https://doi.org/10.1016/j.neurot.2026.e01076
AB - Repeated mild traumatic brain injury (rmbTBI) is associated with persistent neurological deficits in military personnel arising from secondary cerebrovascular and metabolic impairments. Critically, there are no FDA-approved therapeutics for rmbTBI. Phosphodiesterase 5 (PDE5) inhibition has been explored in preclinical and clinical TBI studies; however, its exact therapeutic mechanism remains unclear. Recent data demonstrate that PDE5 inhibition can rescue mitochondrial dysfunction. As such, we hypothesized that PDE5 inhibition with sildenafil restores mitochondrial health following rmbTBI, conferring neurobehavioral improvement after rmbTBI. To model rmbTBI, male rats were exposed to two 11 psi blast waves 24 h apart, and daily sildenafil was initiated either 15 min or 8 weeks post-blast to assess subacute and delayed treatment effects. At 7 d post-injury, sildenafil restored rmbTBI-induced reductions in hippocampal expression of PGC-1α, a master regulator of mitochondrial biogenesis. Transcriptomic analysis revealed enrichment of oxidative phosphorylation pathways in sildenafil-treated animals, and metabolomic profiling indicated that rmbTBI results in cortical accumulation of glycolytic intermediates and altered NAD + redox balance, both attenuated by sildenafil. To assess the mitochondrial signature of brain capillaries after PDE5 inhibition, we show that sildenafil restored mitochondrial bioenergetics in brain capillaries following AAPH-induced oxidative stress and rmbTBI. rmbTBI increased anxiety-like behavior at 3 d and 7 d post-injury, which was partially normalized by sildenafil. At 20 weeks, rmbTBI animals exhibited persistent fear-conditioned behavior, whereas sildenafil facilitated fear extinction. These findings demonstrate that rmbTBI disrupts mitochondrial function and behavior, and that PDE5 inhibition with sildenafil restores these alterations, supporting its potential as a therapeutic intervention for blast-induced TBI.
SN - 1878-7479
SN - 1933-7213
ER -