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Dopaminergic degeneration is enhanced by chronic brain hypoperfusion and inhibited by angiotensin receptor blockage

AGE volume 35, pages 1675–1690 (2013)Cite this article

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.

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Acknowledgments

The authors thank Pilar Aldrey, Iria Novoa, and Jose A. Trillo for their excellent technical assistance. The authors are thankful to Astra Zeneca for providing candesartan for the experiments. Funding: Spanish Ministry of Science and Innovation, Spanish Ministry of Health (RD06/0010/0013 and CIBERNED), Galician Government (XUGA) and European Regional Development Fund (FEDER).

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Affiliations

  1. Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain

    Ana I. Rodriguez-Perez, Antonio Dominguez-Meijide, Maria J. Guerra & Jose L. Labandeira-Garcia

  2. Neurosciences Division, CIMA, University of Navarra, Pamplona, Spain

    Jose L. Lanciego

  3. Networking Research Centre on Neurodegenerative Diseases (CIBERNED), Santiago de Compostela, Spain

    Ana I. Rodriguez-Perez, Antonio Dominguez-Meijide, Jose L. Lanciego, Maria J. Guerra & Jose L. Labandeira-Garcia

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  1. Ana I. Rodriguez-Perez
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  2. Antonio Dominguez-Meijide
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  3. Jose L. Lanciego
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  4. Maria J. Guerra
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  5. Jose L. Labandeira-Garcia
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Corresponding author

Correspondence to Jose L. Labandeira-Garcia.

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Rodriguez-Perez, A.I., Dominguez-Meijide, A., Lanciego, J.L. et al. Dopaminergic degeneration is enhanced by chronic brain hypoperfusion and inhibited by angiotensin receptor blockage. AGE 35, 1675–1690 (2013). https://doi.org/10.1007/s11357-012-9470-2

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  • DOI: https://doi.org/10.1007/s11357-012-9470-2

Keywords

  • Aging
  • Renin–angiotensin system
  • Cerebrovascular disease
  • Ischemia
  • Parkinson
  • Vascular parkinsonism