Adenosine A2A receptor antagonism increases neuronal nitric oxide syntase expression in the striatum of huntington transgenic mice

Huntington disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive disturbances caused by an expansion in CAG repeats in the IT15 gene which encodes the huntingtin. protein. Medium spiny GABAergic projection neurons are progressively lost in HD, whereas there is preferential sparing of the few interneurons co-expressing NPY, somatostatin and neuronal nitric oxide synthase (nNOS). We investigated the effect of the selective adenosine A2A receptor antagonist SCH58261 (0.01 mg/kg, i.p., acutely and chronically administered) on nNOS striatal expression and motor impairment in R6/2 transgenic mice in clearly symptomatic phase (10–11 weeks old mice). SCH58261, acutely administered (90 min before sacrifice), increased the number of nNOS immunoreactive neurons (nNOS-IR) (+22%) in the striatum of HD mice at 11 weeks of age (n=4) in comparison to wild-type mice (n=8). SCH58261, chronically administered (twice a day for two weeks), significantly increased the number of nNOS-IR (+35%)in the striatum of R6/2 mice at 11 weeks of age (n=6) in comparison to wild-type mice (n=8). At this age, 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 A2A receptors in regulating nNOS expression in the striatum. We suggest that the protective effect of A2A antagonism in HD is related to the increase in striatal nNOS-IR neurons.