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Pharmacol Res. 2011 Jun;63(6):525-31. doi: 10.1016/j.phrs.2010.12.008. Epub 2010 Dec 27.

Endothelin receptor antagonists: potential in Alzheimer's disease.

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1
Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, United Kingdom. jen.palmer@bristol.ac.uk

Abstract

Alzheimer's disease (AD) is believed to be initiated by the accumulation of neurotoxic forms of Aβ peptide within the brain. AD patients show reduction of cerebral blood flow (CBF), the extent of the reduction correlating with the impairment of cognition. There is evidence that cerebral hypoperfusion precedes and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs neuronal function, reduces the clearance of Aβ peptide and other toxic metabolites from the brain, and upregulates Aβ production. Studies in animal models of AD have shown the reduction in CBF to be more than would be expected for the reduction in neuronal metabolic activity. Aβ may contribute to the reduction in CBF in AD, as both Aβ₁₋₄₀ and Aβ₁₋₄₂ induce cerebrovascular dysfunction. Aβ₁₋₄₀ acts directly on cerebral arteries to cause cerebral smooth muscle cell contraction. Aβ₁₋₄₂ causes increased neuronal production and release of endothelin-1 (ET-1), a potent vasoconstrictor, and upregulation of endothelin-converting enzyme-2 (ECE-2), the enzyme which cleaves ET-1 from its inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that upregulation of the ECE-2-ET-1 axis by Aβ₁₋₄₂ contributes to the chronic reduction of CBF in AD. At present, only a few symptomatic treatment options exist for AD. The involvement of ET-1 in the pathogenesis of endothelial dysfunction associated with elevated Aβ indicates the potential for endothelin receptor antagonists in the treatment of AD. It has already been demonstrated that the endothelin receptor antagonist bosentan, preserves aortic and carotid endothelial function in Tg2576 mice, and our findings suggest that endothelin receptor antagonists may be beneficial in maintaining CBF in AD.

PMID:
21193044
DOI:
10.1016/j.phrs.2010.12.008
[Indexed for MEDLINE]
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