Genetic and pharmacological inactivation of the adenosine A2A receptor attenuates 3-nitropropionic acid-induced striatal damage.
Adenosine A2A receptor (A2AR) antagonism attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and quinolinic acid-induced excitotoxicity in the neostriatum. As A2ARs are enriched in striatum, we investigated the effect of genetic and pharmacological A2A inactivation on striatal damage produced by the mitochondrial complex II inhibitor 3-nitropriopionic acid (3-NP). 3-NP was administered to A2AR knockout (KO) and wild-type (WT) littermate mice over 5 days. Bilateral striatal lesions were analyzed from serial brain tissue sections. Whereas all of the 3-NP-treated WT mice (C57BL/6 genetic background) had bilateral striatal lesions, only one of eight of the 3-NP-treated A2AR KO mice had detectable striatal lesions. Similar attenuation of 3-NP-induced striatal damage was observed in A2AR KO mice in a 129-Steel background. In addition, the effect of pharmacological antagonism on 3-NP-induced striatal neurotoxicity was tested by pre-treatment of C57Bl/6 mice with the A2AR antagonist 8-(3-chlorostyryl) caffeine (CSC). Although bilateral striatal lesions were observed in all mice treated either with 3-NP alone or 3-NP plus vehicle, there were no demonstrable striatal lesions in mice treated with CSC (5 mg/kg) plus 3-NP and in five of six mice treated with CSC (20 mg/kg) plus 3-NP. We conclude that both genetic and pharmacological inactivation of the A2AR attenuates striatal neurotoxicity produced by 3-NP. Since the clinical and neuropathological features of 3-NP-induced striatal damage resemble those observed in Huntington's disease, the results suggest that A2AR antagonism may be a potential therapeutic strategy in Huntington's disease patients.
Fink
J Stephen
JS
Department of Neurology, Boston University School of Medicine, MA 02118, USA.
Kalda
Anti
A
Ryu
Hoon
H
Stack
Edward C
EC
Schwarzschild
Michael A
MA
Chen
Jiang-Fan
JF
Ferrante
Robert J
RJ
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D043705:Receptor, Adenosine A2A / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
D058917:Adenosine A2 Receptor Antagonists; D009574:Nitro Compounds; D011422:Propionates; D043705:Receptor, Adenosine A2A; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine; C015392:3-nitropropionic acid