Presymptomatic and symptomatic ALS SOD1(G93A) mice differ in adenosine A1 and A2A receptor-mediated tonic modulation of neuromuscular transmission.
Amyotrophic lateral sclerosis (ALS) is a disease leading to neuromuscular transmission impairment. A2A adenosine receptor (A2AR) function changes with disease stage, but the role of the A(1) receptors (A1Rs) is unknown and may have a functional cross-talk with A2AR. The role of A1R in the SOD1(G93A) mouse model of ALS in presymptomatic (4-6 weeks old) and symptomatic (12-14 weeks old) phases was investigated by recording endplate potentials (EPPs), miniature endplate potentials (MEPPs), and quantal content (q.c.) of EPPs, from Mg(2+) paralyzed hemidiaphragm preparations. In presymptomatic mice, the A1R agonist, N (6)-cyclopentyladenosine (CPA) (50 nM), decreased mean EPP amplitude, MEPP frequency, and q.c. of EPPs, an effect quantitatively similar to that in age-matched wild-type (WT) mice. However, coactivation of A2AR with CGS 21680 (5 nM) prevented the effects of CPA in WT mice but not in presymptomatic SOD1(G93A) mice, suggestive of A1R/A2AR cross-talk disruption in this phase of ALS. DPCPX (50 nM) impaired CGS 21680 facilitatory action on neuromuscular transmission in WT but not in presymptomatic mice. In symptomatic animals, CPA only inhibited transmission if added in the presence of adenosine deaminase (ADA, 1 U/mL). ADA and DPCPX enhanced more transmission in symptomatic mice than in age-matched WT mice, suggestive of increase in extracellular adenosine during the symptomatic phase of ALS. The data documents that at the neuromuscular junction of presymptomatic SOD1(G93A) mice, there is a loss of A1R-A2AR functional cross-talk, while in symptomatic mice there is increased A1R tonic activation, and that with disease progression, changes in A1R-mediated adenosine modulation may act as aggravating factors during the symptomatic phase of ALS.
Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal.|Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal.|Neuronal Control of Movement Lab, School of Psychology and Neuroscience, University of St Andrews, St Andrews, Fife, KY18, 9LB, Scotland.
Filipe
F
Nascimento
Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal.|Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal.
Ana M
AM
Sebastião
Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal. jaribeiro@medicina.ulisboa.pt.|Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal. jaribeiro@medicina.ulisboa.pt.
Joaquim A
JA
Ribeiro
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D009045:Motor Endplate / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000235:genetics*; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000235:genetics*; D013482:Superoxide Dismutase / Q000187:drug effects / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C048599:N(6)-cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000241:Adenosine
ALS; Adenosine; Neuromuscular transmission; SOD1(G93A) mice