Arbutin mediated neuroprotection in zebrafish model of traumatic brain injury via modulating Nrf2/NF-κB pathway

Traumatic Brain Injury (TBI) is a major cause of mortality and disability worldwide and is associated with oxidative stress, neuroinflammation, and neurotransmitter imbalance. Arbutin, a naturally occurring glycoside with known antioxidant and anti-inflammatory properties, has the potential to modulate neurochemical alterations following brain injury. The present study was designed to evaluate the neuroprotective effects of arbutin in a zebrafish model of TBI induced by a novel non-invasive mechanical impact method termed "force-induced TBI." Adult zebrafish were randomly divided into seven groups (n = 14 per group): normal control, TBI control, arbutin per se, arbutin-treated groups (25, 50, and 100 mg/kg, i.p.), and a co-treatment group receiving arbutin (100 mg/kg) co-administrated with chrysin (25 mg/kg), a known modulator of the Nrf2/NF-κB signaling pathway. Behavioural assessments, including the open field test, novel tank diving test (NTDT), T-maze, and novel object recognition test (NORT), were conducted on days 1, 4, and 7 to evaluate locomotion activity, anxiety-like behaviour, spatial memory, and recognition ability, respectively. Following behavioural evaluation, brain tissues were analysed for oxidative stress markers (MDA, nitrite, GSH, and SOD), neurotransmitter levels (GABA and glutamate), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and histopathological alterations. Immunohistochemical analysis of Nrf2 and NF-κB was also performed. The results demonstrated that arbutin significantly improved behavioural performance, restored oxidative balance, normalized neurotransmitter levels, and attenuated neuroinflammatory responses. Furthermore, arbutin treatment was associated with increased Nrf2 immunoreactivity and reduced NF-κB immunoreactivity in a dose-dependent manner. The co-treatment with chrysin also exhibited protective effects, supporting its potential modulatory role in oxidative stress and these effects are associated with modulation of oxidative stress, neuroinflammation, neurotransmitter imbalance, and Nrf2/NF-κB immunoreactivity. These findings suggest that arbutin possesses neuroprotective potential against secondary brain injury and is associated with modulation of oxidative stress, inflammatory responses, and Nrf2/NF-κB immunoreactivity.