Blockade of striatal adenosine A2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum.
The aim of the present study was to evaluate whether, and by means of which mechanisms, the adenosine A2A receptor antagonist SCH 58261 [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine] exerted neuroprotective effects in a rat model of Huntington's disease. In a first set of experiments, SCH 58261 (0.01 and 1 mg/kg) was administered intraperitoneally to Wistar rats 20 min before the bilateral striatal injection of quinolinic acid (QA) (300 nmol/1 microl). SCH 58261 (0.01 but not 1 mg/kg, i.p.) did reduce significantly the effects of QA on motor activity, electroencephalographic changes, and striatal gliosis. Because QA acts by both increasing glutamate outflow and directly stimulating NMDA receptors, a second set of experiments was performed to evaluate whether SCH 58261 acted by preventing the presynaptic and/or the postsynaptic effects of QA. In microdialysis experiments in naive rats, striatal perfusion with QA (5 mm) enhanced glutamate levels by approximately 500%. Such an effect of QA was completely antagonized by pretreatment with SCH 58261 (0.01 but not 1 mg/kg, i.p.). In primary striatal cultures, bath application of QA (900 microm) significantly increased intracellular calcium levels, an effect prevented by the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]. In this model, bath application of SCH 58261 (15-200 nm) tended to potentiate QA-induced calcium increase. We conclude the following: (1) the adenosine A2A receptor antagonist SCH 58261 has neuroprotective effects, although only at low doses, in an excitotoxic rat model of HD, and (2) the inhibition of QA-evoked glutamate outflow seems to be the major mechanism underlying the neuroprotective effects of SCH 58261.
Popoli
Patrizia
P
Department of Pharmacology, Istituto Superiore di Sanità, 299 00161 Rome, Italy. patrizia.popoli@iss.it
Pintor
Annita
A
Domenici
Maria Rosaria
MR
Frank
Claudio
C
Tebano
Maria Teresa
MT
Pèzzola
Antonella
A
Scarchilli
Laura
L
Quarta
Davide
D
Reggio
Rosaria
R
Malchiodi-Albedi
Fiorella
F
Falchi
Mario
M
Massotti
Marino
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000378:metabolism*; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000494:pharmacology; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / 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; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014230:Triazoles; D018698:Glutamic Acid; D017378:Quinolinic Acid; D002118:Calcium