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Am J Neurodegener Dis 2012;1(3):226-244

Original Article
Brain angiotensin and dopaminergic degeneration: relevance to
Parkinson’s disease

Jose L Labandeira-Garcia, Jannette Rodriguez-Pallares, Ana I Rodríguez-Perez, Pablo Garrido-Gil, Begoña Villar-
Cheda, Rita Valenzuela, Maria J Guerra

Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine,
University of Santiago de Compostela, Santiago de Compostela; Spain. Networking Research Center on
Neurodegenerative Diseases (CIBERNED), Spain

Received October 9 2012; Accepted November 2, 2012; Epub November 18, 2012; Published November 30, 2012

Abstract: The pathogenic mechanism of Parkinson’s disease (PD) appears to be multifactorial. However, oxidative
stress and neuroinflammation, including activation of NADPH-dependent oxidases, play a major role in the progression
of dopaminergic cell death. The renin-angiotensin system (RAS) was described as a circulating humoral system
that regulates blood pressure and water homeostasis. However, there exist local RAS in many tissues, and locally
formed angiotensin activates NADPH-dependent oxidases, which are a major source of superoxide and are
upregulated in major aging-related diseases such as hypertension, diabetes and atherosclerosis. Furthermore, an
intracellular or intracrine RAS, with still unknown functions, has been identified in several cell types. The brain has an
independent local RAS, which has been involved in several brain disorders, including neurodegenerative diseases. It is
particularly interesting for PD the important interaction observed between angiotensin and dopamine, which
counterregulate each other in renal cells and also in the striatum and substantia nigra. In recent studies, we have
observed both a local and an intracellular RAS in the rodent, monkey and human substantia nigra, and that dopamine
depletion induced RAS upregulation possibly as a compensatory mechanism. However, RAS hyperactivation also
exacerbated oxidative stress and neuroinflammation, which contributed to progression of dopaminergic degeneration.
In addition, we observed increased RAS activity in the nigra of animals with higher vulnerability of dopaminergic
neurons to degeneration, such as aged males, menopausal females and rats subjected to chronic brain
hypoperfusion. RAS activity and dopaminergic vulnerability were significantly reduced by treatment with angiotensin
type I receptor antagonists. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against
dopaminergic degeneration in PD. (AJND1210003).

Keywords: Aging, angiotensin, degenerative disease, dopamine, menopause, neurodegeneration, neuroinflammation,
oxidative stress, Parkinson, renin-angiotensin system

Address all correspondence to:
Dr. Jeffrey L Cummings
Cleveland Clinic Lou Ruvo Center for Brain Health
Camille and Larry Ruvo Chair for Brain Health
Cleveland Clinic Lou Ruvo Center for Brain Health
888 W Bonneville Avenue, Las Vegas, NV 89106.
Tel: 702-483-6029; Fax: 702-483-6028
E-mail: cumminj@ccf.org