Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease.
To study the possible role of the isoenzymes of cyclooxygenase COX-1 and COX-2 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease we used acetylsalicylic acid, a COX-1/COX-2 inhibitor, in comparison with meloxicam, a preferential COX-2 inhibitor. As markers of protection we determined the effects on MPTP-induced striatal dopamine depletion, locomotor activity, cell loss, and tyrosine hydroxylase immunoreactivity (TH-IR) in the substantia nigra pars compacta. Male C57BL/6 mice (n = 82) were treated with a single dose of acetylsalicylic acid (10, 50, 100 mg/kg i.p.) or meloxicam (2, 7.5, 50 mg/kg i.p.) immediately prior to administration of MPTP (30 mg/kg s.c.) or saline. After 7 days the mice were sacrificed to analyze striatal dopamine and metabolite levels. Nigral sections were processed for Nissl-staining and TH-IR. In the saline-treated MPTP control group striatal dopamine levels were reduced to 15.9% of control values. Dopamine depletion was significantly attenuated to values of 37.1 and 38.6% of saline control values by acetylsalicylic acid (50 and 100 mg/kg) and to values of 36 and 40% by meloxicam (7.5 and 50 mg/kg), respectively. MPTP-induced decrease of locomotor activity was significantly attenuated by acetylsalicylic acid and meloxicam. Remarkably, the MPTP-induced decrease of TH-IR as well as the loss of nigral neurons was nearly completely prevented by acetylsalicylic acid (100 mg/kg) and meloxicam (7.5 and 50 mg/kg). In conclusion, the inhibition of either COX-1/COX-2 by acetylsalicylic acid or preferentially COX-2 by meloxicam provided a clear neuroprotection against MPTP-toxicity on the striatal and nigral levels.
Teismann
P
P
Institute of Pharmacology and Toxicology, Faculty of Pharmacy, University of Marburg, Germany.
Ferger
B
B
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D002452:Cell Count; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D000077239:Meloxicam; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017072:Neostriatum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D013843:Thiazines; D013844:Thiazoles; D015102:3,4-Dihydroxyphenylacetic Acid; D014446:Tyrosine 3-Monooxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D001241:Aspirin; D015655:1-Methyl-4-phenylpyridinium; D000077239:Meloxicam; D004298:Dopamine; D006719:Homovanillic Acid