Adenosine and Its Receptors as Potential Drug Targets in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease that involves the progressive degeneration of the motor neurons of the spinal cord and motor cortex. Severe muscle wasting and bioenergetic disturbances are important hallmarks of ALS. Approximately 90% of all ALS cases are sporadic, while only 10% of ALS cases are familial. As of June 2018, mutations in more than 25 genes have been implicated in ALS. Several experimental models have been designed and established based on these disease-causing ALS genes. To date, riluzole and edaravone are the only available clinical drugs, and they can only slow the disease progression of ALS to some extent. Adenosine is a nucleoside that serves as a homeostatic regulator in the brain. It modulates important pathophysiological functions and the bioenergetic network by controlling receptor-dependent and receptor-independent signaling pathways. In the central nervous system, there are four adenosine receptors (ARs, A 1 , A 2A , A 2B , and A 3), two families of adenosine transporters (concentrative nucleoside transporters and equilibrative nucleoside transporters), and a handful of enzymes that modulate adenosine homeostasis extracellularly and/or intracellularly. Accumulating evidence suggests that the components involved in adenosine homeostasis and ARs are altered dynamically in ALS patients and/or experimental models of ALS. In this review, we highlight recent findings on the role of adenosine in ALS and discuss the potential of ARs and the components involved in adenosine homeostasis as drug targets for this devastating disease.