title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Istituto Superiore di Sanità, 299 00161 Rome, Italy. patrizia.popoli@iss.it
authors.forename: Patrizia
authors.initials: P
authors.lastname: Popoli
authors.forename: Annita
authors.initials: A
authors.lastname: Pintor
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Domenici
authors.forename: Claudio
authors.initials: C
authors.lastname: Frank
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Tebano
authors.forename: Antonella
authors.initials: A
authors.lastname: Pèzzola
authors.forename: Laura
authors.initials: L
authors.lastname: Scarchilli
authors.forename: Davide
authors.initials: D
authors.lastname: Quarta
authors.forename: Rosaria
authors.initials: R
authors.lastname: Reggio
authors.forename: Fiorella
authors.initials: F
authors.lastname: Malchiodi-Albedi
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.forename: Marino
authors.initials: M
authors.lastname: Massotti
mesh_terms: 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
chemical_list: 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