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

Abstract

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.

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

“…Consistent with the possible beneficial role of the A 2A R in HD, Mievis and colleagues demonstrated that elimination of the A 2A R exacerbated HD progression in a mouse model of HD (55). Future investigations are required to evaluate the therapeutic potential of A 2A R drugs (56).…”

Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

“…The neuroprotective effect of A 2A R activation in these injury models has been primarily attributed to inhibition of inflammatory processes and vascular effects. Furthermore, the neuroprotective effects of A 2A R agonists and antagonists are dependent on the stages of pathological processes (Li et al, 2006;Popoli et al, 2008), extents of brain injury (Blum et al, 2003), or routes of drug delivery (Jones et al, 1998a).…”

Experimental Models for Identifying Modifiers of Polyglutamine-Induced Aggregation and Neurodegeneration

“…In this platform, expression of mHTT exon 1 fragment (73 CAG) reduced striatal and cortical neuron survival compared with normal Q-length controls. Screening in 96-well plate format led to identification of several compound classes with known and novel neuroprotective actions, including compounds that had been previously identified in screens using different endpoints (e.g., the ROCK inhibitor Y-27632) [25] or acted on gene targets implicated in other HD models (e.g., inhibitor of kappa B (IκB) kinase and the adenosine 2A receptor) [58][59][60].…”