Targeting Adenosine Receptors in Neurological Diseases

Abstract

Adenosine plays a significant role in neurotransmission process by controlling the blood pressure, while adenosine triphosphate (ATP) acts as a neuromodulator and neurotransmitter and by activation of P2 receptors, regulates the contractility of the heart. Adenosine signaling is essential in the process of regeneration by regulating proliferation, differentiation, and apoptosis of stem cells. In this review, we have selected neurological disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy) with clinical trials using antagonists and epigenetic tools targeting adenosine receptor as a therapeutic approach in the treatment of these disorders. Promising results have been reported from many clinical trials. It has been found that higher expression levels of A2A and P2X7 receptors in neurological disorders further complicate the disease condition. Therefore, modulations of these receptors by using antagonists of these receptors or SAM (S-adenosylmethionine) therapy as an epigenetic tool could be useful in reversing the complications of these disorders. Finally, we suggest that modulation of adenosine receptors in neurological disorders can increase the regenerative phase by increasing the rate of proliferation and differentiation in the damaged tissues.

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

“…The functional roles of A 1 R and A 2A R in many neurodegenerative diseases (including AD, HD, ALS, and PD) have been extensively investigated throughout the past two decades. The current progress has been summarized and discussed in detail in recent reviews [ 15 , 91 , 157 ] and thus is not elaborated here. Previously, A 2B R and A 3 R were believed to exert only minor effects in the brain due to their low levels of expression and relatively low affinities for adenosine.…”

“…Nonetheless, the beneficial effects of small molecules targeting adenosine receptors seem moderate and may be effective only in specific treatment windows [ 187 ]. Because recent progress on this topic has been extensively reviewed [ 15 , 74 ], no further elaboration on the function and regulation of adenosine receptors in AD is presented here.…”

Effects of Postnatal Caffeine Exposure on Absence Epilepsy and Comorbid Depression: Results of a Study in WAG/Rij Rats

“…Caffeine is a competitive nonselective P1 receptor antagonist binding to the A1 receptor as well as the A2A receptor [23]. Contrary to A1 receptors, the action of A2A receptors results in activation of adenylate cyclase further causing an increase in glutamatergic transmission [34]. Accordingly, the answer to the question of the effects of caffeine on the development of seizure activity is not simple.…”

“…Previous research showed that caffeine may cause neuronal hyperexcitability by increasing Ca 2 influx, changing potassium currents and antagonism of inhibitory A1 adenosine receptors [23,34,35]. In fact, caffeine was previously proposed as an animal model of seizures [36].…”

A2A Adenosine Receptor as a Potential Biomarker and a Possible Therapeutic Target in Alzheimer’s Disease

“…Numerous efforts of several scientists around the world, working in the purinergic field, point to a role of A 2A receptor antagonists in the therapy of different neurological ailments [88,[120][121][122]. Specifically, clinical studies led to the development of the new firstin-class drug istradefylline, Nourias and Nourianz, in Japan and the US, respectively, for the treatment of Parkinson's disease [98].…”