Adenosine A2A receptor antagonism increases nNOS-immunoreactive neurons in the striatum of Huntington transgenic mice.
Medium spiny GABAergic projection neurons are progressively lost in Huntington's disease (HD), whereas there is preferential sparing of the few interneurons co-expressing NPY, somatostatin and neuronal nitric oxide synthase. We investigated the effect of the selective adenosine A(2A) receptor antagonist SCH58261 (0.01 mg/kg, acutely and chronically administered i.p.) on nNOS striatal expression and motor impairment in R6/2 transgenic mice in clearly symptomatic phase (10-11-week old). SCH58261 chronically administered increased the number of nNOS-immunoreactive neurons (nNOS-IR) in the striatum of R6/2 mice. No glial activation was detected in the striatum or cortex. SCH58261 also improved walking in the inclined plane test but not motor capability evaluated by the rotarod test. These findings demonstrate for the first time a role of adenosine A(2A) receptors in regulating nNOS expression in the striatum. We suggest that the protective effect of A(2A) antagonism in HD is related to the increase in striatal nNOS-IR neurons.
Cipriani
S
S
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
Bizzoco
E
E
Gianfriddo
M
M
Melani
A
A
Vannucchi
M G
MG
Pedata
F
F
D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D026602:Nitrergic Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
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; D018696:Neuroprotective Agents; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D000241:Adenosine