Opposite effects of the A2A receptor agonist CGS21680 in the striatum of Huntington's disease versus wild-type mice.
Huntington's disease (HD) is an inherited neurodegenerative disorder. Adenosine A(2A) receptors (A(2A)Rs) are involved in excitotoxic/neurodegenerative processes, and A(2A)R ligands may be neuroprotective in models of HD. However, changes in the transcription, expression and function of A(2A)Rs have been reported to occur in HD models. The aim of the present work was to verify whether A(2A)R-mediated effects are altered in the striatum of transgenic HD (R6/2) versus wild-type (WT) mice. Extracellular field potentials (FPs) were recorded in corticostriatal slices from R6/2 mice in early (7-8 weeks) or frankly (12-13 weeks) symptomatic phases, and age-matched WT. In 12-13 weeks aged WT animals, the application of 75 microM NMDA induced a transient disappearance of the FP followed by an almost complete recovery at washout. In slices from HD mice, the mean FP recovery was significantly reduced (P<0.01 versus WT). A(2A)R activation oppositely modulated NMDA-induced toxicity in the striatum of HD versus WT mice. Indeed, the A(2A)R agonist CGS21680 reduced the FP recovery in slices from WT mice, while it significantly increased it in slices from R6/2 mice. In early symptomatic (7-8 weeks) mice, no differences were observed between WT and HD animals in terms of basal synaptic transmission and response to NMDA. At the same age, the behavioural effects elicited by CGS21680 were qualitatively identical in WT and HD mice. These findings may have very important implications for the neuroprotective potential of A(2A)R ligands in HD.
Martire
Alberto
A
Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. alberto.martire@iss.it
Calamandrei
Gemma
G
Felici
Fabio
F
Scattoni
Maria Luisa
ML
Lastoria
Giusi
G
Domenici
Maria Rosaria
MR
Tebano
Maria Teresa
MT
Popoli
Patrizia
P
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009924:Organ Culture Techniques; D010627:Phenethylamines / Q000494:pharmacology* / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
D058908:Adenosine A2 Receptor Agonists; D000959:Antihypertensive Agents; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine