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The Journal of Neuroscience, March 1, 2002, 22(5):1967-1975

Blockade of Striatal Adenosine A_2A Receptor Reduces, through a Presynaptic Mechanism, Quinolinic Acid-Induced Excitotoxicity: Possible Relevance to Neuroprotective Interventions in Neurodegenerative Diseases of the Striatum

Patrizia Popoli¹, Annita Pintor¹, Maria Rosaria Domenici¹, Claudio Frank¹, Maria Teresa Tebano¹, Antonella Pèzzola¹, Laura Scarchilli¹, Davide Quarta¹, Rosaria Reggio¹, Fiorella Malchiodi-Albedi², Mario Falchi², and Marino Massotti¹

Departments of ¹ Pharmacology and ² Ultrastructures, Istituto Superiore di Sanità, 299 00161 Rome, Italy

The aim of the present study was to evaluate whether, and by means of which mechanisms, the adenosine A_2A 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 µl). 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 naïve rats, striatal perfusion with QA (5 mM) enhanced glutamate levels by ~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 µM) 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 A_2A 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.

Key words: adenosine A_2A receptors; quinolinic acid; Huntington's disease; neuroprotection; SCH 58261; striatum

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2251967-09$05.00/0

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