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) 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 microM-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 microl). 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.
Sairam
Krishnamurthy
K
Division of Neurosciences, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, 700 032, Calcutta, India.
Saravanan
Karuppagounder S
KS
Banerjee
Rebecca
R
Mohanakumar
Kochupurackal P
KP
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000068579:Celecoxib; D003342:Corpus Striatum / Q000187:drug effects* / Q000293:injuries; D004008:Diclofenac / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005841:Gentisates; D062385:Hydroxybenzoates / Q000633:toxicity; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009026:Mortality; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011720:Pyrazoles; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D012980:Sodium Salicylate / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005841:Gentisates; D062385:Hydroxybenzoates; D018696:Neuroprotective Agents; D011720:Pyrazoles; D013449:Sulfonamides; D004008:Diclofenac; D017665:Hydroxyl Radical; C009135:2,3-dihydroxybenzoic acid; D000068579:Celecoxib; D015655:1-Methyl-4-phenylpyridinium; C010925:2,5-dihydroxybenzoic acid; D004298:Dopamine; D012980:Sodium Salicylate