Adenosine and glutamate extracellular concentrations and mitogen-activated protein kinases in the striatum of Huntington transgenic mice. Selective antagonism of adenosine A2A receptors reduces transmitter outflow.
The basal ganglia and deep layers of cerebral cortex neurodegeneration typically characterize the postmortem brain of Huntington disease (HD) patients. In this study, we employed 10- to 11-week-old transgenic HD mice (R6/2 line), in which the striatal adenosine extracellular levels, measured using the microdialysis technique, are significantly increased in comparison to wild-type mice. An increase in striatal adenosine is probably a precocious index of mitochondrial dysfunction that is described in both the postmortem brain of HD patients and transgenic mice striatal cells. The adenosine increase is matched by activation of the p38 mitogen-activated protein kinase (MAPK) in the striatal neurons of R6/2 mouse but not in the cortex. This result indicates that p38 MAPK is a correlate of striatal damage and suggests a role for p38 in the striatal neuron suffering and apoptosis described in this disease. The selective adenosine A(2A) receptor antagonist SCH 58261, administered through microdialysis fiber into the striatum, significantly decreases the outflow of glutamate in R6/2 mice. Antagonism of adenosine A(2A) receptors might be regarded as potentially useful in the treatment of this disease to control striatal excitotoxicity.
Gianfriddo
M
M
Department of Preclinical and Clinical Pharmacology, University of Florence, 50139, Florence, Italy.
Melani
A
A
Turchi
D
D
Giovannini
M G
MG
Pedata
F
F
D000241:Adenosine / Q000378:metabolism*; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism*; D045604:Extracellular Fluid / Q000201:enzymology / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006816:Huntington Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; 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; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases; D000241:Adenosine