Triamcinolone-Loaded Nanocarriers: A Novel Strategy to Mitigate Cognitive and Emotional Sequelae Induced by Traumatic Brain Injury via Modulation of Oxidative Stress

Aida Marcotti^1,2Sofía de la Fuente^1,2María Lina Formica^3,4Agustin Jorge Montivero^1,2Martina Ramíres^1,2Verónica Leonor Romero^1,2María Florencia Constantin^1,2María Jazmín Silvero³María Cecilia Becerra^3,4Gaston Calfa^1,2Miriam Beatriz Virgolini^1,2Santiago Daniel Palma^3,4Mariela Fernanda Perez^1,2*

• ¹Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Farmacología Otto Orshinger., Córdoba,, Argentina
• ²CONICET, Instituto de Farmacología Experimental de Córdoba (IFEC)., Córdoba, Argentina
• ³Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Ciencias Farmacéuticas, Córdoba, Argentina
• ⁴CONICET, Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), Córdoba, Argentina

Traumatic brain injury is the leading cause of death and disability in individuals under 40 years old. It induces various neuropathological outcomes, including cognitive, emotional, and physiological deficits, likely linked to early neuroinflammatory processes. In an animal model, mild traumatic brain injury (mTBI) has been shown to elevate oxidative stress (OS) biomarkers, such as advanced oxidation protein products (AOPP) and malondialdehyde (MDA), which persist for over a week. Despite extensive research on anti-inflammatory and neuroprotective therapies, most preclinical and clinical studies report limited efficacy. Synthetic glucocorticoids (GCS) offer potential for early treatment of TBI-induced neuroinflammation, but clinical use is hindered by adverse effects and poor central nervous system (CNS) biodistribution. Triamcinolone (TR) possesses anti-inflammatory, antiangiogenic, and microglial inhibitory properties but suffers from poor solubility and limited blood- brain barrier (BBB) penetration. Lipid nanocapsules (LNCs) may enhance TR solubility, bioavailability, BBB permeation, and intracellular delivery. This study aimed to evaluate the efficacy of TR-loaded LNCs (NT) on oxidative stress and cognitive-emotional outcomes following mTBI. Closed-head mTBI was induced in anesthetized male Wistar rats, which received NT, TR, or negative controls (empty LNCs) 15 minutes and 24 hours post-injury. Animals were sacrificed 24 hours, 1 or 7 days later for biochemical analysis of AOPP, MDA, and antioxidant activity in the hippocampus, prefrontal, and motor cortices. Separate cohorts underwent behavioral tests assessing memory (novel object recognition, Y-maze, and fear conditioning). Results showed early NT treatment prevented oxidative damage, normalized antioxidant activity, and improved memory retention and emotional responses. These findings suggest NT as a promising therapeutic approach to mitigate cognitive and emotional sequelae induced by mTBI.