Adenosine A2A Receptors Activation Facilitates Neuromuscular Transmission in the Pre-Symptomatic Phase of the SOD1(G93A) ALS Mice, but Not in the Symptomatic Phase

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease leading to motor neuron dysfunction resulting in impairment of neuromuscular transmission. A2A adenosine receptors have already been considered as a potential therapeutical target for ALS but their neuromodulatory role at the neuromuscular junction in ALS remains to be clarified. In the present work, we evaluated the effects of A2A receptors on neuromuscular transmission of an animal model of ALS: SOD1(G93A) mice either in the pre-symptomatic (4–6 weeks old) or in the symptomatic (12–14 weeks old) stage. Electrophysiological experiments were performed obtaining intracellular recordings in Mg2+ paralyzed phrenic nerve-hemidiaphragm preparations. Endplate potentials (EPPs), quantal content (q. c.) of EPPs, miniature endplate potentials (MEPPs) and giant miniature endplate potential (GMEPPs) were recorded. In the pre-symptomatic phase of the disease (4–6 weeks old mice), the selective A2A receptor agonist, CGS 21680, significantly enhanced (p<0.05 Unpaired t-test) the mean amplitude and q.c. of EPPs, and the frequency of MEPPs and GMEPPs at SOD1(G93A) neuromuscular junctions, the effect being of higher magnitude (p<0.05, Unpaired t-test) than age-matched control littermates. On the contrary, in symptomatic mice (12–14 weeks old), CGS 21680 was devoid of effect on both the amplitude and q.c. of EPPs and the frequency of MEPPs and GMEPPs (p<0.05 Paired t-test). The results herein reported clearly document that at the neuromuscular junction of SOD1(G93A) mice there is an exacerbation of A2A receptor-mediated excitatory effects at the pre-symptomatic phase, whereas in the symptomatic phase A2A receptor activation is absent. The results thus suggest that A2A receptors function changes with ALS progression.

Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis

“…These results provide interesting evidence about a novel toxic effect of adenosine on motor neurons. An enhanced A 2a R signaling in the neuromuscular junctions at the pre-symptomatic (but not at the symptomatic) stages of SOD1G93A mice has also been observed (Nascimento et al, 2014). Although our observation indicates that the A 2a R expression is altered at the symptomatic stage, the specific disease stages from which the A 2a R signaling is altered in SOD1G93A mice likely resulted from different regions examined in our study and the previous study (Nascimento et al, 2014).…”

“…An enhanced A 2a R signaling in the neuromuscular junctions at the pre-symptomatic (but not at the symptomatic) stages of SOD1G93A mice has also been observed (Nascimento et al, 2014). Although our observation indicates that the A 2a R expression is altered at the symptomatic stage, the specific disease stages from which the A 2a R signaling is altered in SOD1G93A mice likely resulted from different regions examined in our study and the previous study (Nascimento et al, 2014). Although chronic administration of caffeine, a non-specific antagonist of all adenosine receptors, significantly shortens overall survival of SOD1G93A mice without obvious effect on the body weight and motor phenotypes (Potenza et al, 2013), this likely resulted from the pan-inhibition of all adenosine receptors, especially the neuroprotective A 1 R.…”

The neuroprotective effects of caffeine in neurodegenerative diseases

“…Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by degeneration of the upper and lower motor neurons, resulting in skeletal muscle atrophy and death by respiratory failure within 3‐5 years of initial symptoms . Pathological hallmarks of this disease include the following: progressive muscle weakness, atrophy, and spasticity .…”

“…An exacerbated A 2A R‐mediated action, along with the reported loss of A 2A R/A 1 R interaction, could induce the neuromuscular transmission toward a hyperexcitable adenosinergic tonus that could contribute to the Ca 2+ ‐mediated excitotoxicity in presymptomatic ALS . In the presymptomatic mouse model of ALS, the A 2A R‐mediated excitatory effects are exacerbated, but this effect disappears in postsymptomatic mice . A 2A R signaling is also terminated in aged, wild‐type mice, suggesting that disease‐induced early aging of the A 2A R influences neuromuscular transmission.…”

The Adenosinergic System

“…A 2A R have been considered potential therapeutic targets for several disorders such as ALS Potenza et al 2013;Yanpallewar et al 2012), though either agonists Yanpallewar et al 2012) or antagonists ) have been regarded as potentially relevant. A recent work (Nascimento et al 2014) demonstrates that in a SOD1 mouse model of ALS there is an exacerbation of the A 2A Rmediated signaling at neuromuscular junctions of pre-symptomatic mice, whereas in the symptomatic phase the A 2A R excitatory action disappears (Nascimento et al 2014). A recent work (Nascimento et al 2014) demonstrates that in a SOD1 mouse model of ALS there is an exacerbation of the A 2A Rmediated signaling at neuromuscular junctions of pre-symptomatic mice, whereas in the symptomatic phase the A 2A R excitatory action disappears (Nascimento et al 2014).…”