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
Autor: | Joe Yamamoto, Kazuo Matsubara, Satoshi Imai, Shunsaku Nakagawa, Atsushi Yonezawa, Tomohiro Omura, Gaia Hashimoto, Yuki Sato, Takayuki Nakagawa, Ikuko Yano, Yoshikazu Tasaki, Miwa Sasaoka |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Programmed cell death 1-Methyl-4-phenylpyridinium Mitochondrial Diseases Eukaryotic Initiation Factor-2 Biophysics Meloxicam Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Humans Phosphorylation Molecular Biology Protein kinase B Cell Death Endoplasmic reticulum Anti-Inflammatory Agents Non-Steroidal Cell Biology Tunicamycin Endoplasmic Reticulum Stress Cell biology 030104 developmental biology chemistry Apoptosis Unfolded protein response Signal transduction Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery |
Zdroj: | Biochemical and biophysical research communications. 503(4) |
ISSN: | 1090-2104 |
Popis: | 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. |
Databáze: | OpenAIRE |
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