Kusakabe Miduki, Hasegawa Yasushi
College of Environmental Technology, Muroran Institute of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan.
Iran J Basic Med Sci. 2021 Jan;24(1):51-57. doi: 10.22038/ijbms.2020.48567.11152.
Nimodipine is an L-type voltage-dependent calcium channel (VDCC) antagonist. However, the actions of nimodipine except calcium blocking are poorly understood. This study aimed to investigate the effect of nimodipine on neurite outgrowth and neuroprotection .
After PC12 cells were treated with different concentrations of nimodipine, neurite outgrowth was estimated using the ImageJ software. Neuroprotective effects of nimodipine against HO and calcium ionophore-induced neurotoxicity were investigated using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the activation of extracellular signal-regulated kinase (ERK) and cyclic AMP-response element-binding protein (CREB) pathway was investigated for clarifying the action mechanism of nimodipine.
Nimodipine treatment at doses of higher than 10 µM induced neurite outgrowth in the cells. Additionally, VDCC knockdown by siRNA significantly suppressed the nimodipine-induced neurite outgrowth in PC12 cells, suggesting that the drug promotes neurite outgrowth by binding to VDCC. HO and calcium ionophore induce oxidative and calcium stress in PC12 cells. Nimodipine exhibited neuroprotective effects against HO- and calcium ionophore-induced neurotoxicity by increasing the mRNA expression levels of neurotrophic factors, calcium-binding proteins, and antioxidants that are transcribed by CREB activation.
This is the first report that nimodipine induces neurite outgrowth and exerts its neuroprotective activity through the ERK/CREB signaling pathway in PC12 cells.
尼莫地平是一种L型电压依赖性钙通道（VDCC）拮抗剂。然而，除了钙阻断作用外，尼莫地平的其他作用尚不清楚。本研究旨在探讨尼莫地平对神经突生长和神经保护的作用。
用不同浓度的尼莫地平处理PC12细胞后，使用ImageJ软件评估神经突生长情况。采用噻唑蓝（MTT）法研究尼莫地平对血红素加氧酶（HO）和钙离子载体诱导的神经毒性的神经保护作用。此外，研究细胞外信号调节激酶（ERK）和环磷酸腺苷反应元件结合蛋白（CREB）通路的激活情况以阐明尼莫地平的作用机制。
高于10 μM剂量的尼莫地平处理可诱导细胞神经突生长。此外，小干扰RNA（siRNA）敲低VDCC可显著抑制PC12细胞中尼莫地平诱导的神经突生长，提示该药物通过与VDCC结合促进神经突生长。HO和钙离子载体可诱导PC12细胞产生氧化应激和钙应激。尼莫地平通过增加由CREB激活转录的神经营养因子、钙结合蛋白和抗氧化剂的mRNA表达水平，对HO和钙离子载体诱导的神经毒性表现出神经保护作用。
这是首次报道尼莫地平在PC12细胞中通过ERK/CREB信号通路诱导神经突生长并发挥其神经保护活性。
