Combating Cadmium‐Induced Neurotoxicity, Oxidative Stress, and Inflammatory Pathways Using DOPA‐31, a Dioxopiperidinamide Derivative in an In Vivo Zebrafish Model

Cadmium (Cd), a prevalent environmental toxin and pollutant capable of causing neurodegenerative diseases (NDs) like Alzheimer's and Parkinson's, primarily through oxidative stress, calcium imbalance, and neuroinflammation-induced mechanisms. Cd exposure increases the level of reactive oxygen species (ROS) and disrupts neurotransmitters by lowering antioxidants, leading to neuron death. Cd exposure in zebrafish results in neurodegeneration, with motor, mental, and behavioral impairments. The efficacy of the DOPA-31 intervention at varying concentrations was evaluated through the behavioral tests, biochemical assays for antioxidant enzyme activities (SOD, CAT, GSH, MDA), and histopathological analysis. Additionally, the alterations in expression levels of inflammation (tnf-α, il-1β) and neuroprotective (bdnf, syn2a) genes were also assessed. The Cd exposure exhibited the major deficits in the key behavioral parameters (motor, anxiety, and cognitive impairment). It disrupted antioxidant enzyme activity, increased lipid peroxidation, and elevated acetyl cholinesterase (AChE) activity, leading to cholinergic dysfunction. Histopathology showed extensive neuronal damage and amyloid-like protein aggregation. DOPA-31 at a 20 µM concentration, substantially exhibited antioxidant and AChE activity by reducing oxidative stress and improving motor and cognitive functions. Molecular analysis of DOPA-31 treatment showed significant downregulation of pro-inflammatory markers and upregulation of neuroprotective factors. In addition, DOPA-31 restored behavioral changes by potentially mitigating neuronal damage and protein aggregation caused by the Cd-induced neurotoxicity. This research investigation suggests the novel drug candidate DOPA-31 as a preliminary treatment for Neurodegenerative Disorder (NDD)-like features and warrants further exploration in higher animal models to assess clinical relevance.