Adenosine A2A receptors and neurotrophic factors: Relevance for parkinson's disease

Abstract

Neurotrophic factors (NTF) or drugs able to boost NTF actions have been frequently considered as promising therapies for neurodegenerative diseases namely for Parkinson's disease (PD). A considerable number of data was published demonstrating that there is a cross talk between NTF and a particular type of adenosine receptors, the A2A receptors (A2AR). Together, those studies show that relevant actions of NTF are dependent on or facilitated by activation of A2AR, so that most NTF actions on synapses are lost upon blockade of A2AR. These findings suggest caution in the use of A2AR antagonists whenever NTF actions are demanded and place the A2AR agonists in a suitable position as a pharmacologic strategy to potentiate NTF mediated actions in neurodegenerative diseases, including PD. However, the negative interaction between A2AR and dopamine D2 receptors in the striatum, together with the A2AR-mediated exacerbation of excitotoxicity mechanisms, points towards the therapeutic potential of A2AR antagonists in PD. Indeed, clinical trials with A2AR antagonists were already conducted. Here we detail the existing, molecular and functional, evidence for the cross-talk between NTF and A2AR and discuss its possible relevance for the treatment of PD. Available data highlights the need for considering appropriate time windows for the different strategies to fight the disease to avoid losing endogenous neurotrophic support in the early phases of the disease where synapses and neurons are to struggling for life.