A Dual Role of Adenosine A2AReceptors in 3-Nitropropionic Acid-Induced Striatal Lesions: Implications for the Neuroprotective Potential of A2AAntagonists
Copyright policy )A Dual Role of Adenosine A2AReceptors in 3-Nitropropionic Acid-Induced Striatal Lesions: Implications for the Neuroprotective Potential of A2AAntagonists
Reduction of A2Areceptor 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 A2Areceptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A2Areceptors 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 A2Areceptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A2Areceptors and the protective activity of postsynaptic A2Areceptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A2Apresynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A2Areceptors has differential effects on striatal cell deathin vivodepending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A2Aantagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective—neurotoxic effects.
Male, Encephalitis -- metabolism, Adenosine, Synapses -- metabolism, Wistar, Huntington Disease -- physiopathology, Signal Transduction -- drug effects, Mice, Receptors, Adenosine -- pharmacology, Huntington Disease -- pathology, Mice, Knockout, Inbred Lew, Cell Death, Encephalitis -- chemically induced, Purinergic P1 -- drug effects, Sciences bio-médicales et agricoles, Nitro Compounds, Corpus Striatum -- drug effects, Propionic Acids, Survival Rate, Huntington Disease, Neuroprotective Agents, Body Weight -- drug effects, Encephalitis -- pathology, Encephalitis, Cell Death -- genetics, Receptor, Phenethylamines -- pharmacology, Purinergic P1 -- genetics, Purinergic P1 -- metabolism, Adenosine -- analogs & derivatives, Knockout, Glutamic Acid, Xanthines -- pharmacology, Drug Administration Schedule, Adenosine A2A, Phenethylamines, Animals, Corpus Striatum -- physiopathology, Signal Transduction -- physiology, Genetic Predisposition to Disease, Cell Death -- drug effects, RNA, Messenger, Messenger -- biosynthesis, Huntington Disease -- chemically induced, Corpus Striatum -- pathology, Animal, Glutamic Acid -- metabolism, Body Weight, Corpus Striatum, Rats, Disease Models, Animal, Disease Models, RNA, Propionates, Neuroprotective Agents -- pharmacology
Male, Encephalitis -- metabolism, Adenosine, Synapses -- metabolism, Wistar, Huntington Disease -- physiopathology, Signal Transduction -- drug effects, Mice, Receptors, Adenosine -- pharmacology, Huntington Disease -- pathology, Mice, Knockout, Inbred Lew, Cell Death, Encephalitis -- chemically induced, Purinergic P1 -- drug effects, Sciences bio-médicales et agricoles, Nitro Compounds, Corpus Striatum -- drug effects, Propionic Acids, Survival Rate, Huntington Disease, Neuroprotective Agents, Body Weight -- drug effects, Encephalitis -- pathology, Encephalitis, Cell Death -- genetics, Receptor, Phenethylamines -- pharmacology, Purinergic P1 -- genetics, Purinergic P1 -- metabolism, Adenosine -- analogs & derivatives, Knockout, Glutamic Acid, Xanthines -- pharmacology, Drug Administration Schedule, Adenosine A2A, Phenethylamines, Animals, Corpus Striatum -- physiopathology, Signal Transduction -- physiology, Genetic Predisposition to Disease, Cell Death -- drug effects, RNA, Messenger, Messenger -- biosynthesis, Huntington Disease -- chemically induced, Corpus Striatum -- pathology, Animal, Glutamic Acid -- metabolism, Body Weight, Corpus Striatum, Rats, Disease Models, Animal, Disease Models, RNA, Propionates, Neuroprotective Agents -- pharmacology
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