Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats

We evaluated the hydroxyl radical ((OH)-O-.) scavenging action of nonsteroidal anti-inflammatory drugs (NSAIDs), sodium salicylate (SA), diclofenac and celecoxib in Fenton's reaction and their neuroprotective effects in 1-methyl-4-phenylpyridinium (MPP+)-induced striatal doparnine (DA) depletion in rats. Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to assay formation of (OH)-O-. in Fenton's reaction in test tubes. While SA dose- and time-dependently hydroxylated itself and inactivated (OH)-O-., celecoxib (up to 10 mM) showed no effect on (OH)-O-. formation and diclofenac caused a reduction in (OH)-O-. generation only at high doses (100 muM-10 mM). Administration of the non-selective cyclooxygenase (COX) inhibitor, SA (50, 100 mg/kg, i.p.) significantly attenuated striatal DA depletion caused by intrastriatal infusion of MPP+ (100 nmol in 4 mul). Treatment with another nonselective, reversible COX inhibitor, diclofenac (5, 10 mg/kg) did not protect against MPP+-induced DA depletion. The selective COX-2 inhibitor, celecoxib (2.5-50-mg/kg) treatment exacerbated MPP+-induced decrease in DA. Failure of celecoxib or diclofenac to render protection in animals against MPP+-induced DA depletion indicates absence of prostaglandin involvement in MPP+ action. These results also suggest that the neuroprotective ability of SA is independent of prostaglandin mediation. A relationship between inactivation of (OH)-O-. by SA and its ability to protect DA depletion in the striatum caused by MPP+ indicates a direct involvement of (OH)-O-. in the action of this neurotoxin. The present study establishes potent neuroprotective activity of SA and suggests the use of aspirin in adjuvant therapy in Parkinson's disease. (C)2002 Elsevier Science B.V. All rights reserved.