title: Dopaminergic degeneration is enhanced by chronic brain hypoperfusion and inhibited by angiotensin receptor blockage.
abstract: The possible interaction between brain hypoperfusion related to aging and/or vascular disease, vascular parkinsonism and Parkinson's disease, as well as the possible contribution of aging-related chronic brain hypoperfusion in the development or severity of Parkinson's disease are largely unknown. We used a rat model of chronic cerebral hypoperfusion to study the long-term effects of hypoperfusion on dopaminergic neurons and the possible synergistic effects between chronic hypoperfusion and factors that are deleterious to dopaminergic neurons, such as the dopaminergic neurotoxin 6-hydroxydopamine. Chronic hypoperfusion induced significant loss of dopaminergic neurons and striatal dopaminergic terminals and a reduction in striatal dopamine levels. Furthermore, intrastriatal administration of 6-hydroxydopamine in rats subjected to chronic hypoperfusion induced a significantly greater loss of dopaminergic neurons than in sham-operated control rats. The dopaminergic neuron loss was significantly reduced by oral treatment with angiotensin type 1 receptor antagonist candesartan (3 mg/kg/day). The levels of angiotensin type 2 receptors were lower and the levels of angiotensin type 1 receptors, interleukin-1 β and nicotinamide adenine dinucleotide phosphate oxidase activity were higher in the substantia nigra of rats subjected to chronic hypoperfusion than in control rats; this was significantly reduced by treatment with candesartan. The results suggest that early treatment of vascular disease should be considered in the treatment of aged Parkinson's disease patients and Parkinson's disease patients with cerebrovascular risk factors. The findings also suggest that inhibition of brain renin-angiotensin activity may be useful as a neuroprotective strategy.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rodriguez-Perez
authors.forename: Antonio
authors.initials: A
authors.lastname: Dominguez-Meijide
authors.forename: Jose L
authors.initials: JL
authors.lastname: Lanciego
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Guerra
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan; D004298:Dopamine