Asanuma M, Nishibayashi-Asanuma S, Miyazaki I, Kohno M, Ogawa N
Department of Neuroscience, Institute of Molecular and Cellular Medicine, Okayama University Medical School, Okayama, Japan.
J Neurochem. 2001 Mar;76(6):1895-904. doi: 10.1046/j.1471-4159.2001.00205.x.
Recently, it has been reported that inflammatory processes are associated with the pathophysiology of Alzheimer's disease and that treatment of non-steroidal anti-inflammatory drugs reduce the risk for Alzheimer's disease. In the present study, we examined nitric oxide radical quenching activity of non-steroidal anti-inflammatory drugs and steroidal drugs using our established direct in vitro nitric oxide radical detecting system by electron spin resonance spectrometry. The non-steroidal anti-inflammatory drugs, aspirin, mefenamic acid, indomethacin and ketoprofen directly and dose-dependently scavenged generated nitric oxide radicals. In experiments of nitric oxide radical donor, NOC18-induced neuronal damage, these four non-steroidal drugs significantly prevented the NOC18-induced reduction of cell viability and apoptotic nuclear changes in neuronal cells without affecting the induction of inducible nitric oxide synthase-like immunoreactivity. However, ibuprofen, naproxen or steroidal drugs, which had less or no scavenging effects in vitro, showed almost no protective effects against NOC18-induced cell toxicity. These results suggest that the protective effects of the former four non-steroidal anti-inflammatory drugs against apoptosis might be mainly due to their direct nitric oxide radical scavenging activities in neuronal cells. These direct NO. quenching activities represent novel effects of non-steroidal anti-inflammatory drugs. Our findings identified novel pharmacological mechanisms of these drugs to exert not only their anti-inflammatory, analgesic, antipyretic activities but also neuroprotective activities against neurodegeneration.
最近，有报道称炎症过程与阿尔茨海默病的病理生理学相关，且非甾体抗炎药治疗可降低患阿尔茨海默病的风险。在本研究中，我们使用已建立的电子自旋共振光谱法体外直接检测一氧化氮自由基系统，检测了非甾体抗炎药和甾体药物的一氧化氮自由基淬灭活性。非甾体抗炎药阿司匹林、甲芬那酸、吲哚美辛和酮洛芬可直接且剂量依赖性地清除产生的一氧化氮自由基。在一氧化氮自由基供体NOC18诱导的神经元损伤实验中，这四种非甾体药物显著预防了NOC18诱导的神经元细胞活力降低和凋亡核变化，且不影响诱导型一氧化氮合酶样免疫反应性的诱导。然而，布洛芬、萘普生或在体外清除作用较小或无清除作用的甾体药物，对NOC18诱导的细胞毒性几乎没有保护作用。这些结果表明，前四种非甾体抗炎药对细胞凋亡的保护作用可能主要归因于它们在神经元细胞中直接清除一氧化氮自由基的活性。这些直接的NO淬灭活性代表了非甾体抗炎药的新作用。我们的研究结果确定了这些药物发挥抗炎、镇痛、解热活性以及对神经退行性变的神经保护活性的新药理学机制。
