Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China.
Biomed Pharmacother. 2023 Dec 31;169:115889. doi: 10.1016/j.biopha.2023.115889. Epub 2023 Nov 18.
Excessive manganese (Mn) exposure has been linked to neurotoxicity, cognitive impairments. Neurotrophic Receptor Kinase 1 (NTRK1) encodes Tropomyosin kinase A (TrkA), a neurotrophic receptor, as a mediator of neuron differentiation and survival. Insulin-like growth factor 2 (IGF2), a pivotal member of the insulin gene family, plays a crucial role in brain development and neuroprotection. Despite this knowledge, the precise mechanisms through which NTRK1 and IGF2 influence cell responses to Mn-induced neuronal damage remain elusive.
Cell apoptosis was assessed using CCK8, TUNEL staining, and Western blot analysis of cleaved Caspase-3. Lentiviral vectors facilitated NTRK1 overexpression, while small interfering RNAs (siRNAs) facilitated IGF2 knockdown. Real-time Quantitative PCR (qPCR) determined gene expression levels, while Western blotting measured protein expression.
The study reveals that NTRK1 inhibits MnCl2-induced apoptosis in SH-SY5Y cells. NTRK1 overexpression significantly upregulated IGF2 expression, and subsequent siRNA-IGF2 experiments confirmed IGF2's pivotal role in NTRK1-mediated neuroprotection. Notably, the study identifies that NTRK1 regulates the expression of IGF2 in the neuroprotective mechanism with the involvement of ER stress pathways.
The study reveals NTRK1's neuroprotective role via IGF2 against Mn-induced neurotoxicity and ER stress modulation in SH-SY5Y cells. These findings offer insights into potential therapies for neurodegenerative disorders related to Mn exposure and NTRK1 dysfunction, driving future research in this domain.
过量的锰（Mn）暴露与神经毒性和认知障碍有关。神经营养受体酪氨酸激酶 1（NTRK1）编码原肌球蛋白激酶 A（TrkA），作为神经元分化和存活的神经营养受体。胰岛素样生长因子 2（IGF2）是胰岛素基因家族的重要成员，在大脑发育和神经保护中起着至关重要的作用。尽管有这些知识，但 NTRK1 和 IGF2 影响细胞对 Mn 诱导的神经元损伤的反应的确切机制仍不清楚。
通过 CCK8、TUNEL 染色和 Western blot 分析裂解的 Caspase-3 评估细胞凋亡。慢病毒载体促进 NTRK1 的过表达，而小干扰 RNA（siRNA）促进 IGF2 的敲低。实时定量 PCR（qPCR）确定基因表达水平，而 Western blot 测量蛋白表达。
该研究表明 NTRK1 抑制 MnCl2 诱导的 SH-SY5Y 细胞凋亡。NTRK1 的过表达显著上调 IGF2 的表达，随后的 siRNA-IGF2 实验证实 IGF2 在 NTRK1 介导的神经保护中起着关键作用。值得注意的是，该研究确定 NTRK1 通过涉及内质网应激途径的 IGF2 调节神经保护机制中的 IGF2 表达。
该研究揭示了 NTRK1 通过 IGF2 对 Mn 诱导的神经毒性和 ER 应激调节的神经保护作用。这些发现为与 Mn 暴露和 NTRK1 功能障碍相关的神经退行性疾病的潜在治疗方法提供了思路，推动了该领域的未来研究。
