Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.

Martine Dubois,Fabrice Morin,Pascal Hilber,Youssef Anouar,Hélène Castel,Vadim Le Joncour,Florence Joly,François Proust,Marie-Christine Tonon,Pierrick Gandolfo

doi:10.1371/journal.pone.0113533

Abstract

Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue.

Highlights

The emergence of potent anticancer agents has improved patient survival, there is increasing evidence that both cancer and its treatments can induce cognitive dysfunctions that affect daily quality of life
The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling cascade is a key molecular target for cancer treatment [6]. mTOR signaling components are expressed at high levels in several areas of the brain [7, 8], and the mTOR pathway is known to be involved in various neurobiological processes, including neurite outgrowth [9], axon regeneration [10], myelination [11], and cellular metabolism [12]
We first evaluated the consequences of a chronic mTOR inhibition on body weight in mice

Summary

Introduction

The emergence of potent anticancer agents has improved patient survival, there is increasing evidence that both cancer and its treatments can induce cognitive dysfunctions that affect daily quality of life. In recent years, targeted agents have been increasingly used in cancer treatment, and previous reports suggest that some of them may permeate the blood-brain barrier and act directly in the brain, affecting cerebral angiogenesis and functioning [2]. Consistent with this hypothesis, administration of bevacizumab in patients with metastatic colorectal cancer and sunitinib in patients with metastatic renal cancer resulted in several reported cases of posterior leukoencephalopathy [3, 4]. It may be proposed that longterm administration of mTOR inhibitors occurring in cancer treatment could affect brain functions involved in cognition and/or metabolism

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