Methamphetamine Exerts Toxic Effects on Subventricular Zone Stem/Progenitor Cells and Inhibits Neuronal Differentiation
Methamphetamine Exerts Toxic Effects on Subventricular Zone Stem/Progenitor Cells and Inhibits Neuronal Differentiation
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DOI：
10.1089/rej.2010.1109
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发表时间：
2011-04-01
影响因子：
2.6
通讯作者：
Agasse, Fabienne
中科院分区：
文献类型：
--
作者：
Bento, Ana Rita;Baptista, Sofia;Agasse, Fabienne
甲基苯丙胺（冰毒）是一种广泛使用的强效精神兴奋剂，可导致大脑功能和结构异常。然而，关于甲基苯丙胺对成人神经源性壁龛的影响的信息很少，事实上，对其对室下区（SVZ）的影响一无所知。因此，本研究旨在阐明甲基安非他明对SVZ干细胞/祖细胞动力学和神经发生的影响。为此，从早期产后小鼠中获得SVZ神经球，并用浓度增加的甲基安非他明（1 μ M至500 μ M）处理。通过碘化丙啶摄取、末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色和促凋亡caspase-3活性的定量评估，暴露于100、250或500 μ M甲基甲基苯丙胺24小时可触发细胞坏死和凋亡。此外，我们发现甲基安非他明通过降低BrdU掺入抑制SVZ祖细胞的增殖。有趣的是,在无毒浓度(1和10μM),冰毒减少神经元分化和成熟,由量化评估的神经元数量nuclei-positive phospho-c-Jun-NH2-terminal激酶信号的神经元和测量轴突增长,分别。总之，我们的数据表明，甲基安非他明对SVZ干细胞/祖细胞有负面影响，诱导细胞死亡并抑制神经发生，这些影响可能会挑战内源性脑干/祖细胞群体所表现出的细胞替代能力。
Methamphetamine (METH) is a potent and widely consumed psychostimulant drug that causes brain functional and structural abnormalities. However, there is little information regarding METH impact on adult neurogenic niches and, indeed, nothing is known about its consequences on the subventricular zone (SVZ). Thus, this work aims to clarify the effect of METH on SVZ stem/progenitor cells dynamics and neurogenesis. For that purpose, SVZ neurospheres were obtained from early postnatal mice and treated with increasing concentrations of METH (1 mu M to 500 mu M). Exposure to 100, 250, or 500 mu M METH for 24 h triggered cell death both by necrosis and apoptosis, as assessed by propidium iodide uptake, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and quantification of the proapoptotic caspase-3 activity. Furthermore, we showed that METH inhibited SVZ progenitor cells proliferation as it decreased BrdU incorporation. Interestingly, at non-toxic concentrations (1 and 10 mu M), METH decreased neuronal differentiation and maturation, which were evaluated by quantification of the number of neuronal nuclei-positive neurons and measurements of phospho-c-Jun-NH2-terminal kinase signal in growing axons, respectively. Altogether, our data demonstrate that METH has a negative impact on SVZ stem/progenitor cells, inducing cell death and inhibiting neurogenesis, effects that in vivo may challenge the cell replacement capacities displayed by endogenous populations of brain stem/progenitor cells.