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.

Effects of Caffeine on Olfactory Learning in Crickets

“…These receptors are effectively inhibited by biologically relevant concentrations of caffeine at the micromolar range (Fredholm et al, 1999;Nehlig, 1999;Rivera-Oliver and Díaz-Ríos, 2014). Adenosine receptors are widely distributed in the brain, in which they are involved in various neural functions.…”

Effect of Caffeine Chronically Consumed During Pregnancy on Adenosine A1 and A2A Receptors Signaling in Both Maternal and Fetal Heart from Wistar Rats

“…16 A growing body of research shows that coffee drinkers may be less likely to develop type 2 diabetes, stroke, depression, and neurodegenerative diseases, including Parkinson's and Alzheimer's. [25][26][27] However, contradictory evidence in the literature about the effect of caffeine in the heart has been described. Thus, habitual moderate coffee intake has been associated with beneficial 28 or neutral 29 effects on cardiovascular health.…”

Therapeutic Opportunities for Caffeine and A_2A Receptor Antagonists in Retinal Diseases

“…The beneficial effects exerted by caffeine on cognitive functions have been documented [18], and it was reported that caffeine consumption prevents memory disturbances associated with ageing [19,20,21]. Also, increasing attention has been given to caffeine since its intake has been associated with a reduced neurological damage in several neurodegenerative diseases [22]. In fact, a decreased risk of developing Parkinson's disease (PD) [23,24] and Alzheimer's disease (AD) [25] was associated with a higher intake of coffee.…”