Pesti István, Varga Valentin, Qorri Erda, Frank Rita, Kata Diana, Vinga Krisztián, Szarvas Péter Archibald, Menyhárt Ákos, Gulya Károly, Bari Ferenc, Farkas Eszter
Hungarian Centre of Excellence for Molecular Medicine - University of Szeged, Cerebral Blood Flow and Metabolism Research Group, Szeged, Hungary.
Department of Cell Biology and Molecular Medicine, Albert Szent-Györgyi Medical School and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
Br J Pharmacol. 2025 Aug;182(16):3800-3817. doi: 10.1111/bph.70060. Epub 2025 Apr 21.
Nimodipine, an L-type voltage-gated calcium channel blocker, is an approved cerebral vasorelaxant. We hypothesized that nimodipine attenuates the pro-inflammatory shift in microglial phenotypes. Here, we analysed the effects of nimodipine on morphological and functional microglial phenotypes as well as their transcriptomic profile.
Live brain slice preparations from C57BL/6 mice and primary microglia cultures from neonatal Sprague Dawley rats were used. Microglia were activated either by ischemia or lipopolysaccharide (LPS), and preparations were treated with nimodipine (5-10-20 μM). Microglial morphological phenotypes, phagocytic activity, Iba1 expression and TNF-α levels were evaluated. Total RNA was isolated from monocultures and processed for next generation RNA sequencing.
LPS resulted in a pro-inflammatory microglial phenotype, affecting the expression of cytokines, the complement system and phagocytosis-related genes. LPS increased the transcription of ionotropic purinergic and TRP channels but decreased the expression of voltage- and ligand-gated calcium channels, down-regulated the expression of Ryr and IP receptors and increased transcription of the SERCA calcium pump. Nimodipine suppressed the amoeboid morphological transformation and phagocytosis and altered the expression of 110 genes in the opposite direction to LPS activation, of which at least 20 were associated with the microglial immune response, seven with cell adhesion and two with autophagy regulation.
The effect of nimodipine goes beyond cerebral vasorelaxation. Nimodipine attenuates microglial activation by modulating Ca-dependent gene expression involved in intracellular signalling cascades to drive microglial immune responses. Consideration should be given to expanding the use of nimodipine beyond vasorelaxation.
尼莫地平是一种L型电压门控钙通道阻滞剂，是一种已获批准的脑血管舒张剂。我们假设尼莫地平可减轻小胶质细胞表型的促炎转变。在此，我们分析了尼莫地平对小胶质细胞形态和功能表型及其转录组谱的影响。
使用来自C57BL/6小鼠的活脑切片制剂和来自新生Sprague Dawley大鼠的原代小胶质细胞培养物。小胶质细胞通过缺血或脂多糖（LPS）激活，制剂用尼莫地平（5 - 10 - 20 μM）处理。评估小胶质细胞形态表型、吞噬活性、Iba1表达和TNF-α水平。从单培养物中分离总RNA并进行下一代RNA测序。
LPS导致促炎性小胶质细胞表型，影响细胞因子、补体系统和吞噬相关基因的表达。LPS增加了离子型嘌呤能和TRP通道的转录，但降低了电压门控和配体门控钙通道的表达，下调了Ryr和IP受体的表达，并增加了SERCA钙泵的转录。尼莫地平抑制了阿米巴样形态转变和吞噬作用，并在与LPS激活相反的方向上改变了110个基因的表达，其中至少20个与小胶质细胞免疫反应相关，7个与细胞粘附相关，2个与自噬调节相关。
尼莫地平的作用超出了脑血管舒张。尼莫地平通过调节参与细胞内信号级联以驱动小胶质细胞免疫反应的钙依赖性基因表达来减轻小胶质细胞激活。应考虑扩大尼莫地平在血管舒张以外的用途。
