Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease.
The aim of this review is to summarize and critically discuss the complex role played by adenosine A(2A) receptors (A(2A)Rs) in Huntington's disease (HD). Since A(2A)Rs are mainly localized on the neurons, which degenerate early in HD, and given their ability to stimulate glutamate outflow and inflammatory gliosis, it was hypothesized that they could be involved in the pathogenesis of HD, and that A(2A)R antagonists could be neuroprotective. This was further sustained by the demonstration that A(2A)Rs and underlying signaling systems undergo profound changes in cellular and animal models of HD. More recently, however, the equation A(2A) receptor blockade=neuroprotection has appeared too simplistic. First, it is now definitely clear that, besides mediating 'bad' responses (for example, stimulation of glutamate outflow and excessive glial activation), A(2A)Rs also promote 'good' responses (such as trophic and antinflammatory effects). This implies that A(2A)R blockade results either in pro-toxic or neuroprotective effects according to the mechanisms involved in a given experimental model. Second, since HD is a chronically progressive disease, the multiple mechanisms involving A(2A)Rs may play different relative roles along the degenerative process. Such different mechanisms can be influenced by A(2A)R activation or blockade in different ways, even leading to opposite outcomes depending on the time of agonist/antagonist administration. The number, and the complexity, of the possible scenarios is further increased by the influence of mutant Huntingtin on both the expression and functions of A(2A)Rs, and by the strikingly different effects mediated by A(2A)Rs expressed by different cell populations within the brain.
Popoli
Patrizia
P
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy. patrizia.popoli@iss.it
Blum
David
D
Martire
Alberto
A
Ledent
Catherine
C
Ceruti
Stefania
S
Abbracchio
Maria P
MP
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A / Q000502:physiology*
D058917:Adenosine A2 Receptor Antagonists; D018696:Neuroprotective Agents; D043705:Receptor, Adenosine A2A