PDE5 inhibition restores mitochondrial function and improves neurobehavioral outcomes after repeated mild blast TBI.

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.