Oxidative stress and energy imbalance strongly correlate in neurodegenerative diseases. Repeated concussion is becoming a serious public health issue with uncontrollable adverse effects in the human population, which involve cognitive dysfunction and even permanent disability. Here, we demonstrate that traumatic brain injury (TBI) evokes oxidative stress, disrupts brain energy homeostasis, and boosts neuroinflammation, which further contributes to neuronal degeneration and cognitive dysfunction in the mouse brain. We also demonstrate that melatonin (an anti-oxidant agent) treatment exerts neuroprotective effects, while overcoming oxidative stress and energy depletion and reducing neuroinflammation and neurodegeneration. Male C57BL/6N mice were used as a model for repetitive mild traumatic brain injury (rmTBI) and were treated with melatonin. Protein expressions were examined via Western blot analysis, immunofluorescence, and ELISA; meanwhile, behavior analysis was performed through a Morris water maze test, and Y-maze and beam-walking tests. We found elevated oxidative stress, depressed phospho-5′AMP-activated protein kinase (p-AMPK) and phospho- CAMP-response element-binding (p-CREB) levels, and elevated p-NF-κB in rmTBI mouse brains, while melatonin treatment significantly regulated p-AMPK, p-CREB, and p-NF-κB in the rmTBI mouse brain. Furthermore, rmTBI mouse brains showed a deregulated mitochondrial system, abnormal amyloidogenic pathway activation, and cognitive functions which were significantly regulated by melatonin treatment in the mice. These findings provide evidence, for the first time, that rmTBI induces brain energy imbalance and reduces neuronal cell survival, and that melatonin treatment overcomes energy depletion and protects against brain damage via the regulation of p-AMPK/p-CREB signaling pathways in the mouse brain.

Chronic social isolation stress (CSIS) disrupts redox homeostasis and promotes neuroinflammation, contributing to depressive-like behavior. Carvacrol (CV), a monoterpenoid phenol with antioxidants and anti-inflammatory properties, has been studied merely in stress-induced depression. Adult male NMRI mice underwent 6 weeks of CSIS and received CV (10 or 20 mg/kg, i.p.) or a positive control during the final 2 weeks. Depressive-like behavior was evaluated using open-field, splash, and forced-swim tests. Medial prefrontal cortex (mPFC) and hippocampal dentate gyrus tissues were assayed for catalase (CAT) and glutathione-S-transferase (GST) activities, reduced glutathione (GSH), and lipid peroxidation (LPO; TBARS), together with selected proinflammatory cytokines. Hematoxylin-eosin staining assessed cytoarchitecture, and molecular docking examined putative interactions of CV with the Nrf2/Keap1 complex and NF-κB. CSIS increased behavioral despair and reduced exploration and grooming, accompanied by decreased CAT, GST, and GSH, elevated TBARS, and higher inflammatory mediators, with neuronal alterations in mPFC and dentate gyrus. CV dose-dependently improved locomotor and grooming behavior, restored antioxidant defenses, reduced TBARS, and lowered inflammatory markers while preserving neuronal structure. Docking supported plausible binding (≈ -5.8 kcal/mol for Nrf2/Keap1; ≈ -5.1 kcal/mol for NF-κB), consistent with the observed molecular changes. These findings indicate that CV produces antidepressant-like effects in CSIS by reinforcing redox balance and attenuating neuroinflammation in stress-sensitive brain regions, supporting its therapeutic potential for stress-related mood disorder.