Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS.
Angiotensin II (AII) plays a major role in the progression of inflammation and NADPH-derived oxidative stress (OS) in several tissues. The brain possesses a local angiotensin system, and OS and inflammation are key factors in the progression of Parkinson's disease. In rat mesencephalic cultures, AII increased 6-OHDA-induced dopaminergic (DA) cell death, generation of superoxide in DA neurons and microglial cells, the expression of NADPH-oxidase mRNA, and the number of reactive microglial cells. These effects were blocked by AII type-1 (AT1) antagonists, NADPH inhibitors, or elimination of glial cells. DA degeneration increased angiotensin converting enzyme activity and AII levels. In rats, 6-OHDA-induced dopaminergic cell loss and microglial activation were reduced by treatment with AT1 antagonists. The present data suggest that AII, via AT1 receptors, increases the dopaminergic degeneration process by amplifying the inflammatory response and intraneuronal levels of OS, and that glial cells play a major role in this process.
Rodriguez-Pallares
J
J
Department of Morphological Sciences, Faculty of Medicine, Laboratory of Neuroanatomy and Experimental Neurology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Rey
P
P
Parga
J A
JA
Muñoz
A
A
Guerra
M J
MJ
Labandeira-Garcia
J L
JL
D018663:Adrenergic Agents / Q000633:toxicity; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D017628:Microglia / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018663:Adrenergic Agents; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D009249:NADP; D016627:Oxidopamine; D004298:Dopamine