Oxicam-derived non-steroidal anti-inflammatory drugs suppress 1-methyl-4-phenyl pyridinium-induced cell death via repression of endoplasmic reticulum stress response and mitochondrial dysfunction in SH-SY5Y cells

• Published in: Biochemical and biophysical research communications 2018-09, Vol.503 (4), p.2963-2969
• Main Authors: Omura, Tomohiro, Sasaoka, Miwa, Hashimoto, Gaia, Imai, Satoshi, Yamamoto, Joe, Sato, Yuki, Nakagawa, Shunsaku, Yonezawa, Atsushi, Nakagawa, Takayuki, Yano, Ikuko, Tasaki, Yoshikazu, Matsubara, Kazuo
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl pyridinium (MPP+); 1-Methyl-4-phenylpyridinium - adverse effects; 60 APPLIED LIFE SCIENCES; Akt; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; APOPTOSIS; Cell Death - drug effects; Cell Line, Tumor; DISEASES; DRUGS; ENDOPLASMIC RETICULUM; Endoplasmic reticulum (ER) stress; Endoplasmic Reticulum Stress - drug effects; Eukaryotic initiation factor 2α (eIF2α); Eukaryotic Initiation Factor-2 - metabolism; Humans; INFLAMMATION; Meloxicam - pharmacology; MITOCHONDRIA; Mitochondrial Diseases; Oxicam-NSAIDs; PHOSPHORYLATION; Proto-Oncogene Proteins c-akt - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.08.078

We have previously reported that oxicam-derived non-steroidal anti-inflammatory drugs (oxicam-NSAIDs), including meloxicam, piroxicam and tenoxicam, elicit protective effects against 1-methyl-4-phenyl pyridinium (MPP+)-induced cell death in a fashion independent of cyclooxygenase (COX) inhibition. We have also demonstrated that oxicam-NSAIDs suppress the decrease in phosphorylation of Akt caused by MPP+. The molecular mechanism through which oxicam-NSAIDs provide cytoprotection remains unclear. In this study, we speculated a possibility that endoplasmic reticulum (ER) stress and/or mitochondrial dysfunction, which are both causative factors of Parkinson's disease (PD), may be involved in the neuroprotective mechanism of oxicam-NSAIDs. We demonstrated here that oxicam-NSAIDs suppressed the activation of caspase-3 and cell death caused by MPP+ or ER stress-inducer, tunicamycin, in SH-SY5Y cells. Furthermore, oxicam-NSAIDs suppressed the increases in the ER stress marker CHOP (apoptosis mediator) caused by MPP+ or tunicamycin, beside suppressing eukaryotic initiation factor 2α (eIF2α) phosphorylation and the increase in ATF4 caused by MPP+. Taken together, these results suggest that oxicam-NSAIDs suppress the eIF2α-ATF4-CHOP pathway, one of the three signaling pathways in the ER stress response. Oxicam-NSAIDs suppressed the decrease in mitochondrial membrane potential depolarization caused by MPP+, indicating they also rescue cells from mitochondrial dysfunction. Akt phosphorylation levels were suppressed after the incubation with MPP+, whereas phosphorylation of eIF2α was enhanced. These results suggest that oxicam-NSAIDs prevented eIF2α phosphorylation and mitochondrial dysfunction by maintaining Akt phosphorylation (reduced by MPP+), thereby preventing cell death. •Oxicam-NSAIDs suppress cell death caused by the ER stress-inducer.•Oxicam-NSAIDs inhibit MPP+-induced cell death caused by the repression of ER stress response and mitochondrial dysfunction.•Oxicam-NSAIDs may inhibit the increase of eIF2a phosphorylation by suppressing the decrease of Akt phosphorylation by MPP+.