Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, 45122, Essen, Germany; Department of Neurosurgery, Charité Universitätsmedizin, 10117, Berlin, Germany.
Institute of Neuropathology, University Hospital Essen, 45122, Essen, Germany.
Neuropharmacology. 2021 Feb 15;184:108424. doi: 10.1016/j.neuropharm.2020.108424. Epub 2020 Dec 5.
Psychiatric symptoms as seen in affective and anxiety disorders frequently appear during glioblastoma (GBM) treatment and disease progression, additionally deteriorate patient's daily life routine. These central comorbidities are difficult to recognize and the causes for these effects are unknown. Since overactivation of mechanistic target of rapamycin (mTOR)- signaling is one key driver in GBM growth, the present study aimed at examining in rats with experimentally induced GBM, neurobehavioral consequences during disease progression and therapy. Male Fisher 344 rats were implanted with syngeneic RG2 tumor cells in the right striatum and treated with the mTOR inhibitor rapamycin (3 mg/kg; once daily, for eight days) before behavioral performance, brain protein expression, and blood samples were analyzed. We could show that treatment with rapamycin diminished GBM tumor growth, confirming mTOR-signaling as one key driver for tumor growth. Importantly, in GBM animals' anxiety-like behavior was observed but only after treatment with rapamycin. These behavioral alterations were moreover accompanied by aberrant glucocorticoid receptor, phosphorylated p70 ribosomal S6 kinase alpha (p-p70s6k), and brain derived neurotrophic factor protein expression in the hippocampus and amygdala in the non-tumor-infiltrated hemisphere of the brain. Despite the beneficial effects on GBM tumor growth, our findings indicate that therapy with rapamycin impaired neurobehavioral functioning. This experimental approach has a high translational value. For one, it emphasizes aberrant mTOR functioning as a central feature mechanistically linking complex brain diseases and behavioral disturbances. For another, it highlights the importance of elaborating the cause of unwanted central effects of immunosuppressive and antiproliferative drugs used in transplantation medicine, immunotherapy, and oncology.
精神症状在情感障碍和焦虑障碍中很常见，常出现在胶质母细胞瘤（GBM）治疗和疾病进展期间，进一步恶化了患者的日常生活。这些中枢合并症很难识别，其发生原因尚不清楚。由于雷帕霉素靶蛋白（mTOR）信号的过度激活是 GBM 生长的一个关键驱动因素，本研究旨在检查实验诱导 GBM 的大鼠中，疾病进展和治疗过程中的神经行为后果。雄性 Fisher 344 大鼠右侧纹状体植入同源 RG2 肿瘤细胞，在行为表现、大脑蛋白表达和血液样本分析之前，用 mTOR 抑制剂雷帕霉素（3mg/kg；每天一次，连续 8 天）进行治疗。我们发现雷帕霉素治疗可减少 GBM 肿瘤生长，证实 mTOR 信号是肿瘤生长的一个关键驱动因素。重要的是，在 GBM 动物中观察到焦虑样行为，但仅在雷帕霉素治疗后观察到。这些行为改变还伴有异常的糖皮质激素受体、磷酸化核糖体 S6 激酶 alpha（p-p70s6k）和脑源性神经营养因子蛋白表达，在大脑未受肿瘤浸润的半球的海马体和杏仁核中。尽管雷帕霉素对 GBM 肿瘤生长有有益作用，但我们的研究结果表明，雷帕霉素治疗会损害神经行为功能。这种实验方法具有很高的转化价值。一方面，它强调了异常的 mTOR 功能是将复杂的脑部疾病和行为障碍在机制上联系起来的核心特征。另一方面，它强调了阐明免疫抑制和抗增殖药物在移植医学、免疫疗法和肿瘤学中用于中枢副作用的原因的重要性。
