Oxicam structure in non-steroidal anti-inflammatory drugs is essential to exhibit Akt-mediated neuroprotection against 1-methyl-4-phenyl pyridinium-induced cytotoxicity

In the treatment of Parkinson's disease, potent disease-modifying drugs are still needed to halt progressive dopaminergic neurodegeneration. We have previously shown that meloxicam, an oxicam non-steroidal anti-inflammatory drug (NSAID), elicits a potent neuroprotective effect against 1-methyl-4-phenyl pyridinium (MPP+)-induced toxicity in human dopaminergic SH-SY5Y neuroblastoma cells. This cyclooxygenase-independent neuroprotection of meloxicam is mediated via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; however, the specific chemical structure involved in inducing neuroprotection remains unresolved. In this study, we therefore investigated the structure-specific for eliciting the neuroprotective effect by examining a series of NSAIDs against MPP+ toxicity in SH-SY5Y cells. Three oxicam-bearing NSAIDs showed potent neuroprotective effects, although none of the other 10 oxicam-nonbearing NSAIDs (3 salicylates, 6 coxibs and 1 polyphenol) or 3 piroxicam analogs (including ampiroxicam, a precursor of piroxicam) exerted any neuroprotection. Tenoxicam and piroxicam prevented MPP+-induced reduction of phosphorylated Akt levels in cells: a protective mechanism similar to that of meloxicam. Therefore, the oxicam structure was likely to be responsible for exhibiting the neuroprotection by sustaining survival-signaling in dopaminergic cells. The present results raise the possibility that the oxicam-bearing NSAIDs may serve as potential therapeutic drugs to retard or terminate progression of Parkinson's disease via a novel mechanism. (C) 2011 Elsevier B.V. All rights reserved.