Investigation of the Neurotoxicity Mechanisms of Ni(2+) in Rat Neocortical Neurons Through Transcriptome Analysis.

The cytotoxic effects of Ni(2+) released from nickel-based alloy implants on tissues have been a longstanding research focus in biocompatibility studies. However, investigations into the neurotoxicity of Ni(2+) remain relatively limited. Building on our previous findings that Ni(2+) can rapidly affect the excitability of neuronal networks, this study further investigated the neurotoxic effects of prolonged Ni(2+) exposure. First, the cytotoxicity effects of Ni(2+) 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(2+) exposure were quantified. Next, transcriptome sequencing was employed to identify differentially expressed genes (DEGs) induced by Ni(2+) treatment, and four DEGs-Hk2, Ldha, Cd9, and Nfasc-were selected for qRT-PCR validation. The ATP content of neurons was measured to assess cellular energy metabolism under Ni(2+) influence. Finally, by comparing these experimental results with our previous findings, this study explored the neurotoxicity mechanisms of Ni(2+) and analyzed the correlation between its neurotoxicity and cytotoxicity. This study revealed that the neurotoxicity mechanisms of Ni(2+) are associated with the concentration of Ni(2+) and the duration of its action. When at low concentrations or with short exposure times, Ni(2+) suppresses the excitability of the neuronal networks by rapidly blocking Ca(2+) 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.