King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, UK.
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Basic and Clinical Neuroscience, London, UK.
Psychoneuroendocrinology. 2018 Sep;95:28-33. doi: 10.1016/j.psyneuen.2018.05.021. Epub 2018 May 16.
The precise effect of antipsychotic drugs on either central or peripheral inflammation remains unclear. An important issue in this debate is to what extent the known peripheral metabolic effects of antipsychotics, including increased adiposity, may contribute to increased inflammation. Adipose tissue is known to contribute to the development of systemic inflammation, which can eventually lead to insulin resistance and metabolic dysregulation. As a first step to address this question, we evaluated whether chronic exposure to clinically comparable doses of haloperidol or olanzapine resulted in the immune activation of rat adipose tissue. Samples of visceral adipose tissue were sampled from male Sprague-Dawley rats exposed to, haloperidol, olanzapine or vehicle (all n = 8), for 8 weeks. From these we measured a cytokine profile, protein expression of F4/80 (a phenotypic macrophage marker) and translocator protein (TSPO), a target for radiotracers putatively indicating microgliosis in clinical neuroimaging studies. Chronic olanzapine exposure resulted in significantly higher adipose IL-6 levels compared with vehicle-controls (ANOVA p = 0.008, Bonferroni post-hoc test p = 0.006); in parallel, animals exposed to olanzapine had significantly higher F4/80 expression when compared with vehicle-controls (Mann Whitney Test, p = 0.014), whereas there was no difference between haloperidol and vehicle groups (Mann Whitney test, p = 0.1). There were no significant effects of either drug on adipose TSPO protein levels. Nevertheless, we found a positive correlation between F4/80 and TSPO adipose protein levels in the olanzapine-exposed rats (Spearman's rho = 0.76, p = 0.037). Our data suggest that chronic exposure to olanzapine, but not haloperidol, increases production of the pro-inflammatory cytokine IL-6 in adipose tissue and increased macrophages expression (F4/80), in the absence of measurable changes in TSPO with respect to vehicle. This may have potentially important consequences in terms of metabolic dysregulation associated with long-term antipsychotic treatment.
抗精神病药物对中枢或外周炎症的确切影响尚不清楚。这场争论中的一个重要问题是，抗精神病药物已知的外周代谢效应，包括肥胖增加，在多大程度上导致炎症增加。众所周知，脂肪组织有助于全身炎症的发展，而全身炎症最终可导致胰岛素抵抗和代谢紊乱。为了解决这个问题，我们首先评估了慢性暴露于临床可比剂量的氟哌啶醇或奥氮平是否会导致大鼠脂肪组织的免疫激活。从接受氟哌啶醇、奥氮平或载体（均为 n=8）治疗 8 周的雄性 Sprague-Dawley 大鼠的内脏脂肪组织中采集样本。我们从这些样本中测量了细胞因子谱、F4/80（一种表型巨噬细胞标志物）和转位蛋白（TSPO）的蛋白表达，TSPO 是临床神经影像学研究中潜在表示小胶质细胞增生的放射性示踪剂的靶标。与载体对照组相比，慢性奥氮平暴露导致脂肪组织中 IL-6 水平显著升高（ANOVA p=0.008，Bonferroni 事后检验 p=0.006）；与此平行，与载体对照组相比，接受奥氮平治疗的动物的 F4/80 表达显著升高（Mann Whitney 检验，p=0.014），而氟哌啶醇组与载体组之间无差异（Mann Whitney 检验，p=0.1）。两种药物均未对脂肪组织 TSPO 蛋白水平产生显著影响。然而，我们发现奥氮平暴露大鼠脂肪组织中 F4/80 和 TSPO 脂肪蛋白水平之间存在正相关（Spearman rho=0.76，p=0.037）。我们的数据表明，与氟哌啶醇相比，慢性暴露于奥氮平会增加脂肪组织中促炎细胞因子 IL-6 的产生，并增加巨噬细胞的表达（F4/80），而与载体相比，TSPO 无明显变化。这可能会对长期抗精神病治疗相关的代谢紊乱产生潜在的重要影响。
