The inflammatory response in the MPTP model of Parkinson's disease is mediated by brain angiotensin: relevance to progression of the disease.
The neurotoxin MPTP reproduces most of the biochemical and pathological hallmarks of Parkinson's disease. In addition to reactive oxygen species (ROS) generated as a consequence of mitochondrial complex I inhibition, microglial NADPH-derived ROS play major roles in the toxicity of MPTP. However, the exact mechanism regulating this microglial response remains to be clarified. The peptide angiotensin II (AII), via type 1 receptors (AT1), is one of the most important inflammation and oxidative stress inducers, and produces ROS by activation of the NADPH-oxidase complex. Brain possesses a local angiotensin system, which modulates striatal dopamine (DA) release. However, it is not known if AII plays a major role in microglia-derived oxidative stress and DA degeneration. The present study indicates that in primary mesencephalic cultures, DA degeneration induced by the neurotoxin MPTP/MPP(+) is amplified by AII and inhibited by AT1 receptor antagonists, and that protein kinase C, NADPH-complex activation and microglial activation are involved in this effect. In mice, AT1 receptor antagonists inhibited both DA degeneration and early microglial and NADPH activation. The brain angiotensin system may play a key role in the self-propelling mechanism of Parkinson's disease and constitutes an unexplored target for neuroprotection, as previously reported for vascular diseases.
Joglar
Belen
B
Department of Morphological Sciences, University of Santiago de Compostela, Networking Research Center on Neurodegenerative Diseases, Santiago de Compostela, Spain.
Rodriguez-Pallares
Jannette
J
Rodriguez-Perez
Ana Isabel
AI
Rey
Pablo
P
Guerra
Maria Jose
MJ
Labandeira-Garcia
Jose Luis
JL
D000809:Angiotensins / Q000502:physiology* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D018836:Inflammation Mediators / Q000502:physiology* / Q000633:toxicity; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010302:Parkinson Disease, Secondary / Q000378:metabolism* / Q000473:pathology*; D051381:Rats
D000809:Angiotensins; D018836:Inflammation Mediators