Neurotoxic mechanisms of dexamethasone in SH-SY5Y neuroblastoma cells: Insights into bioenergetics, oxidative stress, and apoptosis

Abstract

Despite the known therapeutic uses of dexamethasone (DEX), the specific mechanisms underlying its neurotoxic effects in neuronal cells, particularly in undifferentiated human neuroblastoma (SH-SY5Y) cells, remain inadequately understood. This study aims to elucidate these mechanisms, emphasizing bioenergetics, oxidative stress, and apoptosis, thereby providing novel insights into the cellular vulnerabilities induced by chronic DEX exposure. The findings revealed significant reductions in cell viability, altered membrane integrity with LDH leakage, decreased intracellular ATP production, and the electron transport chain complexes I and III activity inhibition. DEX significantly increased the release of the reactive species and peroxidation of lipids, as well as of Nrf2 expression. At the same time, it simultaneously led to a decline in the activities of the antioxidant catalase and superoxide dismutase enzymes, along with a depletion of glutathione reserves. The apoptosis process was exhibited by a significant elevation of caspases 3 and 8 activities with overexpression of mRNA BAX, inhibition of BCL-2, and a significant upregulation of the BAX/BCL-2 ratio. Assessment of neuronal development genes (GAP43, CAMK2A, CAMK2B, TUBB3, and Wnts) by quantitative PCR assay showed increased expression of CAMK2A, CAMK2B, and Wnt3a with a significant reduction in GAP43 mRNA levels. Collectively, this study proved that DEX was cytotoxic to SH-SY5Y via bioenergetic disruption, mitochondrial dysfunction, oxidative stress, and apoptosis.