Meng Chen, Lu Yang, Huang Yan, Lü Xiaoying
State Key Laboratory of Digital Medical Engineering, Southeast University, Nanjing 210096, China.
Int J Mol Sci. 2025 Apr 24;26(9):4014. doi: 10.3390/ijms26094014.
The cytotoxic effects of Ni released from nickel-based alloy implants on tissues have been a longstanding research focus in biocompatibility studies. However, investigations into the neurotoxicity of Ni remain relatively limited. Building on our previous findings that Ni can rapidly affect the excitability of neuronal networks, this study further investigated the neurotoxic effects of prolonged Ni exposure. First, the cytotoxicity effects of Ni on rat neocortical neurons in vitro were evaluated by MTT cell viability assay, and changes in the length of the axon initial segment of neurons caused by Ni exposure were quantified. Next, transcriptome sequencing was employed to identify differentially expressed genes (DEGs) induced by Ni treatment, and four DEGs-, , , and -were selected for qRT-PCR validation. The ATP content of neurons was measured to assess cellular energy metabolism under Ni influence. Finally, by comparing these experimental results with our previous findings, this study explored the neurotoxicity mechanisms of Ni and analyzed the correlation between its neurotoxicity and cytotoxicity. This study revealed that the neurotoxicity mechanisms of Ni are associated with the concentration of Ni and the duration of its action. When at low concentrations or with short exposure times, Ni suppresses the excitability of the neuronal networks by rapidly blocking Ca channels, whereas at high concentrations or with prolonged exposure, it further inhibits the network's excitability by activating the HIF-1α pathway and inducing obvious cytotoxicity.
镍基合金植入物释放的镍对组织的细胞毒性作用一直是生物相容性研究中的长期研究重点。然而，关于镍的神经毒性的研究仍然相对有限。基于我们之前的发现，即镍可迅速影响神经元网络的兴奋性，本研究进一步调查了长期暴露于镍的神经毒性作用。首先，通过MTT细胞活力测定评估镍对体外培养的大鼠新皮质神经元的细胞毒性作用，并对镍暴露引起的神经元轴突起始段长度变化进行定量分析。接下来，采用转录组测序来鉴定镍处理诱导的差异表达基因（DEGs），并选择四个DEGs——、、和——进行qRT-PCR验证。测量神经元的ATP含量以评估镍影响下的细胞能量代谢。最后，通过将这些实验结果与我们之前的发现进行比较，本研究探索了镍的神经毒性机制，并分析了其神经毒性与细胞毒性之间的相关性。本研究表明，镍的神经毒性机制与镍的浓度及其作用持续时间有关。当处于低浓度或短暴露时间时，镍通过快速阻断钙通道来抑制神经元网络的兴奋性，而在高浓度或长时间暴露时，它通过激活HIF-1α途径并诱导明显的细胞毒性来进一步抑制网络的兴奋性。
