Microglial TNF-α mediates enhancement of dopaminergic degeneration by brain angiotensin.
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.
['Borrajo|Ana|A|', 'Rodriguez-Perez|Ana I|AI|', 'Diaz-Ruiz|Carmen|C|', 'Guerra|Maria J|MJ|', 'Labandeira-Garcia|Jose L|JL|']
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine D000804:Angiotensin II D047228:Angiotensin II Type 1 Receptor Blockers D000818:Animals D001562:Benzimidazoles D001713:Biphenyl Compounds D002478:Cells, Cultured D003563:Cyclic CMP D059290:Dopaminergic Neurons D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D007610:Kallikreins D008297:Male D008636:Mesencephalon D051379:Mice D008810:Mice, Inbred C57BL D017628:Microglia D009410:Nerve Degeneration D009474:Neurons D009498:Neurotoxins D010184:Pancreatic Extracts D013777:Tetrazoles D014409:Tumor Necrosis Factor-alpha
Parkinson NADPH-oxidase dopamine glia neuroinflammation oxidative stress