Neurotoxicity of melittin: Role of mitochondrial oxidative phosphorylation system in synaptic plasticity dysfunction

Melittin (Mel), a main active peptide component of bee venom, has been proven to possess strong antitumor activity. Previous studies have shown that Mel caused severe cell membrane lysis and acted on the central nervous system (CNS). Here, this study was designed to investigate the effects of Mel on CNS and explore the potential mechanism. We confirmed the neurotoxic effect of melittin by in vivo and in vitro experiments. After subcutaneous administration of Mel (4 mg/kg, 8 mg/kg) for 14 days, the mice exhibited obvious depression-like behavior in a dose dependent manner. Besides, RNA-sequencing analysis revealed that oxidative phosphorylation (OXPHOS) signaling pathway was mostly enriched in hippocampus. Consistently, we found that Mel distinctly inhibited the activity of OXPHOS complex I and induced oxidative stress injury. Moreover, Mel significantly induced synaptic plasticity dysfunction in hippocampus via BDNF/TrkB/CREB signaling pathway. Taken together, the neurotoxic effect of Mel was involved in impairing OXPHOS system and hippocampal synaptic plasticity. These novel findings provide new insights into fully understanding the health risks of Mel and are conducive to the development of Mel related drugs.