蜂毒中的主要活性肽成分蜜蜂胶肽（Mel）已被证实具有强烈的抗肿瘤活性。先前的研究表明，Mel引起了严重的细胞膜裂解，并作用于中枢神经系统（CNS）。因此，本研究旨在调查Mel对CNS的影响，并探索其潜在机制。我们通过体内和体外实验证实了蜜蜂胶肽的神经毒性作用。在连续14天亚皮下给予Mel（4mg/kg, 8mg/kg）后，小鼠呈现出明显的剂量依赖性抑郁样行为。此外，RNA测序分析显示氧化磷酸化（OXPHOS）信号通路主要富集在海马体内。一致地，我们发现Mel明显抑制OXPHOS复合物I的活性，并诱导氧化应激损伤。此外，Mel通过BDNF/TrkB/CREB信号通路显著诱导了海马体突触可塑性功能异常。综上所述，Mel的神经毒性效应与损害OXPHOS系统和海马体突触可塑性有关。这些新发现为充分了解Mel的健康风险提供了新的见解，并有助于Mel相关药物的开发。版权所有 © 2023 Elsevier B.V. 保留所有权利。

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 (4mg/kg, 8mg/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.Copyright © 2023 Elsevier B.V. All rights reserved.