State Key Laboratory of NBC Protection for Civilian, Changping, Beijing 102205, China.
Aging (Albany NY). 2023 Oct 5;15(19):10428-10452. doi: 10.18632/aging.205087.
The frequently repeated administration of alprazolam (Alp), a highly effective benzodiazepine sedative-hypnotic agent, in anxiety, insomnia, and other diseases is closely related to many negative adverse reactions that are mainly manifested as memory impairment. However, the exact molecular mechanisms underlying these events are poorly understood. Therefore, we conducted a proteomic analysis on the hippocampus in mice that received repeated administration of Alp for 24 days. A total of 439 significantly differentially expressed proteins (DEPs) were identified in mice with repeated administration of Alp compared to the control group, and the GO and KEGG analysis revealed the enrichment of terms related to mitochondrial function, cycle, mitophagy and cognition. experiments have shown that Alp may affect the cell cycle, reduce the mitochondrial membrane potential (MMP) to induce apoptosis in HT22 cells, and affect the progress of mitochondrial energy metabolism and morphology in the hippocampal neurons. Furthermore, behavioral experiments including IntelliCage System (ICS) and nover object recognition (NOR), hippocampal neuronal pathological changes with HE staining, and the expression levels of brain-deprived neuron factor (BDNF) with immunohistochemistry showed a significant decrease in memory consolidation in mice with repeated administration of Alp, which could be rescued by the co-administration of the mitochondrial protector NSI-189. To the best of our knowledge, this is the first study to identify a link between repeated administration of Alp and mitochondrial dysfunction and that mitochondrial impairment directly causes the attenuation of memory consolidation in mice.
阿普唑仑（Alp）是一种高效的苯二氮䓬类镇静催眠药，在焦虑、失眠和其他疾病中的频繁重复给药与许多负面的不良反应密切相关，主要表现为记忆力减退。然而，这些事件的确切分子机制尚不清楚。因此，我们对接受 24 天重复 Alp 给药的小鼠海马进行了蛋白质组学分析。与对照组相比，接受 Alp 重复给药的小鼠中鉴定出 439 个差异表达蛋白（DEPs），GO 和 KEGG 分析显示与线粒体功能、周期、自噬和认知相关的术语富集。实验表明，Alp 可能影响细胞周期，降低线粒体膜电位（MMP）诱导 HT22 细胞凋亡，并影响海马神经元中线粒体能量代谢和形态的进展。此外，包括 IntelliCage System (ICS) 和新物体识别 (NOR) 在内的行为实验、HE 染色的海马神经元病理变化以及免疫组织化学的脑缺失神经元因子 (BDNF) 表达水平显示，反复给予 Alp 的小鼠记忆巩固能力显著下降，而线粒体保护剂 NSI-189 的共同给药可挽救这种下降。据我们所知，这是第一项研究表明，阿普唑仑的重复给药与线粒体功能障碍之间存在联系，并且线粒体损伤直接导致小鼠记忆巩固能力的减弱。
