Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease mice.
The effect of chronic treatment with the selective adenosine A2A receptor antagonist SCH 58261 on the behavioral and electrophysiological alterations typical of R6/2 mice (a transgenic mouse model of Huntington's disease, HD), has been studied. Starting from 5 weeks of age, R6/2 and wild type (WT) mice were treated daily with SCH 58261 (0.01 mg/kg i.p.) for 7 days. In the following weeks, the ability of mice to perform in the rotarod, plus maze and open field tests were evaluated. In addition, with electrophysiological experiments in corticostriatal slices we tested whether the well-known increased NMDA vulnerability of R6/2 mice was prevented by SCH 58261 treatment. We found that chronic treatment with SCH 58262: i) fully prevented the alterations in emotional/anxious responses displayed by R6/2 mice; ii) did not prevent the impairment in motor coordination; iii) abolished the increase in NMDA-induced toxicity observed in the striatum of HD mice. On balance, targeting A2A receptors seems to have some beneficial effects in HD even though, given the complexity of A2A receptor pharmacology and HD pathogenesis, further studies are necessary to clarify whether A2A receptor antagonists have therapeutic potential in HD.
Domenici
M R
MR
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. mariarosaria.domenici@iss.it
Scattoni
M L
ML
Martire
A
A
Lastoria
G
G
Potenza
R L
RL
Borioni
A
A
Venerosi
A
A
Calamandrei
G
G
Popoli
P
P
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007859:Learning Disabilities / Q000188:drug therapy / Q000209:etiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D001523:Mental Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011743:Pyrimidines / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D018698:Glutamic Acid