Oxicam structure in non-steroidal anti-inflammatory drugs is essential to exhibit Akt-mediated neuroprotection against 1-methyl-4- phenyl, pyridinium-induced cytotoxicity.
Oxicam structure in non-steroidal anti-inflammatory drugs is essential to exhibit Akt-mediated neuroprotection against 1-methyl-4- phenyl, pyridinium-induced cytotoxicity.
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非甾体类抗炎药中的奥昔康结构对于展示 Akt 介导的针对 1-甲基-4-苯基、吡啶鎓诱导的细胞毒性的神经保护作用至关重要。
DOI：
10.1016/j.ejphar.2011.11.046
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Matsubara K.
中科院分区：
文献类型：
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作者：
Tasaki Y;Yamamoto J;Omura T;Noda T;Kamiyama N;Yoshida K;Satomi M;Sakaguchi T;Asari M;Ohkubo T;Shimizu K;Matsubara K.
在帕金森病的治疗中，仍然需要有效的疾病调节药物来阻止进行性多巴胺能神经变性。我们之前已经证明，美洛昔康，一种奥昔康非甾体抗炎药（NSAID），对1-甲基-4-苯基吡啶（MPP+）诱导的人多巴胺能SH-SY5Y神经母细胞瘤细胞的毒性具有有效的神经保护作用。美洛昔康的这种不依赖环加氧酶的神经保护作用是通过磷脂酰肌醇3-激酶(PI3K)/Akt通路介导的；然而，诱导神经保护的具体化学结构仍未得到解决。因此，在本研究中，我们通过检测一系列非甾体抗炎药对SH-SY5Y细胞的MPP+毒性，研究了结构特异性的神经保护作用。三种含奥昔康的非甾体抗炎药显示出有效的神经保护作用，尽管其他10种不含奥昔康的非甾体抗炎药（3种水杨酸类、6种考昔布斯类和1种多酚类）或3种吡罗西康类似物（包括吡罗西康，吡罗西康的前体）都没有任何神经保护作用。替诺昔康和吡罗西康可阻止MPP+诱导的细胞中磷酸化Akt水平的降低，其保护机制与美洛昔康相似。因此，奥昔康结构可能通过维持多巴胺能细胞的生存信号传导来表现出神经保护作用。目前的结果提出了一种可能性，即含奥昔康的非甾体抗炎药可能通过一种新机制作为潜在的治疗药物来延缓或终止帕金森病的进展。
In the treatment of Parkinson's disease, potent disease-modifying drugs are still needed to halt progressive dopaminergic neurodegeneration. We have previously shown that meloxicam, an oxicam non-steroidal anti-inflammatory drug (NSAID), elicits a potent neuroprotective effect against 1-methyl-4-phenyl pyridinium (MPP+)-induced toxicity in human dopaminergic SH-SY5Y neuroblastoma cells. This cyclooxygenase-independent neuroprotection of meloxicam is mediated via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; however, the specific chemical structure involved in inducing neuroprotection remains unresolved. In this study, we therefore investigated the structure-specific for eliciting the neuroprotective effect by examining a series of NSAIDs against MPP+toxicity in SH-SY5Y cells. Three oxicam-bearing NSAIDs showed potent neuroprotective effects, although none of the other 10 oxicam-nonbearing NSAIDs (3 salicylates, 6 coxibs and 1 polyphenol) or 3 piroxicam analogs (including ampiroxicam, a precursor of piroxicam) exerted any neuroprotection. Tenoxicam and piroxicam prevented MPP+-induced reduction of phosphorylated Akt levels in cells: a protective mechanism similar to that of meloxicam. Therefore, the oxicam structure was likely to be responsible for exhibiting the neuroprotection by sustaining survival-signaling in dopaminergic cells. The present results raise the possibility that the oxicam-bearing NSAIDs may serve as potential therapeutic drugs to retard or terminate progression of Parkinson's disease via a novel mechanism.