Microglial TNF-[alpha] mediates enhancement of dopaminergic degeneration by brain angiotensin

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