Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Institute of Neuropathology, University Hospital Essen, Essen, Germany.
Int J Neuropsychopharmacol. 2018 Jun 1;21(6):592-602. doi: 10.1093/ijnp/pyy017.
Clinical data indicate that therapy with small-molecule immunosuppressive drugs is frequently accompanied by an incidence rate of neuropsychiatric symptoms. In the current approach, we investigated in rats whether repeated administration of rapamycin, reflecting clinical conditions of patients undergoing therapy with this mammalian target of rapamycin inhibitor, precipitates changes in neurobehavioral functioning.
Male adult Dark Agouti rats were daily treated with i.p. injections of rapamycin (1, 3 mg/kg) or vehicle for 8 days. On days 6 and 7, respectively, behavioral performance in the Elevated Plus-Maze and the Open-Field Test was evaluated. One day later, amygdala tissue and blood samples were taken to analyze protein expression ex vivo.
The results show that animals treated with rapamycin displayed alterations in Elevated Plus-Maze performance with more pronounced effects in the higher dose group. Besides, an increase in glucocorticoid receptor density in the amygdala was seen in both treatment groups even though p-p70 ribosomal S6 kinase alpha, a marker for mammalian target of rapamycin functioning, was not affected. Protein level of the neuronal activity marker c-Fos was again only elevated in the higher dose group. Importantly, effects occurred in the absence of acute peripheral neuroendocrine changes.
Our findings indicate that anxiety-related behavior following rapamycin treatment was not directly attributed to mTOR-dependent mechanisms or stress but rather due to hyperexcitability of the amygdala together with glucocorticoid receptor-regulated mechanism(s) in this brain region. Together, the present results support the contention that subchronic treatment with rapamycin may induce neurobehavioral alterations in healthy, naive subjects. We here provide novel insights in central effects of systemic rapamycin in otherwise healthy subjects but also raise the question whether therapy with this drug may have detrimental effects on patients' neuropsychological functioning during immune therapy.
临床数据表明，小分子免疫抑制剂治疗常伴有神经精神症状的发生率。在目前的方法中，我们在大鼠中研究了雷帕霉素的重复给药，反映了接受这种哺乳动物雷帕霉素靶蛋白抑制剂治疗的患者的临床情况，是否会引发神经行为功能的变化。
雄性成年 Dark Agouti 大鼠每天接受腹腔注射雷帕霉素（1、3mg/kg）或载体 8 天。分别在第 6 和第 7 天评估高架十字迷宫和旷场试验中的行为表现。一天后，取杏仁核组织和血液样本进行离体分析蛋白表达。
结果表明，雷帕霉素处理的动物在高架十字迷宫中的表现出现改变，高剂量组的影响更为明显。此外，尽管哺乳动物雷帕霉素靶蛋白功能的标志物 p-p70 核糖体 S6 激酶 alpha 没有受到影响，但在两个治疗组中都观察到了糖皮质激素受体密度的增加。神经元活性标志物 c-Fos 的蛋白水平仅在高剂量组中升高。重要的是，这些效应的发生与急性外周神经内分泌变化无关。
我们的发现表明，雷帕霉素治疗后的焦虑相关行为并非直接归因于 mTOR 依赖性机制或应激，而是由于杏仁核过度兴奋以及该脑区的糖皮质激素受体调节机制。总之，目前的结果支持亚慢性雷帕霉素治疗可能在健康、未受治疗的受试者中引起神经行为改变的观点。我们在这里提供了系统雷帕霉素对健康受试者中枢作用的新见解，但也提出了一个问题，即这种药物的治疗是否会对免疫治疗期间患者的神经心理功能产生不利影响。
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