Transcranial direct current stimulation promotes functional recovery in rats with traumatic brain injury by inhibiting SLC7A11-mediated Disulfidptosis and Neuroinflammation.

BACKGROUND: Traumatic brain injury (TBI) lacks effective pharmaceutical treatments. While transcranial direct current stimulation (tDCS) shows promise in neurorehabilitation, its potential to mitigate disulfidptosis, a novel cell death mechanism driven by disulfide stress, remains unexplored.

OBJECTIVE: This study aimed to investigate whether tDCS facilitates neurofunctional recovery in TBI by modulating SLC7A11-associated disulfidptosis.

METHODS: A rat model of TBI was established using controlled cortical impact. Integrated transcriptomic and untargeted metabolomic analyses were performed to identify metabolic and transcriptomic alterations after TBI. Temporal changes in SLC7A11 and NQO1 protein expression were assessed by Western blotting, while NADPH levels, SOD activity, and the NADP+/NADPH ratio were measured using biochemical assays on days 1, 3, 7, 14, 21, and 28 post-surgery. Following TBI, rats in the therapeutic efficacy experiment underwent an 8-week anodal tDCS intervention. In the SLC7A11-overexpression experiment, behavioral and molecular assessments were performed after 4 weeks of tDCS treatment. Neurological function was monitored using rotarod, open field, and Y-maze tests at weeks 1, 2, 4, 6, and 8 after intervention. Histopathological damage and apoptosis were assessed by HE staining, Nissl staining, transmission electron microscopy, and TUNEL staining. In addition, neuronal survival, SLC7A11 expression, NQO1 protein expression, oxidative stress, apoptotic markers, and cytoskeletal alterations were evaluated using immunostaining, Western blotting, biochemical assays, and ELISA. To validate the role of SLC7A11, an SLC7A11-overexpressing adenovirus was injected intracerebrally one week before TBI induction, followed by tDCS treatment. Behavioral performance, pathological injury, apoptosis, F-actin expression, IBA1 immunoreactivity, and serum levels of IL-1β, IL-6, and TNF-α were then assessed.

RESULTS: Multi-omics analysis revealed significant upregulation of SLC7A11 and enrichment of disulfidptosis-associated metabolic pathways in TBI tissues. Temporally, TBI induced sustained SLC7A11 upregulation, reduced NQO1 expression, decreased NADPH and SOD levels, and increased NADP+/NADPH ratios. tDCS intervention significantly ameliorated neurobehavioral deficits, reduced hippocampal and cortical tissue damage, and suppressed oxidative stress and apoptosis. Notably, tDCS preserved NeuN-positive neurons, downregulated SLC7A11, partially restored NQO1 expression, and improved NAD(P)H-associated redox homeostasis. No significant F-actin alteration was detected at the examined time point. Furthermore, SLC7A11 overexpression attenuated the neuroprotective effects of tDCS, impairing behavioral recovery and enhancing neuronal injury, apoptotic signaling, and neuroinflammatory responses.

CONCLUSION: tDCS promotes functional recovery in rats with TBI, at least in part, by attenuating SLC7A11-mediated disulfidptosis and neuroinflammation, highlighting a potential therapeutic mechanism for brain injury rehabilitation.