Increased catechol-O-methyltransferase activity and protein expression in OX-42-positive cells in the substantia nigra after lipopolysaccharide microinfusion.
Activated microglial cells are found in the substantia nigra and the striatum of Parkinson's disease patients. These cells have been shown to express catechol-O-methyltransferase activity which may increase during pathological conditions. Lipopolysaccharides are potent activators of microglial cells. After paranigral lipopolysaccharide infusion to rats we observed intense microglial activation around the lesion area followed by a delayed injury in nigrostriatal pathway in 2 weeks. Simultaneously, catechol-O-methyltransferase activity in the substantia nigra was gradually increased up to 213%. In the Western blot the amount of soluble COMT and membrane bound COMT proteins were increased by 255% and 86%, respectively. Increased catechol-O-methyltransferase immunoreactivity was located primarily into the activated microglial cells in the lesion area. Interestingly, catechol-O-methyltransferase and OX-42 stained also intensively microglia/macrophage-like cells which surrounded the adjacent blood vessels. Inhibition of catechol-O-methyltransferase activity by tolcapone or entacapone did not increase lipopolysaccharide-induced neurotoxicity. We conclude that catechol-O-methyltransferase activity and protein expression were increased in the substantia nigra after inflammation induced by lipopolysaccharides. These changes in glial and perivascular catechol-O-methyltransferase activity may have clinical relevance for Parkinson's disease drug treatment due to increased metabolism of levodopa in the brain.
Helkamaa
Teemu
T
Institute of Biomedicine, Pharmacology, University of Helsinki, Finland. teemu.helkamaa@helsinki.fi
Reenilä
Ilkka
I
Tuominen
Raimo K
RK
Soinila
Seppo
S
Väänänen
Antti
A
Tilgmann
Carola
C
Rauhala
Pekka
P
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004660:Encephalitis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation / Q000502:physiology; D005911:Gliosis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000494:pharmacology; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000201:enzymology*; D010300:Parkinson Disease / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000201:enzymology* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D015415:Biomarkers; D039481:CD11b Antigen; C509295:ITGAM protein, human; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D007980:Levodopa; D002394:Catechol O-Methyltransferase; D004298:Dopamine