Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals.
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.
Department of Neuroscience, Institute of Molecular and Cellular Medicine, Okayama University Medical School, Okayama, Japan. asachan@cc.okayama-u.ac.jp
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M
Asanuma
S
S
Nishibayashi-Asanuma
I
I
Miyazaki
M
M
Kohno
N
N
Ogawa
D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001565:Benzoates; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005609:Free Radicals; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007093:Imidazoles; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation; D008528:Mefenamic Acid / Q000494:pharmacology; D009288:Naproxen / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D051381:Rats; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D016166:Free Radical Scavengers; D005609:Free Radicals; D007093:Imidazoles; C093285:NOC 18; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D008528:Mefenamic Acid; D009288:Naproxen; D003907:Dexamethasone; D001241:Aspirin; D006854:Hydrocortisone; D007213:Indomethacin