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

Abstract

We evaluated the hydroxyl radical ( ⋅OH) 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 dopamine (DA) depletion in rats. Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to assay formation of ⋅OH in Fenton’s reaction in test tubes. While SA dose- and time-dependently hydroxylated itself and inactivated ⋅OH, celecoxib (up to 10 mM) showed no effect on ⋅OH formation and diclofenac caused a reduction in ⋅OH generation only at high doses (100 μM–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 μl). 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 by SA and its ability to protect DA depletion in the striatum caused by MPP + indicates a direct involvement of ⋅OH 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.