Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis
Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis
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DOI：
10.1073/pnas.0404990102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Cadet, JL
中科院分区：
文献类型：
--
作者：
Jayanthi, S;Deng, XL;Cadet, JL
甲基苯丙胺 [METH（“速度”）] 是一种滥用的精神兴奋剂，可导致人类精神病、认知和精神运动障碍。这些体征和症状被认为与大脑基底神经节结构的功能障碍有关。为了确定这些临床表现的可能分子基础，我们首先使用 cDNA 微阵列技术来测量用诱导细胞凋亡剂量的药物治疗的大鼠纹状体中 METH 诱导的转录反应。注射冰毒导致转录因子 (TF) 的 Jun、Egr 和 Nur77 亚家族成员的表达增加，定量 PCR 证实了这一变化。由于与这些因子相关的途径涉及 Fas 配体 (FasL) 的上调，因此对 FasL mRNA 进行了定量并发现其增加。免疫组织化学研究还表明，METH 诱导表达脑啡肽的纹状体 GABA 能神经元中 FasL 蛋白表达增加。此外，METH 介导的钙调神经磷酸酶增加，以及活化 T 细胞核因子 (NFAT)c3 和 NFATc4 从细胞质到细胞核的穿梭，这些机制也已知参与 FasL 调节。此外，METH 还诱导含有 FasL 和 Fas 的神经元中 caspase-3 的裂解。最后，多巴胺 D1 受体拮抗剂 SCH23390 预处理减弱了 METH 诱导的 FasL-Fas 死亡途径的变化，这也减弱了 METH 诱导的细胞凋亡。这些观察结果表明，METH 引起一些神经退行性效应，部分是通过刺激 Fas 介导的细胞死亡途径，从而导致多个 TF 激活介导的 FasL 上调。
Methamphetamine [METH ("speed")] is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for these clinical manifestations, we first used cDNA microarray technology to measure METH-induced transcriptional responses in the striatum of rats treated with an apoptosis-inducing dose of the drug. METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR. Because pathways linked to these factors are involved in the up-regulation of Fas ligand (FasL), FasL mRNA was quantified and found to be increased. Immunohistochemical studies also revealed METH-induced increased FasL protein expression in striatal GABAergic neurons that express enkephalin. Moreover, there were METH-mediated increases in calcineurin, as well as shuttling of nuclear factor of activated T cells (NFAT)c3 and NFATc4 from the cytosol to the nucleus of METH-treated rats, mechanisms also known to be involved in FasL regulation. Furthermore, METH induced cleavage of caspase-3 in FasL- and Fas-containing neurons. Finally, the METH-induced changes in the FasL-Fas death pathway were attenuated by pretreatment with the dopamine D1 receptor antagonist, SCH23390, which also caused attenuation of METH-induced apoptosis. These observations indicate that METH causes some of its neurodegenerative effects, in part, via stimulation of the Fas-mediated cell death pathway consequent to FasL up-regulation mediated by activation of multiple TFs.