Proteomic Landscape of H₂S-Releasing Peptide Mediated Neuroprotection in Traumatic Brain Injury

Traumatic brain injury (TBI) constitutes a health burden, with outcomes shaped by the primary injury and the progressive secondary injury cascades leading to the impairment of neuronal integrity, brain homeostasis, and cognitive functions. In the absence of therapies targeting the molecular aftermath of TBIs and the conventional limitations associated with the H₂S donors, the novel H₂S-releasing peptides (SVRN-4) with potent neuroprotective effects provide a rational and promising therapeutic option. In the present study, we evaluated the therapeutic efficacy of SVRN-4 in a mouse model of weight loss TBI (WD-TBI). Our results revealed that SVRN-4 administration significantly reduced TBI-induced tissue disruption and nitric oxide-induced tissue damage and restored mitochondrial integrity. Additionally, neurobehavioral assessments indicated improved neurocognitive functions and motor performance. Furthermore, the global proteomic analysis of WD-TBI revealed altered molecular pathways associated with energy metabolism, apoptosis, neurodevelopment, and protein turnover. Interestingly, SVRN-4 treatment restored alterations in the pathological protein expression involved in mitochondrial function and ATP production and normalized the inflammatory markers. In summary, the proteomic landscape of the H₂S-releasing peptide, SVRN-4-mediated neuroprotection in WD-TBIs revealed its ameliorative effect on the progressive secondary injuries and underscored its potential as a promising therapeutic candidate for promoting functional recovery in TBIs.