Tabatabaei Mirakabad Fatemeh Sadat, Khoramgah Maryam Sadat, Abdollahifar Mohammad-Amin, Tehrani Atefeh Shirazi, Rezaei-Tavirani Mostafa, Niknazar Somayeh, Tahmasebinia Foozhan, Mahmoudiasl Gholam-Reza, Khoshsirat Shahrokh, Abbaszadeh Hojjat Allah
Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
J Chem Neuroanat. 2021 Jul;114:101942. doi: 10.1016/j.jchemneu.2021.101942. Epub 2021 Mar 3.
Methamphetamine (Meth) is a neuro-stimulator substrate which might lead to neural cell death and the activation of several interconnected cellular pathways as well. However, the precise molecular mechanisms underlying Meth-induced neural cell death remained unclear yet. The current study aimed to assess the specific relationship between long-term Meth exposure and several endoplasmic reticulum stress, autophagy, and apoptosis associated markers including C/EBP homologous protein (CHOP), Tribbles homolog 3(Trib3), Nuclear protein 1(NUPR1), and Beclin-1 expression in postmortem human striatum. Therefore, the effects of long-term Meth exposure on autophagy and apoptosis in the striatum of postmortem users were evaluated and molecular, immunehistochemical, and histological examinations were performed on 10 control and 10 Meth-addicted brains. The level of CHOP, Trib3, NUPR1, and Beclin-1, Microtubule-associated proteins 1A/1B light chain 3B(LC3), Caspase 3, and Autophagy protein 5 (ATG5) were measured by using qPCR and immunohistochemistry. Stereological neural cell counting, Hematoxylin and Eosin, Nissl and Tunel staining were also performed. Based on our findings, the expression level of CHOP, Trib3, NUPR1, and Beclin-1 in the striatum of Meth group were significantly higher than the control group. Besides, the neuronal cell death was substantially increased in the striatum based on data obtained from the Tunel assay and the stereological analysis. Long-term presence of Meth in the brain can induce ER stress and overexpression of NUPR1 which is associated with the upregulation of CHOP, a pro-apoptotic transcription factor. Moreover, an increase in Trib3 expression is implicated in CHOP-dependent autophagic cell death during Meth-induced ER stress accompanied by an increase in neuronal cell death in the striatum of the postmortem human brains. Beclin 1 expression was also upregulated which may due to the activation of autophagic mechanisms upon prolonged Meth exposure.
甲基苯丙胺（冰毒）是一种神经刺激物底物，可能导致神经细胞死亡，并激活多个相互关联的细胞通路。然而，冰毒诱导神经细胞死亡的精确分子机制仍不清楚。当前研究旨在评估长期接触冰毒与几种内质网应激、自噬和凋亡相关标志物之间的特定关系，这些标志物包括C/EBP同源蛋白（CHOP）、 Tribbles同源物3（Trib3）、核蛋白1（NUPR1）以及死后人类纹状体中Beclin-1的表达。因此，评估了长期接触冰毒对死后使用者纹状体自噬和凋亡的影响，并对10个对照大脑和10个冰毒成瘾大脑进行了分子、免疫组织化学和组织学检查。通过qPCR和免疫组织化学检测CHOP、Trib3、NUPR1、Beclin-1、微管相关蛋白1A/1B轻链3B（LC3）、半胱天冬酶3和自噬蛋白5（ATG5）的水平。还进行了体视学神经细胞计数、苏木精和伊红染色、尼氏染色和Tunel染色。基于我们的研究结果，冰毒组纹状体中CHOP、Trib3、NUPR1和Beclin-1的表达水平显著高于对照组。此外，根据Tunel检测和体视学分析获得的数据，纹状体中的神经元细胞死亡显著增加。大脑中冰毒的长期存在可诱导内质网应激和NUPR1的过度表达，这与促凋亡转录因子CHOP的上调有关。此外，Trib3表达的增加与冰毒诱导的内质网应激期间CHOP依赖的自噬性细胞死亡有关，同时伴有死后人类大脑纹状体中神经元细胞死亡的增加。Beclin 1表达也上调，这可能是由于长期接触冰毒后自噬机制的激活。
