Neuroprotective effects of non‐steroidal anti‐inflammatory drugs by direct scavenging of nitric oxide radicals

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Abstract
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.