Campos-Esparza María Rosario, Sánchez-Gómez María Victoria, Matute Carlos
Departamento de Neurociencias, Facultad de Medicina y Odontología. Universidad del País Vasco, and CIBERNED, Leioa, Spain.
Cell Calcium. 2009 Apr;45(4):358-68. doi: 10.1016/j.ceca.2008.12.007. Epub 2009 Feb 7.
Excessive activation of glutamate receptors, or excitotoxicity, contributes to acute and chronic neurological disorders including stroke. We previously showed that two natural polyphenol antioxidants, mangiferin and morin, are neuroprotective in a model of ischemic brain damage. In this study, we analyzed the molecular mechanisms underlying neuroprotection by mangiferin and morin in an in vitro model of excitotoxic neuronal death involving NMDA receptor overactivation. We observed that both polyphenols reduce the formation of reactive oxygen species, activate the enzymatic antioxidant system, and restore the mitochondrial membrane potential. Moreover, both antioxidants inhibit glutamate-induced activation of calpains, normalize the levels of phosphorylated Akt kinase and Erk1/2, as well as of cytosolic Bax, inhibit AIF release from mitochondria, and regulate the nuclear translocation of NF-kappaB. Each of these effects contributes to the substantial reduction of apoptotic neuronal death induced by glutamate. These results demonstrate that mangiferin and morin exhibit excellent antioxidant and antiapoptotic properties, supporting their clinical application as trial neuroprotectors in pathologies involving excitotoxic neuronal death.
谷氨酸受体的过度激活，即兴奋性毒性，会导致包括中风在内的急慢性神经疾病。我们之前表明，两种天然多酚抗氧化剂，芒果苷和桑色素，在缺血性脑损伤模型中具有神经保护作用。在本研究中，我们分析了在涉及NMDA受体过度激活的兴奋性毒性神经元死亡体外模型中，芒果苷和桑色素神经保护作用的分子机制。我们观察到，这两种多酚都能减少活性氧的形成，激活酶抗氧化系统，并恢复线粒体膜电位。此外，这两种抗氧化剂均能抑制谷氨酸诱导的钙蛋白酶激活，使磷酸化Akt激酶、Erk1/2以及细胞溶质Bax的水平正常化，抑制线粒体释放AIF，并调节NF-κB的核转位。这些作用中的每一种都有助于显著减少谷氨酸诱导的凋亡性神经元死亡。这些结果表明，芒果苷和桑色素具有出色的抗氧化和抗凋亡特性，支持它们作为试验性神经保护剂在涉及兴奋性毒性神经元死亡的病症中的临床应用。
