title: Purinergic modulation of glutamate release under ischemic-like conditions in the hippocampus.
abstract: The aim of the present study was to explore whether endogenous activation of different purine receptors by ATP and adenosine contributes to or inhibits excess glutamate release evoked by ischemic-like conditions in rat hippocampal slices. Combined oxygen-glucose deprivation (OGD) elicited a substantial, [Ca(2+)](o)-independent release of [(3)H]glutamate, which was tetrodotoxin (1 microM)-sensitive and temperature-dependent. The P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 0.1-10 microM), and the selective P2X(7) receptor antagonist Brilliant Blue G (1-100 nM), decreased OGD-evoked [(3)H]glutamate efflux indicating that endogenous ATP facilitates ischemia-evoked glutamate release. The selective A(1)-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.1-250 nM) and the selective A(2A) receptor antagonists 4-(2-[7-amino-2-)2-furyl(triazolo-[1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385, 0.1-20 nM) and 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261, 2-100 nM) decreased OGD-evoked [(3)H]glutamate efflux, indicating that endogenous adenosine also facilitates glutamate release under these conditions. The effect of DPCPX and ZM241385 was reversed, whereas the action of P2 receptor antagonists was potentiated by the selective ecto-ATPase inhibitor 6-N,N-diethyl-D-beta,gamma-dibromomethyleneATP (ARL67156, 50 microM). The binding characteristic of the A(2A) ligand [(3)H]CGS21680 to hippocampal membranes did not change significantly in response to OGD. Taken together these data suggest that while A(1) receptors might became desensitized, A(2A) and P2X receptor-mediated facilitation of glutamate release by endogenous ATP and its breakdown product adenosine remains operational under long-term OGD. Therefore the inhibition of P2X/A(2A) receptors rather than the stimulation of A(1) adenosine receptors could be an effective approach to attenuate glutamatergic excitotoxicity and thereby counteract ischemia-induced neurodegeneration.
authors.affiliation: Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Szigony u. 43., Hungary. sperlagh@koki.hu
authors.forename: B
authors.initials: B
authors.lastname: Sperlágh
authors.forename: G
authors.initials: G
authors.lastname: Zsilla
authors.forename: M
authors.initials: M
authors.lastname: Baranyi
authors.forename: P
authors.initials: P
authors.lastname: Illes
authors.forename: E S
authors.initials: ES
authors.lastname: Vizi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications; D066298:In Vitro Techniques; D007511:Ischemia / Q000209:etiology / Q000473:pathology*; D008297:Male; D010627:Phenethylamines / Q000378:metabolism; D058913:Purinergic Agonists; D058914:Purinergic Antagonists; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011983:Receptors, Purinergic / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / 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; C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D000700:Analgesics; D010627:Phenethylamines; D058913:Purinergic Agonists; D058914:Purinergic Antagonists; D011743:Pyrimidines; D011983:Receptors, Purinergic; D026941:Sodium Channel Blockers; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D018698:Glutamic Acid; D013779:Tetrodotoxin; D000255:Adenosine Triphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D005947:Glucose; D000241:Adenosine