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Adenosine A2A receptor blockade differentially influences excitotoxic mechanisms at pre- and postsynaptic sites in the rat striatum.
J Neurosci Res. 2004 Jul 01; 77(1):100-7.JN

Abstract

Adenosine A(2A) receptor antagonists are being regarded as potential neuroprotective drugs, although the mechanisms underlying their effects need to be better studied. The aim of this work was to investigate further the mechanism of the neuroprotective action of A(2A) receptor antagonists in models of pre- and postsynaptic excitotoxicity. In microdialysis studies, the intrastriatal perfusion of the A(2A) receptor antagonist ZM 241385 (5 and 50 nM) significantly reduced, in an inversely dose-dependent way, the raise in glutamate outflow induced by 5 mM quinolinic acid (QA). In rat corticostriatal slices, ZM 241385 (30-100 nM) significantly reduced 4-aminopyridine (4-AP)-induced paired-pulse inhibition (PPI; an index of neurotransmitter release), whereas it worsened the depression of field potential amplitude elicited by N-methyl-D-aspartate (NMDA; 12.5 and 50 microM). The A(2A) antagonist SCH 58261 (30 nM) mimicked the effects of ZM 241385, whereas the A(2A) agonist CGS 21680 (100 nM) showed a protective influence toward 50 microM NMDA. In rat striatal neurons, 50 nM ZM 241385 did not affect the increase in [Ca(2+)](i) or the release of lactate dehydrogenase (LDH) induced by 100 and 300 microM NMDA, respectively. The ability of ZM 241385 to prevent QA-induced glutamate outflow and 4-AP-induced effects confirms that A(2A) receptor antagonists have inhibitory effects on neurotransmitter release, whereas the results obtained toward NMDA-induced effects suggest that A(2A) receptor blockade does not reduce, or even amplifies, excitotoxic mechanisms due to direct NMDA receptor stimulation. This indicates that the neuroprotective potential of A(2A) antagonists may be evident mainly in models of neurodegeneration in which presynaptic mechanisms play a major role.

Authors+Show Affiliations

Department of Pharmacology, Istituto Superiore di Sanità, Rome, Italy. tebano@iss.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15197743

Citation

Tebano, Maria Teresa, et al. "Adenosine A2A Receptor Blockade Differentially Influences Excitotoxic Mechanisms at Pre- and Postsynaptic Sites in the Rat Striatum." Journal of Neuroscience Research, vol. 77, no. 1, 2004, pp. 100-7.
Tebano MT, Pintor A, Frank C, et al. Adenosine A2A receptor blockade differentially influences excitotoxic mechanisms at pre- and postsynaptic sites in the rat striatum. J Neurosci Res. 2004;77(1):100-7.
Tebano, M. T., Pintor, A., Frank, C., Domenici, M. R., Martire, A., Pepponi, R., Potenza, R. L., Grieco, R., & Popoli, P. (2004). Adenosine A2A receptor blockade differentially influences excitotoxic mechanisms at pre- and postsynaptic sites in the rat striatum. Journal of Neuroscience Research, 77(1), 100-7.
Tebano MT, et al. Adenosine A2A Receptor Blockade Differentially Influences Excitotoxic Mechanisms at Pre- and Postsynaptic Sites in the Rat Striatum. J Neurosci Res. 2004 Jul 1;77(1):100-7. PubMed PMID: 15197743.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adenosine A2A receptor blockade differentially influences excitotoxic mechanisms at pre- and postsynaptic sites in the rat striatum. AU - Tebano,Maria Teresa, AU - Pintor,Annita, AU - Frank,Claudio, AU - Domenici,Maria Rosaria, AU - Martire,Alberto, AU - Pepponi,Rita, AU - Potenza,Rosa Luisa, AU - Grieco,Rosa, AU - Popoli,Patrizia, PY - 2004/6/16/pubmed PY - 2004/8/25/medline PY - 2004/6/16/entrez SP - 100 EP - 7 JF - Journal of neuroscience research JO - J Neurosci Res VL - 77 IS - 1 N2 - Adenosine A(2A) receptor antagonists are being regarded as potential neuroprotective drugs, although the mechanisms underlying their effects need to be better studied. The aim of this work was to investigate further the mechanism of the neuroprotective action of A(2A) receptor antagonists in models of pre- and postsynaptic excitotoxicity. In microdialysis studies, the intrastriatal perfusion of the A(2A) receptor antagonist ZM 241385 (5 and 50 nM) significantly reduced, in an inversely dose-dependent way, the raise in glutamate outflow induced by 5 mM quinolinic acid (QA). In rat corticostriatal slices, ZM 241385 (30-100 nM) significantly reduced 4-aminopyridine (4-AP)-induced paired-pulse inhibition (PPI; an index of neurotransmitter release), whereas it worsened the depression of field potential amplitude elicited by N-methyl-D-aspartate (NMDA; 12.5 and 50 microM). The A(2A) antagonist SCH 58261 (30 nM) mimicked the effects of ZM 241385, whereas the A(2A) agonist CGS 21680 (100 nM) showed a protective influence toward 50 microM NMDA. In rat striatal neurons, 50 nM ZM 241385 did not affect the increase in [Ca(2+)](i) or the release of lactate dehydrogenase (LDH) induced by 100 and 300 microM NMDA, respectively. The ability of ZM 241385 to prevent QA-induced glutamate outflow and 4-AP-induced effects confirms that A(2A) receptor antagonists have inhibitory effects on neurotransmitter release, whereas the results obtained toward NMDA-induced effects suggest that A(2A) receptor blockade does not reduce, or even amplifies, excitotoxic mechanisms due to direct NMDA receptor stimulation. This indicates that the neuroprotective potential of A(2A) antagonists may be evident mainly in models of neurodegeneration in which presynaptic mechanisms play a major role. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/15197743/Adenosine_A2A_receptor_blockade_differentially_influences_excitotoxic_mechanisms_at_pre__and_postsynaptic_sites_in_the_rat_striatum_ L2 - https://doi.org/10.1002/jnr.20138 DB - PRIME DP - Unbound Medicine ER -