PDF(Pubmed)
Abstract：
BACKGROUND: Olfactory dysfunction occurs frequently in Parkinson\'s disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice.
METHODS: MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R-) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines.
RESULTS: Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R- HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis.
CONCLUSIONS: This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.
METHODS: MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R-) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines.
RESULTS: Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R- HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis.
CONCLUSIONS: This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.
摘要：
背景：嗅觉功能障碍在帕金森病（PD）中经常发生。在这项研究中,我们旨在探索尼古丁治疗1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的PD小鼠嗅觉功能障碍的潜在生物标志物和潜在分子途径.
方法：将MPTP引入C57BL/6雄性小鼠中以产生PD模型。关于体内实验，我们进行了行为学测试,以评估尼古丁对MPTP诱导的PD小鼠的保护作用.RNA测序和传统的分子方法被用来识别分子，通路,PD小鼠模型嗅球的生物学过程。然后，进行了体外实验以评估尼古丁是否可以激活HEK293T细胞系和用1-甲基-4-苯基吡啶鎓（MPP）处理的原代嗅觉神经元中的prok2R/Akt/FoxO3a信号通路。接下来,prok2R过表达（prok2R+）和敲低（prok2R-）引入慢病毒，并进一步探索Akt/FoxO3a信号通路。最后,在prok2R过表达（prok2R）HEK293T细胞系中评估MPP的损伤作用。
结果：尼古丁干预可显着减轻PD小鼠的嗅觉和运动功能障碍。尼古丁处理后prok2R/Akt/FoxO3a信号通路被激活。因此,嗅觉感觉神经元凋亡显著减少。此外，prok2R+和prok2R-HEK293T细胞系表现出Akt/FoxO3a信号通路的上调和下调，分别。此外,prok2R+HEK293T细胞对MPP+诱导的凋亡具有抗性。
结论：本研究显示了尼古丁在改善PD小鼠中的表达不足的有效性和潜在机制。这些改善与通过激活的prok2R/Akt/FoxO3a轴减少嗅觉感觉神经元的凋亡相关。这些结果解释了尼古丁在PD患者中的潜在保护功能。
方法：将MPTP引入C57BL/6雄性小鼠中以产生PD模型。关于体内实验，我们进行了行为学测试,以评估尼古丁对MPTP诱导的PD小鼠的保护作用.RNA测序和传统的分子方法被用来识别分子，通路,PD小鼠模型嗅球的生物学过程。然后，进行了体外实验以评估尼古丁是否可以激活HEK293T细胞系和用1-甲基-4-苯基吡啶鎓（MPP）处理的原代嗅觉神经元中的prok2R/Akt/FoxO3a信号通路。接下来,prok2R过表达（prok2R+）和敲低（prok2R-）引入慢病毒，并进一步探索Akt/FoxO3a信号通路。最后,在prok2R过表达（prok2R）HEK293T细胞系中评估MPP的损伤作用。
结果：尼古丁干预可显着减轻PD小鼠的嗅觉和运动功能障碍。尼古丁处理后prok2R/Akt/FoxO3a信号通路被激活。因此,嗅觉感觉神经元凋亡显著减少。此外，prok2R+和prok2R-HEK293T细胞系表现出Akt/FoxO3a信号通路的上调和下调，分别。此外,prok2R+HEK293T细胞对MPP+诱导的凋亡具有抗性。
结论：本研究显示了尼古丁在改善PD小鼠中的表达不足的有效性和潜在机制。这些改善与通过激活的prok2R/Akt/FoxO3a轴减少嗅觉感觉神经元的凋亡相关。这些结果解释了尼古丁在PD患者中的潜在保护功能。
