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
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto (Japan)
- Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical University, Asahikawa, Hokkaido (Japan)
Highlights: • Oxicam-NSAIDs suppress cell death caused by the ER stress-inducer. • Oxicam-NSAIDs inhibit MPP{sup +}-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{sup +}. 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{sup +})-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{sup +}. 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{sup +} 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{sup +} or tunicamycin, beside suppressing eukaryotic initiation factor 2α (eIF2α) phosphorylation and the increase in ATF4 caused by MPP{sup +}. 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{sup +}, indicating they also rescue cells from mitochondrial dysfunction. Akt phosphorylation levels were suppressed after the incubation with MPP{sup +}, 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{sup +}), thereby preventing cell death.
- OSTI ID:
- 23134262
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 4; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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