Department of Neurosurgery, the First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, 230022, Anhui, China.
Department of Anatomy, Anhui Medical University, Meishan Road 81, Hefei, 230032, China.
J Transl Med. 2024 Apr 12;22(1):350. doi: 10.1186/s12967-024-05171-1.
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.
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.
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.
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.
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。
将 MPTP 引入 C57BL/6 雄性小鼠中以生成 PD 模型。关于体内实验，我们进行了行为测试以评估尼古丁对 MPTP 诱导的 PD 小鼠的保护作用。使用 RNA 测序和传统分子方法鉴定 PD 小鼠模型嗅球中的分子、途径和生物过程。然后，在体外实验中，评估尼古丁是否可以激活用 1-甲基-4-苯基吡啶鎓（MPP）处理的 HEK293T 细胞系和原代嗅觉神经元中的 prok2R/Akt/FoxO3a 信号通路。接下来，用慢病毒引入 prok2R 过表达（prok2R）和敲低（prok2R），并进一步探索 Akt/FoxO3a 信号通路。最后，评估 MPP 在 prok2R 过表达（prok2R）HEK293T 细胞系中的损伤作用。
尼古丁干预可显著改善 PD 小鼠的嗅觉和运动功能障碍。尼古丁处理后激活了 prok2R/Akt/FoxO3a 信号通路。因此，嗅觉感觉神经元的凋亡明显减少。此外，prok2R 和 prok2R HEK293T 细胞系分别上调和下调 Akt/FoxO3a 信号通路。此外，prok2R HEK293T 细胞对 MPP 诱导的凋亡具有抗性。
本研究表明尼古丁在改善 PD 小鼠嗅觉障碍方面的有效性及其潜在机制。这些改善与通过激活 prok2R/Akt/FoxO3a 轴减少嗅觉感觉神经元凋亡有关。这些结果解释了尼古丁在 PD 患者中的潜在保护作用。
