Facchinetti Fabrizio, Fasolato Cristina, Del Giudice Elda, Burgo Andrea, Furegato Sara, Fusco Mariella, Basso Elisa, Seraglia Roberta, D'Arrigo Antonello, Leon Alberta
Research and Innovation (R&I) Company, Padova, Italy.
Neurobiol Aging. 2006 Feb;27(2):218-27. doi: 10.1016/j.neurobiolaging.2005.02.006.
Several lines of evidence indicate that perturbed cellular Ca2+ homeostasis may play a prominent role in synaptic dysfunction and neuronal death in Alzheimer's disease (AD), suggesting a potential benefit of drugs capable to stabilize Ca2+ homeostasis. We here investigated the effects of a panel of L-type Ca2+ channel antagonists on the secretion of the amyloid beta-peptide (Abeta), which abnormally accumulates in the senile plaques of the brain of AD patients. We found that, in primary and immortalized neuronal cells in culture, nimodipine robustly stimulated secretion (up to about four-fold at 30 microM) of the highly amyloidogenic 42-residue isoform of Abeta (Abeta42), while leaving largely unaffected total Abeta secretion. An analogous effect was also observed in vivo, as the administration of a single dose of nimodipine (10 mg/kg i.p.) induced a significant rise of Abeta42 levels in plasma of Tg2576 mice. The effect of nimodipine was independent of blockage of L-type Ca2+ channels and capacitative calcium entry. Accordingly, nimodipine effect was largely Ca2+-independent, as neither depletion nor rise of extracellular Ca2+ abolished it. Hence, by showing that the effect of nimodipine on Abeta42 production is distinct from its ability to block Ca2+-influx pathways, we provide evidence for a previously uncharacterized effect of this long known molecule also used in clinical practice.
多项证据表明，细胞钙稳态紊乱可能在阿尔茨海默病（AD）的突触功能障碍和神经元死亡中起重要作用，这表明能够稳定钙稳态的药物可能具有潜在益处。我们在此研究了一组L型钙通道拮抗剂对淀粉样β肽（Aβ）分泌的影响，Aβ在AD患者大脑的老年斑中异常积累。我们发现，在培养的原代和永生化神经元细胞中，尼莫地平强烈刺激了具有高度淀粉样生成性的42个残基的Aβ异构体（Aβ42）的分泌（在30微摩尔时高达约四倍），而对总Aβ分泌基本没有影响。在体内也观察到了类似的效果，因为单次注射尼莫地平（10毫克/千克腹腔注射）导致Tg2576小鼠血浆中Aβ42水平显著升高。尼莫地平的作用与L型钙通道的阻断和容量性钙内流无关。因此，尼莫地平的作用在很大程度上不依赖于钙，因为细胞外钙的耗尽或升高都没有消除它。因此，通过表明尼莫地平对Aβ42产生的作用与其阻断钙内流途径的能力不同，我们为这种临床实践中也使用的广为人知的分子的一种先前未被描述的作用提供了证据。
