Zonisamide suppresses endoplasmic reticulum stress-induced neuronal cell damage in vitro and in vivo.
Zonisamide suppresses endoplasmic reticulum stress-induced neuronal cell damage in vitro and in vivo.
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DOI：
10.1016/j.ejphar.2014.09.023
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发表时间：
2015-01
影响因子：
5
通讯作者：
Saori Tsujii;M. Ishisaka;M. Shimazawa;T. Hashizume;H. Hara
中科院分区：
文献类型：
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作者：
Saori Tsujii;M. Ishisaka;M. Shimazawa;T. Hashizume;H. Hara
据报道，唑尼沙胺对癫痫和帕金森病具有保护作用，并通过多种作用机制发挥作用，如抑制单胺氧化酶-B和增强酪氨酸羟化酶。最近，有人认为唑尼沙胺本身具有神经保护作用。因此，在本研究中，我们研究了唑尼沙胺对内质网（ER）应激的神经保护作用。我们使用人神经母细胞瘤（SH-SY 5 Y）细胞，并研究唑尼沙胺对衣霉素和毒胡萝卜素诱导的神经元细胞死亡的保护作用。此外，我们研究了唑尼沙胺对1-甲基-4-苯基吡啶鎓（MPP+）诱导的细胞死亡的影响以及对ER应激的保护机制。在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的帕金森病小鼠模型中。唑尼沙胺不仅能抑制MPP+诱导的细胞死亡，而且能抑制ER应激诱导的细胞死亡，并抑制ER应激相关因子如C/EBO同源蛋白（CHOP）的表达。唑尼沙胺抑制caspase-3的激活。这些结果表明，唑尼沙胺通过caspase-3影响ER应激。我们认为，内质网应激，特别是caspase-3的机制，参与了唑尼沙胺对帕金森病实验模型的神经保护作用。
Zonisamide has been reported to have protective effects on epilepsy and Parkinson׳s disease and to work via various mechanisms of action, such as inhibition of monoamine oxidase-B and enhancement of tyrosine hydroxylase. Recently, it has been suggested that zonisamide itself shows neuroprotective actions. Therefore, in the present study we investigated the neuroprotective effects of zonisamide against endoplasmic reticulum (ER) stress. We used human neuroblastoma (SH-SY5Y) cells and investigated the protective effects of zonisamide against tunicamycin- and thapsigargin-induced neuronal cell death. In addition, we investigated the effect of zonisamide against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and the mechanism of protection against ER stress.In vivo, we investigated the effect of zonisamide (20 mg/kg, p.o.) in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson׳s disease. Zonisamide not only suppressed MPP+-induced cell death, but also inhibited ER stress-induced cell death and suppressed the expression of ER stress-related factors such as C/EBO homologous protein (CHOP)in vivo. Furthermore, zonisamide inhibited the activation of caspase-3in vitro. These results suggest that zonisamide affected ER stressviacaspase-3. We think that ER stress, particularly the mechanismviacaspase-3, is involved in part of the neuroprotective effect of zonisamide against the experimental models of Parkinson׳s disease.