Adenosine and related drugs in brain diseases: present and future in clinical trials

Adenosine is a naturally occurring nucleoside present ubiquitously throughout the body as a metabolic intermediate. Besides its metabolic role within the cells, adenosine is released into the extracellular space either by neurons or astrocytes acting as a neuromodulator. Extracellular adenosine exerts its action by activating multiple G-protein coupled receptors (subtypes A(1), A(2A), A(2B) and A(3)) having a wide range of physiological effects in the brain. Adenosine levels rise markedly in response to ischemia, hypoxia, excitotoxicity or inflammation being a neuroprotectant under these conditions. However, adenosine may also contribute to neuronal damage and cell death in other circumstances. These actions are firmly established using multiple animal models. Therefore, increasing attention is now given to the role of adenosine in human brain function and its potential benefit for clinical applications. This review covers recent studies undertaken mostly in humans revealing the actions of adenosine and related drugs in cognition and memory as well as in various pathological situations such as psychiatric disorders, drug addiction and neurodegenerative disorders. The actual use of adenosine or adenosine receptor ligands in ongoing clinical trials for the treatment of schizophrenia, panic disorder and anxiety, cocaine dependence and Parkinson's disease is discussed. The evidence herein reviewed highlights the promising potential of adenosine or adenosine receptor ligands as therapeutic agents in several brain disorders.