PDF(Pubmed)
Abstract：
Lomerizine is a calcium channel blocker that crosses the blood-brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet.
To assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer\'s disease (AD) excitatory neurons differentiated from induced pluripotent stem cells (iPSCs), and in LPS-treated wild type mice.
In BV2 microglial cells, lomerizine pretreatment significantly reduced LPS-evoked proinflammatory cytokine and NLRP3 mRNA levels. Similarly, lomerizine pretreatment significantly suppressed the increases in Iba-1, GFAP, proinflammatory cytokine and NLRP3 expression induced by LPS in wild-type mice. In addition, lomerizine posttreatment significantly decreased LPS-stimulated proinflammatory cytokine and SOD2 mRNA levels in BV2 microglial cells and/or wild-type mice. In LPS-treated wild-type mice and AD excitatory neurons differentiated from iPSCs, lomerizine pretreatment ameliorated tau hyperphosphorylation. Finally, lomerizine abolished the LPS-mediated activation of GSK3α/β and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice.
These data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases.
To assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer\'s disease (AD) excitatory neurons differentiated from induced pluripotent stem cells (iPSCs), and in LPS-treated wild type mice.
In BV2 microglial cells, lomerizine pretreatment significantly reduced LPS-evoked proinflammatory cytokine and NLRP3 mRNA levels. Similarly, lomerizine pretreatment significantly suppressed the increases in Iba-1, GFAP, proinflammatory cytokine and NLRP3 expression induced by LPS in wild-type mice. In addition, lomerizine posttreatment significantly decreased LPS-stimulated proinflammatory cytokine and SOD2 mRNA levels in BV2 microglial cells and/or wild-type mice. In LPS-treated wild-type mice and AD excitatory neurons differentiated from iPSCs, lomerizine pretreatment ameliorated tau hyperphosphorylation. Finally, lomerizine abolished the LPS-mediated activation of GSK3α/β and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice.
These data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases.
摘要：
洛美利嗪是一种穿过血脑屏障的钙通道阻滞剂，临床上用于治疗偏头痛。然而,洛美利嗪是否对调节神经炎症反应有益尚未进行测试.
为了评估洛美利嗪用于治疗神经炎症的可能性，我们研究了洛美利嗪对LPS诱导的BV2小胶质细胞促炎反应的影响，从诱导多能干细胞（iPSCs）分化的阿尔茨海默病（AD）兴奋性神经元，和在LPS处理的野生型小鼠中。
在BV2小胶质细胞中，洛美利嗪预处理显著降低LPS诱发的促炎细胞因子和NLRP3mRNA水平。同样，洛美利嗪预处理显著抑制Iba-1，GFAP，LPS在野生型小鼠中诱导的促炎细胞因子和NLRP3表达。此外,洛美利嗪治疗后显着降低了BV2小胶质细胞和/或野生型小鼠中LPS刺激的促炎细胞因子和SOD2mRNA水平。在LPS处理的野生型小鼠和从iPSC分化的AD兴奋性神经元中，洛美利嗪预处理改善了tau蛋白过度磷酸化。最后,洛美利嗪消除了LPS介导的GSK3α/β活化和DYRK1A上调,负责tau过度磷酸化，在野生型小鼠中。
这些数据表明洛美利嗪可减弱LPS介导的神经炎症反应和tau蛋白过度磷酸化，是治疗神经炎症或tau蛋白病相关疾病的潜在药物。
为了评估洛美利嗪用于治疗神经炎症的可能性，我们研究了洛美利嗪对LPS诱导的BV2小胶质细胞促炎反应的影响，从诱导多能干细胞（iPSCs）分化的阿尔茨海默病（AD）兴奋性神经元，和在LPS处理的野生型小鼠中。
在BV2小胶质细胞中，洛美利嗪预处理显著降低LPS诱发的促炎细胞因子和NLRP3mRNA水平。同样，洛美利嗪预处理显著抑制Iba-1，GFAP，LPS在野生型小鼠中诱导的促炎细胞因子和NLRP3表达。此外,洛美利嗪治疗后显着降低了BV2小胶质细胞和/或野生型小鼠中LPS刺激的促炎细胞因子和SOD2mRNA水平。在LPS处理的野生型小鼠和从iPSC分化的AD兴奋性神经元中，洛美利嗪预处理改善了tau蛋白过度磷酸化。最后,洛美利嗪消除了LPS介导的GSK3α/β活化和DYRK1A上调,负责tau过度磷酸化，在野生型小鼠中。
这些数据表明洛美利嗪可减弱LPS介导的神经炎症反应和tau蛋白过度磷酸化，是治疗神经炎症或tau蛋白病相关疾病的潜在药物。
