A Critical Evaluation of Adenosine A2A Receptors as Potentially “Druggable” Targets in Huntingtons Disease

Author(s): Patrizia Popoli, David Blum, Maria Rosaria Domenici, Sylvie Burnouf, Yijuang Chern

Journal Name: Current Pharmaceutical Design

Volume 14 , Issue 15 , 2008

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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

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Article Details

Year: 2008
Page: [1500 - 1511]
Pages: 12
DOI: 10.2174/138161208784480117
Price: $65

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