title: Oxicam structure in non-steroidal anti-inflammatory drugs is essential to exhibit Akt-mediated neuroprotection against 1-methyl-4-phenyl pyridinium-induced cytotoxicity.
abstract: 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.
authors.affiliation: Department of Hospital Pharmacy & Pharmacology, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tasaki
authors.forename: Joe
authors.initials: J
authors.lastname: Yamamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Omura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Noda
authors.forename: Naoya
authors.initials: N
authors.lastname: Kamiyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Machiko
authors.initials: M
authors.lastname: Satomi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Masaru
authors.initials: M
authors.lastname: Asari
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkubo
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000633:toxicity*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003603:Cytotoxins; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015655:1-Methyl-4-phenylpyridinium