Protective Agents in Parkinson's Disease: Caffeine and Adenosine A2A Receptor Antagonists

The pharmacologic management of Parkinson’s disease is based on drugs that act on the motor symptoms, whereas there are currently no drugs available that can alter the progressive neurodegeneration of dopaminergic neurons. Based on recent findings suggesting that the adenosinergic system is one of the most interesting in the field of neuroprotection in Parkinson’s disease, this chapter describes the functions of adenosine and its receptors in the central nervous system, with particular emphasis on their role in neurotoxicity/neuroprotection. Results of epidemiologic surveys demonstrating that intake of caffeine, an adenosine A1/A2A receptor antagonist, is inversely correlated with Parkinson’s disease are summarized. Moreover, evidence originating from preclinical studies showing that the antagonism of the adenosine A2A receptor is responsible for the neuroprotective effects of caffeine is also presented. This chapter therefore provides a comprehensive analysis of the current literature concerning the adenosinergic-based neuroprotective intervention strategy for Parkinson’s disease

Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss