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- 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- inhibitors. Treatment of primary cultures with angiotensin induced a marked increase in levels of TNF-, which was inhibited by treatment with angiotensin type-1-receptor antagonists, NADPH-oxidase inhibitors and NFK- inhibitors. However, TNF- levels were not significantly affected by treatment with angiotensin in the absence of microglia. The microglial origin of the angiotensin-induced increase in TNF- 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- levels. Treatment of the dopaminergic cell line with TNF- revealed that NFK- activation mediates the deleterious effect of microglial TNF- on dopaminergic neurons. Treatment of mice with MPTP also induced significant increases in striatal and nigral TNF- levels, which were inhibited by angiotensin type-1-receptor antagonists or NFK- inhibitors. The present results show that microglial TNF- plays a major role in angiotensin-induced dopaminergic cell death and that the microglial release of TNF- is mediated by activation of angiotensin type-1 receptors, NADPH-oxidase, Rho-kinase and NFK-. GLIA 2014;62:145-157