Dopaminergic neurotoxicity by 6-OHDA and MPP+: differential requirement for neuronal cyclooxygenase activity.
Cyclooxygenase (COX), a key enzymatic mediator of inflammation, is present in microglia and surviving dopaminergic neurons in Parkinson's disease (PD), but its role and place in the chain of neurodegenerative events is unclear. Epidemiologic evidence showed that regular use of nonsteroidal antiinflammatory drugs (NSAIDs), specifically non-aspirin COX inhibitors like ibuprofen, lowers the risk for PD; however, the putative cause-and-effect relationship between COX activity in activated microglia and neuronal loss was challenged recently. We examined whether neuronal COX activity is involved directly in dopaminergic cell death after neurotoxic insult. Using low concentrations of 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridium ion (MPP+), neurotoxicants used to model selective dopaminergic cell loss in PD, and cultures of embryonic rat mesencephalic neurons essentially devoid of glia, we tested whether the nonselective COX inhibitor ibuprofen attenuated 6-OHDA and MPP+ neurotoxicity. At levels close to its IC50 for both COX isoforms, ibuprofen protected dopaminergic neurons against 6-OHDA but not MPP+ toxicity. Experiments with selective inhibitors of COX-1 (SC-560) and COX-2 (NS-398 and Cayman 10404), indicated that COX-2, but not COX-1, was involved in 6-OHDA toxicity. Accordingly, 6-OHDA, but not MPP+, increased prostaglandin (PG) levels twofold and this increase was blocked by ibuprofen. At concentrations well above its IC50 for COX, ibuprofen also prevented MPP+ toxicity, but had only limited efficacy against loss of structural complexity. Taken together, our data suggest that selective 6-OHDA toxicity to dopaminergic neurons is associated with neuronal COX-2, whereas MPP+ toxicity is COX independent. This difference may be important for understanding and manipulating mechanisms of dopaminergic cell death.
Carrasco
Emilce
E
Albert Einstein College of Medicine, Department of Neurology, Bronx, New York 10461, USA.
Casper
Diana
D
Werner
Peter
P
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D007052:Ibuprofen / Q000494:pharmacology*; D007527:Isoenzymes; D009410:Nerve Degeneration / Q000201:enzymology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011453:Prostaglandins; D016627:Oxidopamine; D011451:Prostaglandin-Endoperoxide Synthases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D007052:Ibuprofen