Russo Emilio, Leo Antonio, Crupi Rosalia, Aiello Rossana, Lippiello Pellegrino, Spiga Rosangela, Chimirri Serafina, Citraro Rita, Cuzzocrea Salvatore, Constanti Andrew, De Sarro Giovambattista
Science of Health Department, School of Medicine, University of Catanzaro, Italy.
Science of Health Department, School of Medicine, University of Catanzaro, Italy.
J Psychiatr Res. 2016 Jul;78:1-10. doi: 10.1016/j.jpsychires.2016.03.008. Epub 2016 Mar 19.
Everolimus (EVR) is an orally-administered rapamycin analog that selectively inhibits the mammalian target of rapamycin (mTOR) kinase (mainly mTORC1 and likely mTORC2) and the related signaling pathway. mTOR is a serine/threonine protein kinase regulating multiple important cellular functions; dysfunction of mTOR signaling has also been implicated in the pathophysiology of several neurological, neurodegenerative, developmental and cognitive disorders. EVR is widely used as an anti-neoplastic therapy and more recently in children with tuberous sclerosis complex (TSC). However, no clear correlation exists between EVR use and development of central side effects e.g. depression, anxiety or cognitive impairment. We studied the effects of a 3 weeks administration of EVR in mice chronically treated with betamethasone 21-phosphate disodium (BTM) as a model of depression and cognitive decline. EVR treatment had detrimental effects on depressive- and anxiety-like behavior while improving cognitive performance in both control (untreated) and BTM-treated mice. Such effects were accompanied by an increased hippocampal neurogenesis and synaptogenesis. Our results therefore might support the proposed pathological role of mTOR dysregulation in depressive disorders and confirm some previous data on the positive effects of mTOR inhibition in cognitive decline. We also show that EVR, possibly through mTOR inhibition, may be linked to the development of anxiety. The increased hippocampal neurogenesis by EVR might explain its ability to improve cognitive function or protect from cognitive decline. Our findings suggest some caution in the use of EVR, particularly in the developing brain; patients should be carefully monitored for their psychiatric/neurological profiles in any clinical situation where an mTOR inhibitor and in particular EVR is used e.g. cancer treatment, TSC or immunosuppression.
依维莫司（EVR）是一种口服的雷帕霉素类似物，可选择性抑制哺乳动物雷帕霉素靶蛋白（mTOR）激酶（主要是mTORC1，可能还有mTORC2）及相关信号通路。mTOR是一种丝氨酸/苏氨酸蛋白激酶，可调节多种重要的细胞功能；mTOR信号通路功能障碍也与多种神经、神经退行性、发育和认知障碍的病理生理学有关。EVR被广泛用作抗肿瘤疗法，最近也用于治疗结节性硬化症（TSC）患儿。然而，使用EVR与中枢副作用如抑郁、焦虑或认知障碍的发生之间没有明确的相关性。我们以长期接受21 - 磷酸二钠倍他米松（BTM）治疗的小鼠作为抑郁和认知衰退模型，研究了连续3周给予EVR的效果。EVR治疗对对照（未治疗）小鼠和BTM治疗小鼠的抑郁样和焦虑样行为均有不利影响，但改善了认知表现。这些作用伴随着海马神经发生和突触形成增加。因此，我们的结果可能支持mTOR失调在抑郁症中所提出的病理作用，并证实了先前关于mTOR抑制对认知衰退有积极作用的一些数据。我们还表明，EVR可能通过抑制mTOR与焦虑的发生有关。EVR引起的海马神经发生增加可能解释了其改善认知功能或预防认知衰退的能力。我们的研究结果提示在使用EVR时应谨慎，尤其是在发育中的大脑；在使用mTOR抑制剂特别是EVR的任何临床情况下，如癌症治疗、TSC或免疫抑制，都应仔细监测患者的精神/神经状况。
