High glucose levels sensitize neuron-like cells to damage induced by oxidative and neurotoxic agents

Type 2 diabetes has been associated with cognitive decline and an increased risk of neurodegenerative diseases, although the cellular mechanisms underlying this relationship remain unclear. We investigated whether high-glucose exposure induces neuronal damage and increases susceptibility to secondary oxidative and neurotoxic insults in vitro. SH-SY5Y cells were differentiated into neuron-like cells and exposed to increasing glucose concentrations. Based on the viability results, cells exposed to high glucose (HG; 100 mM, 120 h) were further analyzed and challenged with hydrogen peroxide (H₂O₂) or okadaic acid (OA). Cell viability, DNA damage, mitochondrial superoxide production, cell cycle distribution, cell death, and gene expression were evaluated. Differentiation was confirmed by increased neurite length and expression of neuronal markers (β-III-tubulin and MAP2). High glucose reduced cell viability in a concentration- and time-dependent manner. HG exposure increased oxidative DNA damage, mitochondrial superoxide levels, and apoptosis, accompanied by reduced OGG1 gene expression. Combined treatments with HG and H₂O₂ or OA further decreased cell viability and increased the sub-G1 fraction compared with controls and single treatments. These findings demonstrate that HG exerts cytotoxic and genotoxic effects and sensitizes neuron-like cells to subsequent oxidative and neurotoxic insults, thereby contributing to mechanisms underlying neuronal dysfunction and neurodegenerative processes.