Biochemical and Biophysical Research Communications, Vol.503, No.4, 2963-2969, 2018
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
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 2 alpha (eIF2 alpha) phosphorylation and the increase in ATF4 caused by MPP+. Taken together, these results suggest that oxicam-NSAIDs suppress the elF2 alpha-ATF4-CHOP pathway, one of the three signaling pathways in the ER stress response. Oxicam-NSAIDs suppressed the decrease in mitochondria' 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 elF2 alpha was enhanced. These results suggest that oxicam-NSAIDs prevented elF2 alpha phosphorylation and mitochondrial dysfunction by maintaining Akt phosphorylation (reduced by MPP+), thereby preventing cell death. (C) 2018 Elsevier Inc. All rights reserved.