中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (4): 588-595.doi: 10.4103/1673-5374.205098

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

替勃龙调节老年雄性小鼠海马神经元可塑性：可能的作用途径

  

  • 收稿日期:2017-03-22 出版日期:2017-04-15 发布日期:2017-04-15
  • 基金资助:

    墨西哥FIS/IMSS项目

Tibolone modulates neuronal plasticity through regulating Tau, GSK3β/Akt/PI3K pathway and CDK5 p35/p25 complexes in the hippocampus of aged male mice

Teresa Neri-Gómez1, 2, Judith Espinosa-Raya2, Sofía Díaz-Cintra3, Julia Segura-Uribe4, Sandra Orozco-Suárez4, Juan Manuel Gallardo5, Christian Guerra-Araiza1   

  1. 1 Unidad de Investigación Médica en Farmacología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México; 2 Laboratorio de Farmacología Conductual, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón Col. Sto. Tomás, Ciudad de México, México; 3 Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México Campus Juriquilla, Querétaro, Querétaro, México; 4 Enfermedades Neurológicas (Neurological Diseases), Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México; 5 Enfermedades Nefrológicas (Kidney Diseases), Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, Mexico
  • Received:2017-03-22 Online:2017-04-15 Published:2017-04-15
  • Contact: Christian Guerra-Araiza,christianguerra2001@gmail.com.
  • Supported by:

    This study was supported by FIS/IMSS project No. FIS/IMSS/PROT/G13/1216, COFAA, SIP-IPN and by DGAPA-UNAM IN203616.

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摘要：

神经原纤维缠结是阿尔茨海默病患者大脑的特征性病理改变，是Tau蛋白发生过度磷酸化所致。性激素替代治疗可以减少神经元纤维缠结，但有致瘤的风险。合成激素替勃龙因副作用相对较小，已用于激素替代治疗，但替勃龙对老年男性脑中Tau蛋白及其信号级联活化的影响较少报道。实验旨在评估替勃龙灌胃12周对老年雄性小鼠海马中Tau及其磷酸化蛋白水平以及Tau蛋白磷酸化的调节激酶GSK3β和CDK5涉及的GSK3β/Akt/PI3K通路和CDK5/p35/p25复合物调节的长程作用。实验发现，替勃龙可以降低Tau蛋白过度磷酸化水平和Akt磷酸化形式，降低P110和p85的磷酸化水平，但对GSK3β 或PI3K活化形式无明显影响。替勃龙对影响神经元可塑性的细胞周期蛋白依赖性蛋白激酶CDK5水平的影响呈剂量依赖性：低剂量提高其表达，高剂量降低其表达。TIB 使CDK5激活剂p35水平升高，p25水平降低。这些现象说明，替勃龙可通过调节老年雄性小鼠海马中Tau蛋白及GSK3β/Akt/PI3K通路和CDK5/p35/p25复合物，起到调节神经元可塑性的作用。

ORCID:0000-0002-7164-4116(Christian Guerra-Araiza)

关键词: 替勃龙, 海马, 老年小鼠, 性激素, 雄激素, Tau, Akt, GSK3β, PI3K, 神经原纤维缠结

Abstract:

Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles (NFTs); these hormones can regulate Tau phosphorylation and the principal kinase GSK3β involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone (TIB) have been used for hormone replacement therapy. The aim of this work was to evaluate the long-term effects of TIB (0.01 mg/kg and 1 mg/kg, intragastrically for 12 weeks) on the content of total and hyperphosphorylated Tau (PHF-1) proteins and the regulation of GSK3β/Akt/PI3K pathway and CDK5/p35/p25 complexes in the hippocampus of aged male mice. We observed that the content of PHF-1 decreased with TIB administration. In contrast, no changes were observed in the active form of GSK3β or PI3K. TIB decreased the expression of the total and phosphorylated form of Akt while increased that of p110 and p85. The content of CDK5 was differentially modified with TIB: it was increased at low doses and decreased at high doses. When we analyzed the content of CDK5 activators, an increase was found on p35; however, the content of p25 decreased with administration of low dose of TIB. Our results suggest a possible mechanism of action of TIB in the hippocampus of aged male mice. Through the regulation of Tau and GSK3β/Akt/PI3K pathway, and CDK5/p35/p25 complexes, TIB may modulate neuronal plasticity and regulate learning and memory processes.

Key words: nerve regeneration, Tibolone, hippocampus, aged mice, sex steroids, Akt, GSK3β, PI3K, neural plasticity, Tau, neurofibrillary tangles, neural regeneration