Abstract
Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A2A receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A2A receptors might play a pathogenetic role in HD. In agreement, changes in A2A receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A2A receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A2A receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A2A receptors may represent a suitable target to develop drugs against HD.
Keywords: Adenosine A2A receptors, Huntington's disease, excitotoxicity, mitochondrial dysfunction, experimental models, BDNF, Dopamine, Heterodimers
Current Pharmaceutical Design
Title: A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease
Volume: 14 Issue: 15
Author(s): Patrizia Popoli, David Blum, Maria Rosaria Domenici, Sylvie Burnouf and Yijuang Chern
Affiliation:
Keywords: Adenosine A2A receptors, Huntington's disease, excitotoxicity, mitochondrial dysfunction, experimental models, BDNF, Dopamine, Heterodimers
Abstract: Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A2A receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A2A receptors might play a pathogenetic role in HD. In agreement, changes in A2A receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A2A receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A2A receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A2A receptors may represent a suitable target to develop drugs against HD.
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Popoli Patrizia, Blum David, Domenici Rosaria Maria, Burnouf Sylvie and Chern Yijuang, A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease, Current Pharmaceutical Design 2008; 14 (15) . https://dx.doi.org/10.2174/138161208784480117
DOI https://dx.doi.org/10.2174/138161208784480117 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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