A critical evaluation of adenosine A2A receptors as potentially "druggable" targets in Huntington's disease.
Huntington's 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 A(2A) 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 A(2A) receptors might play a pathogenetic role in HD. In agreement, changes in A(2A) receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A(2A) 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 A(2A) receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A(2A) receptors may represent a suitable target to develop drugs against HD.
Popoli
Patrizia
P
Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy. patrizia.popoli@iss.it
Blum
David
D
Domenici
Maria Rosaria
MR
Burnouf
Sylvie
S
Chern
Yijuang
Y
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D015398:Signal Transduction
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D018696:Neuroprotective Agents; D043705:Receptor, Adenosine A2A