MPP+-induced COX-2 activation and subsequent dopaminergic neurodegeneration.
The importance of cyclooxygenase-2 (COX-2) in mediating Parkinson's disease (PD) was suggested in reports, indicating that COX-2 selective inhibitors or genetic knockout reduce 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurotoxicity in a mouse model of PD. However, cell types and mechanisms underlying the activation of COX-2 have not been clearly elucidated in these animal studies. Using primary neuron-glia cultures, we aimed to determine 1) whether microglia participate in 1-methyl-4-phenylpryridinium (MPP)-induced COX-2 activation and 2) whether the activation of COX-2 contributes to subsequent neurotoxicity. MPP, in a concentration-dependent manner, increased prostaglandin E2 (PGE2) production in mixed neuron-microglia cultures but not in enriched neuron, microglia, or astroglia cultures nor in mixed neuron-astroglia cultures. MPP-induced PGE2 increase was completely abolished by treatment with DuP697, a COX-2 selective inhibitor. DuP697 also significantly reduced MPP-induced DA neurotoxicity as determined by DA uptake assay. Immunocytochemistry and confocal microscopy studies showed enhanced COX-2 expression in both microglia and neurons after MPP treatment. However, neuronal increase in COX-2 expression was not totally dependent on the production of PGE2 from microglia, since microglia deficient in COX-2 only attenuated, but did not completely block, MPP-increased PGE2 production in mixed neuron-microglia cultures, suggesting that part of PGE2 production was originated from neurons. Together, these results indicate that MPP-induced COX-2 expression and subsequent PGE2 production depend on interactions between neurons and microglia. Microgliosis may also be responsible for the COX-2 activation in neurons, leading to the enhanced DA neurotoxicity, which, in turn, reinforces microgliosis. Thus inhibition of microgliosis and COX-2 activity may stop this vicious circle and be valuable strategies in PD therapy.
Wang
Tongguang
T
Neuropharmacology Section, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Pei
Zhong
Z
Zhang
Wei
W
Liu
Bin
B
Langenbach
Robert
R
Lee
Christopher
C
Wilson
Belinda
B
Reece
Jeffrey M
JM
Miller
David S
DS
Hong
Jau-Shyong
JS
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020267:MPTP Poisoning / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology
D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D015655:1-Methyl-4-phenylpyridinium