Toxic Effects of Extracellular Histones on Neuronal Cells: Mitochondrial Dysfunction and Apoptosis

Extracellular histones, emerging as critical inflammatory mediators, have unclear yet significant implications in nerve injury. This study, through in vitro assays using PC-12 and SH-SY5Y neuronal cells, reveals the toxicological mechanisms of histones. Histones trigger calcium influx and disrupt mitochondrial function by opening the MPTP, resulting in a marked decline in MMP. This mitochondrial perturbation further leads to Cyt-C release and upregulation of Caspase-3, triggering apoptotic cell death. However, interventions with MgSO4 and CsA mitigate histone-induced toxicity by blocking calcium influx and inhibiting MPTP opening. These results enhance our understanding of histone-related neurotoxicity and may contribute to developing antidotes against histone-mediated nerve damage at the biochemical and molecular toxicology levels.