Background/Objectives: Mild traumatic brain injury (mTBI) is common and may result in persistent cognitive and affective disturbances driven, at least in part, by delayed secondary injury mechanisms, including oxidative stress, neuroinflammation, apoptosis-related signaling, and impaired neuroplasticity. Pharmacological strategies targeting these interconnected processes remain limited. The present study investigated leucovorin, also known as folinic acid, a clinically approved reduced folate, as a potential repurposing candidate in an experimental model of mTBI. Methods: Male Wistar rats were subjected to mild diffuse brain injury using a modified weight-drop model and received a single intraperitoneal dose of leucovorin (20 mg/kg). Behavioral performance was evaluated using the open field, elevated plus maze, forced swim, and novel object recognition tests. Oxidative stress markers, including total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), as well as inflammatory mediators tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2), caspase-3, brain-derived neurotrophic factor (BDNF), and acetylcholinesterase (AChE), were measured in hippocampal tissue and plasma. Histopathological and immunohistochemical evaluations were also performed in cortical and hippocampal regions. Results: Experimental mTBI was associated with anxiety-like and depressive-like behaviors and impaired recognition memory, whereas basal locomotor activity was not significantly altered. Trauma was also associated with increased oxidative stress, elevated inflammatory and apoptosis-related markers, reduced BDNF levels, altered AChE activity, and histopathological abnormalities. Compared with untreated mTBI animals, leucovorin-treated animals showed attenuation of biochemical and tissue alterations, accompanied by improved behavioral outcomes. Immunohistochemical findings were consistent with reduced inflammatory labeling and relative preservation of tissue architecture following leucovorin treatment. Conclusions: Leucovorin attenuated behavioral, biochemical, histopathological, and immunohistochemical alterations associated with experimental mTBI. These findings suggest that leucovorin may have neuroprotective potential in this setting; however, further studies are needed to clarify the underlying mechanisms, optimal treatment paradigms, and translational relevance.

Objective: This study aimed to investigate the effects of Perga supplementation on glucose metabolism, body weight regulation, and amyloid-beta (Aβ) accumulation in a streptozotocin (STZ)-induced type 2 diabetes (T2D) rat model, focusing specifically on insulin, leptin, and fibroblast growth factor 21 (FGF21) signaling pathways. Methods: Male Wistar rats were divided into Sham (S), T2D, and T2D+Perga (T2DP) groups. T2D was induced by a single intraperitoneal (i.p.) STZ injection (60 mg/kg). Perga (200 mg/kg/day) was administered to the T2DP group by gavage 14 days after diabetes induction. Plasma and brain insulin and leptin levels, liver and plasma FGF21 concentrations, Homeostasis Model Assessment of Beta Cell Function (HOMA-β) index, fasting glucose levels, body weight changes, and brain amyloid-beta (Aβ) accumulation were evaluated. Results: STZ-induced T2D resulted in hypoinsulinemia, decreased HOMA-β scores, weight loss, reduced plasma leptin, increased brain leptin, decreased FGF21 levels, and significant Aβ accumulation in the hippocampus. Perga treatment significantly improved plasma and brain insulin levels, increased HOMA-β, reduced fasting glucose, and attenuated weight loss. Plasma leptin levels returned to normal, brain leptin levels decreased, and hippocampus Aβ burden was significantly reduced. In addition, perga supplementation almost normalized liver and plasma FGF21 levels. Conclusion: Perga supplementation effectively ameliorates metabolic dysfunction and neurodegenerative markers in the T2D model. Its regulatory effects on insulin, leptin, and FGF21 signaling highlight its potential as a natural therapeutic agent in managing T2D and associated AD-like pathology. Further research is needed to evaluate its clinical applicability.

Cerebral ischemia (CI), characterized by restricted blood supply leading to neuronal damage, remains a significant cause of morbidity and mortality and a weighty economic distress on healthcare and...