Many elderly American women use CNS depressant benzodiazepine (BZD) to ameliorate anxiety or insomnia. However, the chronic use of BZD (cBZD) is prevalent, causing adverse effects of BZD that include movement deficit. We previously reported that cBZD upregulates neurotoxic amyloid β42 (Aβ42) and downregulates neuroprotective translocator protein (TSPO) in the cerebellum, the brain area of movement and balance. The aim of the current study is two-fold: 1) to determine a direct effect of TSPO (inhibition) on cBZD-induced Aβ42 and Aβ-associated molecules; Aβ-producing-protein presenilin-1 (PS1) and Aβ-degrading-enzyme neprilysin and 2) to determine whether Aβ42 upregulation and motoric deficit occur upon a long-term (cBZD) rather than a short-term BZD (sBZD) treatment. Old female mice received BZD (lorazepam) for 20 days (cBZD) or 3 days (sBZD) with or without prototype TSPO ligand PK11195 and were tested for motoric performance for 3 days using Rotarod. ELISA was conducted to measure Aβ42 level and neprilysin activity in cerebellum. RT-PCR and immunoblot were conducted to measure the mRNA and protein levels of TSPO, PS1, and neprilysin. cBZD treatment decreased TSPO and neprilysin but increased Aβ42 accompanied by motoric deficit. Chronic PK11195 treatment acted as a TSPO inhibitor by suppressing TSPO expression and mimicked or exacerbated the effects of cBZD on all parameters measured except for PS1. None of the molecular and behavioral changes induced by cBZD were reproduced by sBZD treatment. These data suggest that cBZD upregulates Aβ42 and downregulates neprilysin in part through TSPO inhibition, the mechanisms distinct from sBZD, collectively contributing to motoric deficit.

许多美国老年妇女使用中枢神经系统抑制剂苯二氮卓（BZD）缓解焦虑或失眠。但是，长期使用BZD（cBZD）十分普遍，会引起BZD的不良反应，包括运动不足。我们先前曾报道cBZD上调小脑，运动和平衡大脑区域中神经毒性的淀粉样蛋白β42（Aβ42）并下调神经保护性转运蛋白（TSPO）。当前研究的目的有两个方面：1）确定TSPO（抑制）对cBZD诱导的Aβ42和Aβ相关分子的直接作用；Aβ产生蛋白早老素-1（PS1）和Aβ降解酶neprilysin和2）以确定长期（cBZD）而非短期BZD（sBZD）治疗时是否发生Aβ42上调和运动缺陷。老年雌性小鼠在有或没有原型TSPO配体PK11195的情况下接受BZD（劳拉西m）治疗20天（cBZD）或3天（sBZD），并使用Rotarod测试3天的运动表现。进行了ELISA检测小脑中Aβ42水平和中性溶酶的活性。进行RT-PCR和免疫印迹以测量TSPO，PS1和中性溶酶的mRNA和蛋白水平。cBZD治疗可降低TSPO和脑啡肽酶，但Aβ42升高并伴有运动缺陷。慢性PK11195处理通过抑制TSPO表达而充当TSPO抑制剂，并模拟或加剧了cBZD对除PS1以外的所有参数的影响。sBZD处理未复制cBZD诱导的分子和行为变化。这些数据表明cBZD部分通过TSPO抑制上调Aβ42并下调neprilysin，