Amyotrophic Lateral Sclerosis (ALS) and Adenosine Receptors

Abstract

In the present review we discuss the potential involvement of adenosinergic signaling, in particular the role of adenosine receptors, in amyotrophic lateral sclerosis (ALS). Though the literature on this topic is not abundant, the information so far available on adenosine receptors in animal models of ALS highlights the interest to continue to explore the role of these receptors in this neurodegenerative disease. Indeed, all motor neurons affected in ALS are responsive to adenosine receptor ligands but interestingly, there are alterations in pre-symptomatic or early symptomatic stages that mirror those in advanced disease stages. Information starts to emerge pointing toward a beneficial role of A_2A receptors (A_2AR), most probably at early disease states, and a detrimental role of caffeine, in clear contrast with what occurs in other neurodegenerative diseases. However, some evidence also exists on a beneficial action of A_2AR antagonists. It may happen that there are time windows where A_2AR prove beneficial and others where their blockade is required. Furthermore, the same changes may not occur simultaneously at the different synapses. In line with this, it is not fully understood if ALS is a dying back disease or if it propagates in a centrifugal way. It thus seems crucial to understand how motor neuron dysfunction occurs, how adenosine receptors are involved in those dysfunctions and whether the early changes in purinergic signaling are compensatory or triggers for the disease. Getting this information is crucial before starting the design of purinergic based strategies to halt or delay disease progression.

Keywords: adenosine receptors; amyotrophic lateral sclerosis (ALS); glial cells; neuromuscular junction; spinal cord motor neurons.

FIGURE 1

Schematic diagram of the reported changes in adenosine signaling at the neuromuscular junction in an ALS mice model. In wild type (A) neuromuscular junctions, adenosine activates both inhibitory A₁R and excitatory A_2AR, modulating acetylcholine release from motor nerve terminals. In ALS mice at the pre-symptomatic stage (B) there is a loss of A₁R/A_2AR functional cross-talk at the neuromuscular junction and the excitatory action of A_2AR is exacerbated. At the symptomatic stage (C) there is an increase of A₁R tonic activation, which may be contributing to neurotransmission failure on late disease stages, whereas the excitatory action of A_2AR disappears. For details see Nascimento et al. (2014, 2015). Perisynaptic Schwann cells contribute to the pool of ATP at the synaptic cleft but ATP signaling in these cells seems unchanged in ALS, in contrast with mACh signaling (Arbour et al., 2015). Interestingly, the exacerbated A_2AR signaling at the pre-symptomatic stage correlates with an enhanced release of ACh from nerve terminals and with signs of dysregulated calcium buffering at motor nerve endings (Rocha et al., 2013; Arbour et al., 2017).