Crespo-Biel Natalia, Camins Antoni, Pelegrí Carme, Vilaplana Jordi, Pallàs Mercè, Canudas Anna M
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.
Neurosci Lett. 2007 Jun 21;421(1):77-81. doi: 10.1016/j.neulet.2007.05.038. Epub 2007 May 26.
3-Nitropropionic acid (3-NP) is a neurotoxin that inhibits mitochondrial complex II and is used in an experimental model of Huntington's disease. Treatment of rats with 3-NP 30mgkg(-1) i.p. once a day for 5 days induced an increase in calpain activation in rat striatum, measured by the formation of 145kDa fragment of alpha-spectrin breakdown and by an increase in enzymatic calpain activity. In this neurotoxic model, Western blot studies revealed that calpain activity increase was followed by changes in cyclin-dependent kinase 5 (cdk5) and its activator p25. Our results indicated, after 10 days of treatment with 3-NP, a decrease in myocyte enhancer factor phosphorylation, a neuronal prosurvival factor. Thus, a decrease in its expression indicates a new potential mechanism of neuronal cell death mediated by the neurotoxin 3-NP. Accordingly, in our study we demonstrated in rat striatum the activation of the calpain/cdk5/p25 pathway in the 3-NP model. Previous studies have linked the deregulation of cdk5 with neurodegenerative diseases, such as Alzheimer's and Parkinson's. We suggest that calpain/cdk5 activation could also be a common pathway activated in other neurodegenerative diseases, which is liable to be targeted.
3-硝基丙酸（3-NP）是一种神经毒素，它能抑制线粒体复合物II，被用于亨廷顿病的实验模型。以30mg/kg体重腹腔注射3-NP，每天一次，连续5天处理大鼠，可导致大鼠纹状体中钙蛋白酶激活增加，这是通过α-血影蛋白分解产生145kDa片段以及钙蛋白酶酶活性增加来测定的。在这个神经毒性模型中，蛋白质免疫印迹研究显示，钙蛋白酶活性增加之后，细胞周期蛋白依赖性激酶5（cdk5）及其激活剂p25发生了变化。我们的结果表明，在用3-NP处理10天后，肌细胞增强因子磷酸化减少，肌细胞增强因子是一种神经元存活因子。因此，其表达减少表明由神经毒素3-NP介导的神经元细胞死亡有了一种新的潜在机制。相应地，在我们的研究中，我们在大鼠纹状体中证明了3-NP模型中钙蛋白酶/cdk5/p25途径的激活。先前的研究已将cdk5失调与神经退行性疾病（如阿尔茨海默病和帕金森病）联系起来。我们认为，钙蛋白酶/cdk5激活也可能是在其他神经退行性疾病中激活的一条常见途径，这条途径易于成为靶点。
