Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4
Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4
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DOI：
10.1016/j.bcp.2018.10.008
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发表时间：
2019-04-01
影响因子：
5.8
通讯作者：
Homma，Yoshimi
中科院分区：
文献类型：
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作者：
Ogura，Masato;Kikuchi，Haruhisa;Homma，Yoshimi
神经保护剂的开发是治疗神经退行性疾病的必要条件。在这里，我们报道了PQA-11，一种戊基化喹啉羧酸（PQA）衍生物，作为一种有效的神经保护剂。PQA-11抑制海马培养中谷氨酸诱导的细胞死亡和caspase-3激活，以及抑制n -甲基-4-苯基碘化吡啶和淀粉样蛋白β1-42诱导的SH-SY5Y细胞死亡。PQA-11还抑制由这些神经毒素激活的丝裂原活化蛋白激酶激酶4 （MKK4）和c-jun n-末端激酶（JNK）信号。石英晶体微天平分析和蛋白激酶实验显示PQA-11与MKK4相互作用，抑制鞘氨醇诱导的MKK4活化。腹腔注射PQA-11可减轻1-甲基-4-苯基-1,2,3,6-四氢吡啶所致小鼠黑质纹状体多巴胺能神经元变性。这些结果表明PQA-11是一种独特的MKK4抑制剂，在体外和体内具有有效的神经保护作用。PQA-11可能是开发新型神经保护剂的重要线索。
The development of neuroprotective agents is necessary for the treatment of neurodegenerative diseases. Here, we report PQA-11, a prenylated quinolinecarboxylic acid (PQA) derivative, as a potent neuroprotectant. PQA-11 inhibits glutamate-induced cell death and caspase-3 activation in hippocampal cultures, as well as inhibits N-Methyl-4-phenylpyridinium iodide- and amyloid β1-42-induced cell death in SH-SY5Y cells. PQA-11 also suppresses mitogen-activated protein kinase kinase 4 (MKK4) and c-jun N-terminal kinase (JNK) signaling activated by these neurotoxins. Quartz crystal microbalance analysis andin vitrokinase assay reveal that PQA-11 interacts with MKK4, and inhibits its sphingosine-induced activation. The administration of PQA-11 by intraperitoneal injection alleviates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopaminergic neurons in mice. These results suggest that PQA-11 is a unique MKK4 inhibitor with potent neuroprotective effectsin vitroandin vivo. PQA-11 may be a valuable lead for the development of novel neuroprotectants.