Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review

Abstract

Caffeine is the most consumed pychostimulant in the world, and it is known to affect basic and fundamental human processes such as sleep, arousal, cognition and learning and memory. It works as a nonselective blocker of adenosine receptors (A1, A2a, A2b and A3) and has been related to the regulation of heart rate, the contraction/relaxation of cardiac and smooth muscles, and the neural signaling in the central nervous system (CNS). Since the late 1990s, studies using adenosine receptor antagonists, such as Caffeine, to block the A1 and A2a adenosine receptor subtypes have shown to reduce the physical, cellular and molecular damages caused by a spinal cord injury (SCI) or a stroke (cerebral infarction) and by other neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Interestingly, other studies using adenosine receptor agonists have also shown to provide a neuroprotective effect on various models of neurodegenerative diseases through the reduction of excitatory neurotransmitter release, apoptosis and inflammatory responses, among others. The seemingly paradoxical use of both adenosine receptor agonists and antagonists as neuroprotective agents has been attributed to differences in dosage levels, drug delivery method, extracellular concentration of excitatory neurotransmitters and stage of disease progression. We discuss and compare recent findings using both antagonists and agonists of adenosine receptors in animal models and patients that have suffered spinal cord injuries, brain strokes, and Parkinson's and Alzheimer's diseases. Additionally, we propose alternative interpretations on the seemingly paradoxical use of these drugs as potential pharmacological tools to treat these various types of neurodegenerative diseases.

Keywords: Adenosine receptors; Alzheimer's disease; Caffeine; Parkinson's disease; Spinal cord injury; Stroke.

Fig. 1

Summary of the reported results of using adenosine receptor agonists and antagonists to treat the main detrimental effects caused by a spinal cord injury, stroke, and Parkinson's and Alzheimer's diseases. *The effects of A2a receptor agonists on cell death caused by a stroke have been shown to include a neuroprotective role in acute experiments and a neurally detrimental role in chronic experiments after brain damage (Stone et al., 2009).

Fig. 1

Summary of the reported results of using adenosine receptor agonists and antagonists to treat the main detrimental effects caused by a spinal cord injury, stroke, and Parkinson's and Alzheimer's diseases. *The effects of A2a receptor agonists on cell death caused by a stroke have been shown to include a neuroprotective role in acute experiments and a neurally detrimental role in chronic experiments after brain damage (Stone et al., 2009).