title: A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions: implications for the neuroprotective potential of A2A antagonists.
abstract: Reduction of A2A 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 A2A receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A2A receptors in the pathogenesis of HD remains obscure. In the present study, using A2A-/- mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A2A receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A2A receptors and the protective activity of postsynaptic A2A receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A2A presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A2A receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A2A antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.
authors.affiliation: Laboratory of Neurophysiology, CP601, Université Libre de Bruxelles-Erasme, 1070 Brussels, Belgium. dablum@ulb.ac.be
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Galas
authors.forename: Annita
authors.initials: A
authors.lastname: Pintor
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Christa E
authors.initials: CE
authors.lastname: Muller
authors.forename: Kadiombo
authors.initials: K
authors.lastname: Bantubungi
authors.forename: Mariangela
authors.initials: M
authors.lastname: Galluzzo
authors.forename: David
authors.initials: D
authors.lastname: Gall
authors.forename: Laetitia
authors.initials: L
authors.lastname: Cuvelier
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Rolland
authors.forename: Patrizia
authors.initials: P
authors.lastname: Popoli
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009574:Nitro Compounds; D010627:Phenethylamines / Q000494:pharmacology; D011422:Propionates; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015996:Survival Rate; D013569:Synapses / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*
chemical_list: C113602:MSX 3 compound; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D010627:Phenethylamines; D011422:Propionates; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D018698:Glutamic Acid; D000241:Adenosine; C015392:3-nitropropionic acid