title: Meloxicam ameliorates motor dysfunction and dopaminergic neurodegeneration by maintaining Akt-signaling in a mouse Parkinson's disease model.
abstract: A series of oxicam non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be neuroprotective against 1-methyl-4-phenyl pyridinium in human neuroblastoma SH-SY5Y cells via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway independent of cyclooxygenase (COX) inhibition. The present study endeavored to establish this novel effect of meloxicam (MLX), an oxicam NSAID, in a mouse Parkinson's disease (PD) model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male C57BL/6 mice, which received MPTP (30 mg/kg/day; s.c.) for 5 consecutive days (chronic model) with 10-day follow-up saline administrations, showed significant motor dysfunction in the pole test due to reduced tyrosine hydroxylase (TH) protein levels in the brain on day 16 after MPTP/saline treatment. Daily coadministrations of MLX (10mg/kg/day; i.p.) and MPTP for the first 5 days and follow-up 10 days with MLX administrations alone (MPTP/MLX treatment) significantly ameliorated MPTP-induced behavioral abnormalities in mice. Concomitant decreases of TH protein levels in the striatum and midbrain of MPTP/MLX-treated mice were not only significantly (p<0.01 and p<0.05, respectively) ameliorated but phosphorylated Akt (pAkt473) expression in the midbrain was also significantly (p<0.01) increased in the midbrain when compared with MPTP/saline-treated mice. These results suggest that MLX, an oxicam NSAID, attenuated dopaminergic neuronal death in the experimental MPTP-PD model by maintenance of the Akt-signaling. Oxicam NSAIDs may serve as potential drugs for PD treatment via a novel mechanism of action.
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: Tomoki
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Norihisa
authors.initials: N
authors.lastname: Kimura
authors.forename: Ko-Ichi
authors.initials: K
authors.lastname: Ohtaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Ono
authors.forename: Manabu
authors.initials: M
authors.lastname: Suno
authors.forename: Masaru
authors.initials: M
authors.lastname: Asari
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkubo
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Noda
authors.forename: Toshio
authors.initials: T
authors.lastname: Awaya
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018476:Hypokinesia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D008297:Male; D000077239:Meloxicam; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D013843:Thiazines; D013844:Thiazoles; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077239:Meloxicam; D004298:Dopamine