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.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive neurodegenerative disease characterized by the selective loss of motor neuron function leading to muscle atrophy and weakness
To evaluate the role of A2A receptors on neuromuscular transmission, while comparing the effect of CGS 21680 on the mean amplitude of Endplate potentials (EPPs) recorded in both groups of animals, it could be concluded that at 3 nM there were no significant differences between groups (p.0.05, Unpaired t-test) while at 5 nM and 10 nM the facilitation caused by CGS 21680 on EPPs amplitude was significantly higher in pre-symptomatic SOD1(G93A) mice (5 nM: n = 13; 10 nM: n = 5; p,0.05, Unpaired t-test), when compared to the WT group (5 nM: n = 14; 10 nM: n = 7)
The main finding of the present work was that the role of adenosine A2A receptors at the neuromuscular junction of the ALS SOD1(G93A) mouse model changes with disease progression
Summary
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive neurodegenerative disease characterized by the selective loss of motor neuron function leading to muscle atrophy and weakness. Most of the diagnosed cases carry an unknown genetic link (sporadic ALS) and a few (5– 10%) are related to known mutations in specific proteins (familial ALS). The first gene associated with the inherited form of the disease was the SOD1 gene encoding for the superoxide dismutase 1 enzyme which accounts for 20% of the familial forms of ALS [3]. This led to the design of the first animal model of ALS, the SOD1(G93A) mouse, which currently is the most used and well characterized rodent model for this disease [4]. We recently showed that the SOD1(G93A) mice neuromuscular transmission impairment starts long before symptomatic onset [7]
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