Unitat de Farmacologia i Farmacognòsia i Institut de Biomedicina (IBUB) i Centro de Investigación de Biomedicina en Red de Enfermedades Neurodegenerativas (CIBERNED), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
Bipolar Disord. 2010 Jun;12(4):425-36. doi: 10.1111/j.1399-5618.2010.00825.x.
We investigated the neuroprotective effects of lithium in an experimental neurodegeneration model gated to kainate (KA) receptor activation.
The hippocampus from KA-treated mice and hippocampal cell cultures were used to evaluate the pathways regulated by chronic lithium pretreatment in both in vivo and in vitro models.
Treatment with KA, as measured by fragmentation of alpha-spectrin and biochemically, induced the activation of calpain resulting in p35 cleavage to p25, indicating activation of cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3ss (GSK-3ss) and an increase in tau protein phosphorylation. Treatment with lithium reduced calpain activation and reduced the effects of cdk5 and GSK-3ss on tau. KA treatment of cultures resulted in neuronal demise. According to nuclear condensed cell counts, the addition of lithium to neuronal cell cultures (0.5-1 mM) a few days before KA treatment had neuroprotective and also antiapoptotic effects. The action of lithium on calpain/cdk5 and GSK-3ss pathways produced similar results in vivo. As calpain is activated by an increase in intracellular calcium, we showed that lithium reduced calcium concentrations in basal and KA-treated hippocampal cells, which was accompanied by an increase in NCX3, a Na+/Ca2+ exchanger pump.
A robust neuroprotective effect of lithium in the excitotoxic process induced by KA in mouse hippocampus was demonstrated via modulation of calcium entry and the subsequent inhibition of the calpain pathway. These mechanisms may act in an additive way with other mechanisms previously described for lithium, suggesting that it may be useful as a possible therapeutic strategy for Alzheimer's disease.
我们研究了锂在门控到激肽（KA）受体激活的实验性神经退行性变模型中的神经保护作用。
使用 KA 处理的小鼠海马体和海马细胞培养物来评估慢性锂预处理调节的途径，以评估体内和体外模型。
KA 处理，如α- spectrin 的片段化和生物化学测量所示，诱导钙蛋白酶的激活导致 p35 切割为 p25，表明 cyclin 依赖性激酶 5（cdk5）和糖原合成酶激酶 3ss（GSK-3ss）的激活和tau 蛋白磷酸化增加。锂处理可降低钙蛋白酶的激活，并降低 cdk5 和 GSK-3ss 对 tau 的影响。KA 处理培养物导致神经元死亡。根据核浓缩细胞计数，在 KA 处理前几天向神经元细胞培养物（0.5-1 mM）中添加锂具有神经保护和抗凋亡作用。锂对 calpain/cdk5 和 GSK-3ss 途径的作用在体内产生了相似的结果。由于钙蛋白酶通过细胞内钙的增加而激活，我们表明锂降低了基础和 KA 处理的海马细胞中的钙浓度，这伴随着 NCX3 的增加，即 Na+/Ca2+交换泵。
通过调节钙内流和随后抑制钙蛋白酶途径，在小鼠海马体中由 KA 诱导的兴奋性毒性过程中证明了锂的强大神经保护作用。这些机制可能与锂以前描述的其他机制以附加的方式起作用，表明它可能作为阿尔茨海默病的一种潜在治疗策略是有用的。
