Early treatment with triamcinolone-loaded nanocarriers ameliorates cognitive and emotional sequelae induced by traumatic brain injury and modulates oxidative stress

Abstract

Traumatic brain injury (TBI) causes a variety of neuropathological manifestations including cognitive, emotional and physiological deficits, probably related to early neuroinflammatory processes. We have previously shown that TBI increases levels of protein (AOPP) and lipid (MDA) peroxidation, considered oxidative stress (OS) biomarkers that persisted over a week. Regardless the research investment on the development of anti-inflammatory and neuroprotective treatments, most pre-clinical studies did not report significant effects, probably because of the limited blood brain barrier permeability of clinically available anti-inflammatory drug formulations. Objective: to evaluate the effectiveness of nanocarriers loaded with the synthetic glucocorticoid triamcinolone (NA-TA), to prevent oxidative stress (OS) processes and to reduce the cognitive and emotional sequelae induced by TBI. Materials and methods: TBI was induced in anesthetized adult male Wistar rats, which 15 min and 24 h later received a dose of NA-TA. Animals were sacrificed 1 or 7 days after treatment to measure AOPP and MDA levels in different brain areas. Additionally, a group of animals was submitted novel object recognition (NOR) test 7 days after TBI induction. Finally, other groups were exposed to contextual fear conditioning 6 days after TBI and treatment. Twenty-four h (test 1) and 6 days (test 2, 12 days after TBI) after conditioning, fear memory expression was evaluated. Results: TBI induced a significant decrease in the discrimination index of a novel object 7 days after trauma (t-test) that could be prevented by early administration of NA-TA. On the other hand, TBI induced a significant decrease in the % freezing only in test 2 compared to the controls (two-way ANOVA). Interestingly, preliminary data suggest that animals treated with NA-TA did not show changes in fear memory. Also, TA prevented increments in AOPP and MDA levels (one-way ANOVA). Conclusions: TBI induced neuroinflammatory mediators that could have detrimental actions on recognition memory and fear memory retention probably through cognitive and emotional processing alteration. NA-TA administration could be a therapeutic alternative for the early treatment of neuroinflammation mediated by TBI, that contribute to the cognitive and emotional sequelae prevention.