Duration-dependent neuroprotective reversal by melatonin in a chronic aluminum toxicity induced zebrafish model

Aluminum is a potent neurotoxin, whose accumulation in the central nervous system (CNS) is considered a critical factor in driving neuronal disorders. Chronic aluminum exposure, leads to disturbances in oxidative stress levels, cognitive impairment, behavioural function, cholinergic transmission and histopathological tissue alterations. While melatonin is well known for its antioxidant and neuroprotective properties most existing studies emphasize its preventive effects rather than its potential to reverse already established neurotoxic insults. The present study aimed to develop a robust zebrafish (ZF) model which experimentally depicts the restorative capacity of melatonin in reversing pre-existing oxidative damage, neurobehavioral impairments, and tissue degeneration in both brain and gut, thereby investigating post-damage recovery in Aluminum chloride(AlCl₃) mediated chronic neurotoxicity. This study aims to establish an experimental model, which depicts the ability of melatonin to reverse the physiology changes and neurotoxic insults that arises otherwise due to aluminium chloride (AlCl₃) chronic neurotoxicity as established in our previously established ZF model of AlCl₃ induced toxicity. Melatonin treatment was initiated in both AlCl₃ dosage groups (0.02 mM and 0.04 mM AlCl₃), and the number of days required for behavioural, cognitive, biochemical and histological parameters restoration to control levels was quantified. Melatonin reversed the behavioural, cognitive, biochemical and histological insults after 4, 9, 14, and 20 days in the 0.02 mM AlCl₃ dosage group following 7, 14, 21, and 28 days of AlCl₃ exposure, respectively, whereas the corresponding reversal times in the 0.04 mM AlCl₃ dosage group were 10, 18, 23, and 30 days. However, at 0.04 mM AlCl₃ exposure, a longer recovery period was required, indicating severity-dependent melatonin responsiveness. Our findings show that melatonin demonstrates significant restorative potential when tissue and functional impairments remain moderate, however its efficacy markedly decreases when severe or deeper pathological damage has occurred. The current ZF model indicates that melatonin's restorative potential is not uniform across all levels of severity; instead, it depends on the depth and duration of prior damage. By identifying the limits of melatonin's reversibility window, our study emphasizes the critical importance of timing in therapeutic intervention; which is a concept that has significant implications for effects rendered due to chronic exposure to neurotoxicants.