Acute systemic rapamycin induces neurobehavioral alterations in rats
Acute systemic rapamycin induces neurobehavioral alterations in rats
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DOI：
10.1016/j.bbr.2014.06.056
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发表时间：
2014-10-14
影响因子：
2.7
通讯作者：
Schedlowski, Manfred
中科院分区：
文献类型：
--
作者：
Hadamitzky, Martin;Herring, Arne;Schedlowski, Manfred
雷帕霉素是一种具有抗增殖和免疫抑制特性的药物，广泛用于预防急性移植排斥反应和癌症治疗。它特异性抑制哺乳动物雷帕霉素靶蛋白（mTOR）的活性，mTOR是一种已知在细胞生长、增殖和抗体产生中起重要作用的蛋白激酶。临床观察表明，接受免疫抑制药物治疗的患者经常患有情感障碍，如焦虑或抑郁。然而，这些症状是否归因于不同化合物的作用仍然相当难以捉摸。本研究探讨了急性雷帕霉素治疗对大鼠神经行为的影响。单次低剂量雷帕霉素（3 mg/kg）的全身给药导致通过脑内脑电图和药物注射后90 min的FOS蛋白表达分析的杏仁核中神经元活动增强。此外，行为调查显示，雷帕霉素诱导的焦虑相关行为的增加，在高架十字迷宫和开放领域。行为改变与杏仁核中KLK 8和FKBP 51的表达增强相关，这些蛋白质与焦虑和抑郁的发展有关。总之，这些结果表明，急性雷帕霉素给药对mTOR信号传导的急性阻断不仅引起神经元活性的变化，而且还导致除了mTOR之外的蛋白激酶途径中的蛋白表达升高，从而促进焦虑样行为的发展。鉴于杏仁核在情绪调节、联想学习和认知功能调节中的关键作用，我们的研究结果提出了雷帕霉素治疗是否会引起患者神经心理功能改变的问题。(C)2014爱思唯尔有限公司版权所有。
Rapamycin is a drug with antiproliferative and immunosuppressive properties, widely used for prevention of acute graft rejection and cancer therapy. It specifically inhibits the activity of the mammalian target of rapamycin (mTOR), a protein kinase known to play an important role in cell growth, proliferation and antibody production. Clinical observations show that patients undergoing therapy with immunosuppressive drugs frequently suffer from affective disorders such as anxiety or depression. However, whether these symptoms are attributed to the action of the distinct compounds remains rather elusive. The present study investigated in rats neurobehavioral consequences of acute rapamycin treatment. Systemic administration of a single low dose rapamycin (3 mg/kg) led to enhanced neuronal activity in the amygdala analyzed by intracerebral electroencephalography and FOS protein expression 90 min after drug injection. Moreover, behavioral investigations revealed a rapamycin-induced increase in anxiety-related behaviors in the elevated plus-maze and in the open-field. The behavioral alterations correlated to enhanced amygdaloid expression of KLK8 and FKBP51, proteins that have been implicated in the development of anxiety and depression. Together, these results demonstrate that acute blockade of mTOR signaling by acute rapamycin administration not only causes changes in neuronal activity, but also leads to elevated protein expression in protein kinase pathways others than mTOR, contributing to the development of anxiety-like behavior. Given the pivotal role of the amygdala in mood regulation, associative learning, and modulation of cognitive functions, our findings raise the question whether therapy with rapamycin may induce alterations in patients neuropsychological functioning. (C) 2014 Elsevier B.V. All rights reserved.