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.

In 6-hydroxydopamine-lesioned rats, the selective mGlu 5 receptor agonist (1)(2)(3)(4)(5)(6)

Reduction of A 2A receptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A 2A receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A 2A receptors in the pathogenesis of HD remains obscure. In the present study, using A 2A Ϫ/Ϫ mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A 2A receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A 2A receptors and the protective activity of postsynaptic A 2A receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A 2A presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A 2A receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A 2A antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.