Huehnchen P, Boehmerle W, Springer A, Freyer D, Endres M
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik und Hochschulambulanz für Neurologie, Berlin, Germany.
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Neurocure Cluster of Excellence, Berlin, Germany.
Transl Psychiatry. 2017 Aug 1;7(8):e1185. doi: 10.1038/tp.2017.149.
Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230 nm l, which was sevenfold higher compared with the neocortex. Histologic analysis revealed a reduced hippocampal cell proliferation. In vitro, we observed severe toxicity in slowly proliferating neural stem cells (NSC) as well as human neuronal progenitor cells after 2 h exposure to low nanomolar concentrations of PTX. In comparison, mature post-mitotic hippocampal neurons and cell lines of malignant cells were less vulnerable. In PTX-treated NSC, we observed an increase of intracellular calcium levels, as well as an increased activity of calpain- and caspase 3/7, suggesting a calcium-dependent mechanism. This cell death pathway could be specifically inhibited with lithium, but not glycogen synthase kinase 3 inhibitors, which protected NSC in vitro. In vivo, preemptive treatment of mice with lithium prevented PTX-induced memory deficits and abnormal adult hippocampal neurogenesis. In summary, we identified a molecular pathomechanism, which invokes PTX-induced cytotoxicity in NSC independent of cell cycle status. This pathway could be pharmacologically inhibited with lithium without impairing paclitaxel's tubulin-dependent cytostatic mode of action, enabling a potential translational clinical approach.
化疗引起的中枢神经系统（CNS）神经毒性是一个尚未满足的医学需求。患者经常报告在化疗的同时出现认知能力下降，特别是对于依赖海马体的语言和视觉空间能力。我们用12×20mg/kg的紫杉醇（PTX）治疗成年C57Bl/6小鼠，模拟剂量密集化疗的临床情况，随后注射溴脱氧尿苷（BrdU）脉冲以标记分裂细胞。在这个模型中，小鼠出现了视觉空间记忆障碍，我们测量到海马体中的PTX峰值浓度为230nM/L，这比新皮质高7倍。组织学分析显示海马体细胞增殖减少。在体外，我们观察到低纳摩尔浓度的PTX暴露2小时后，缓慢增殖的神经干细胞（NSC）以及人类神经元祖细胞出现严重毒性。相比之下，成熟的有丝分裂后海马神经元和恶性细胞系较不易受影响。在PTX处理的NSC中，我们观察到细胞内钙水平升高，以及钙蛋白酶和半胱天冬酶3/7的活性增加，提示存在钙依赖性机制。这种细胞死亡途径可以被锂特异性抑制，但糖原合酶激酶3抑制剂则不能，锂在体外保护了NSC。在体内，用锂对小鼠进行预防性治疗可预防PTX诱导的记忆缺陷和异常的成年海马神经发生。总之，我们确定了一种分子发病机制，该机制引发了PTX在NSC中诱导的细胞毒性，而与细胞周期状态无关。这条途径可以用锂进行药理学抑制，而不会损害紫杉醇依赖微管蛋白的细胞生长抑制作用模式，从而实现一种潜在的转化临床方法。
