Impacts of methylxanthines and adenosine receptors on neurodegeneration: human and experimental studies

Neurodegenerative disorders are some of the most feared illnesses in modern society, with no effective treatments to slow or halt this neurodegeneration. Several decades after the earliest attempt to treat Parkinson's disease using caffeine, tremendous amounts of information regarding the potential beneficial effect of caffeine as well as adenosine drugs on major neurodegenerative disorders have accumulated. In the first part of this review, we provide general background on the adenosine receptor signaling systems by which caffeine and methylxanthine modulate brain activity and their role in relationship to the development and treatment of neurodegenerative disorders. The demonstration of close interaction between adenosine receptor and other G protein coupled receptors and accessory proteins might offer distinct pharmacological properties from adenosine receptor monomers. This is followed by an outline of the major mechanism underlying neuroprotection against neurodegeneration offered by caffeine and adenosine receptor agents. In the second part, we discuss the current understanding of caffeine/methylxantheine and its major target adenosine receptors in development of individual neurodegenerative disorders, including stroke, traumatic brain injury Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple sclerosis. The exciting findings to date include the specific in vivo functions of adenosine receptors revealed by genetic mouse models, the demonstration of a broad spectrum of neuroprotection by chronic treatment of caffeine and adenosine receptor ligands in animal models of neurodegenerative disorders, the encouraging development of several A(2A) receptor selective antagonists which are now in advanced clinical phase III trials for Parkinson's disease. Importantly, increasing body of the human and experimental studies reveals encouraging evidence that regular human consumption of caffeine in fact may have several beneficial effects on neurodegenerative disorders, from motor stimulation to cognitive enhancement to potential neuroprotection. Thus, with regard to neurodegenerative disorders, these potential benefits of methylxanthines, caffeine in particular, strongly argue against the common practice by clinicians to discourage regular human consumption of caffeine in aging populations.