Metal-organic framework UiO-66 dose-dependently mitigates oxidative stress and astrocyte activation in the rat hippocampus

Abstract

Although the metal-organic framework (MOF) UiO-66 is used as a drug delivery system, its potential harmful effects on the nervous system remain underexplored. This study evaluated the subacute impact of UiO-66 nanoparticles on working and spatial memory, neuronal integrity, oxidative stress, and astrocyte activation in the rat hippocampus. Fifty-six Wistar rats were randomly assigned to four groups. The control group received intravenous injections of normal saline, while the treatment groups were administered UiO-66 at doses of 1, 10, or 50 mg/kg over two weeks (four injections, twice weekly). After the final injection, the animals were subjected to behavioral assessments via the Morris water maze, Y-maze test, novel arm discrimination test (NADT), and novel object recognition test (NORT). Subsequently, brain samples were collected for histological and biochemical analyses. Behavioral evaluations revealed no significant differences in learning, working memory, or spatial memory among the groups. The NADT and NORT data revealed recognition memory deficits at the highest UiO-66 dose. However, biochemical assays demonstrated a dose-dependent increase in free radical production with increasing UiO-66 doses. Histopathological examinations revealed dose-related neuronal alterations, including cellular fragmentation, vacuolization, and tissue disarray. Moreover, GFAP immunostaining confirmed significant astrocyte activation in the hippocampus at higher doses, which was correlated with increased neuronal damage and cell death. Overall, while subacute exposure to UiO-66 nanoparticles at lower doses did not markedly impair cognitive performance, higher concentrations of UiO-66 were associated with elevated oxidative stress, histopathological damage, increased neuronal loss, and astrocyte activation in the brains of the rats.