Adenosine receptors and Huntington's disease: implications for pathogenesis and therapeutics

Huntington's disease (HD) is a devastating hereditary neurodegenerative disorder, the progression of which cannot be prevented by any neuroprotective approach, despite major advances in the understanding of its pathogenesis. The study of several animal models of the disease has led to the discovery of both loss-of-normal and gain-of-toxic functions of the mutated huntingtin protein and the elucidation of the mechanisms that underlie the formation of huntingtin aggregates and nuclear inclusions. Moreover, these models also provide good evidence of a role for excitotoxicity and mitochondrial metabolic impairments in striatal neuronal death. Adenosine has neuroprotective potential in both acute and chronic neurological disorders such as stroke or Parkinson's disease. Here we review experimental data on the role of A(1) and A(2A) adenosine receptors in HD that warrant further investigation of the beneficial effects of A(1) agonists and A(2A) antagonists in animal models of HD. Future pharmacological analysis of adenosine receptors could justify the use of A(1) agonists and A(2A) antagonists for the treatment of HD in clinical trials.