title: Microglial TNF-α mediates enhancement of dopaminergic degeneration by brain angiotensin.
abstract: In vitro and in vivo models of Parkinson's disease were used to investigate whether TNF-α plays a major role in the enhancement of the microglial response and dopaminergic degeneration induced by brain angiotensin hyperactivity. Treatment of primary mesencephalic cultures with low doses of the neurotoxin MPP(+) induced a significant loss of dopaminergic neurons, which was enhanced by cotreatment with angiotensin II and inhibited by TNF-α inhibitors. Treatment of primary cultures with angiotensin induced a marked increase in levels of TNF-α, which was inhibited by treatment with angiotensin type-1-receptor antagonists, NADPH-oxidase inhibitors and NFK-β inhibitors. However, TNF-α levels were not significantly affected by treatment with angiotensin in the absence of microglia. The microglial origin of the angiotensin-induced increase in TNF-α levels was confirmed using dopaminergic (MES 23.5) and microglial (N9) cell lines. Inhibition of the microglial Rho-kinase activity also blocked the AII-induced increase in TNF-α levels. Treatment of the dopaminergic cell line with TNF-α revealed that NFK-β activation mediates the deleterious effect of microglial TNF-α on dopaminergic neurons. Treatment of mice with MPTP also induced significant increases in striatal and nigral TNF-α levels, which were inhibited by angiotensin type-1-receptor antagonists or NFK-β inhibitors. The present results show that microglial TNF-α plays a major role in angiotensin-induced dopaminergic cell death and that the microglial release of TNF-α is mediated by activation of angiotensin type-1 receptors, NADPH-oxidase, Rho-kinase and NFK-β.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Borrajo
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rodriguez-Perez
authors.forename: Carmen
authors.initials: C
authors.lastname: Diaz-Ruiz
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Guerra
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D003563:Cyclic CMP / Q000031:analogs & derivatives / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007610:Kallikreins / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D010184:Pancreatic Extracts / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D010184:Pancreatic Extracts; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; C033969:angiotrofin; D000804:Angiotensin II; D003563:Cyclic CMP; C053441:dibutyryl cyclic-3',5'-cytidine monophosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007610:Kallikreins; C081643:candesartan
keywords: NADPH-oxidase; Parkinson; dopamine; glia; neuroinflammation; oxidative stress