ABSTRACT
Adenosine A2A receptor (A2AR) is a G-protein coupled receptor that regulates several important functions in the central nervous system. Large amount of preclinical data suggests that the A2AR could represent a target for the development of new therapeutic strategies for different neuropsychiatric conditions. In this review we will recapitulate and discuss the most relevant studies on the role of A2ARs in neurodegenerative, neurodevelopmental and psychiatric diseases, which led to suggest a therapeutic use of A2AR agonists in certain diseases (Niemann-Pick disease, autism-spectrum disorders, schizophrenia) and A2AR antagonists in others (Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, fragile X syndrome, depression, anxiety). Moreover, we will try to analyze which are the main obstacles to the conduction of clinical trials with A2AR ligands for the treatment of neuropsychiatric disease.
Subject(s)
Mental Disorders/metabolism , Neurodegenerative Diseases/metabolism , Receptor, Adenosine A2A/metabolism , Animals , Humans , Mental Disorders/drug therapy , Neurodegenerative Diseases/drug therapyABSTRACT
Adenosine A1 receptor (A1R) stimulation exerts beneficial effects in response to various insults to the brain and, although it was found neuroprotective in a lesional model of Huntington's disease (HD), the features of this receptor in genetic models of HD have never been explored. In the present study we characterized the expression, affinity and functional effects of A1Rs in R6/2 mice (the most widely used transgenic model of HD) and in a cellular model of HD. Binding studies revealed that the density of A1Rs was significantly reduced in the cortex and the striatum of R6/2 mice compared to age-matched wild-type (WT), while receptor affinity was unchanged. The selective A1R agonist cyclopentyladenosine (CPA, 300nM) was significantly more effective in reducing synaptic transmission in corticostriatal slices from symptomatic R6/2 than in age-matched WT mice. Such an effect was due to a stronger inhibition of glutamate release from the pre-synaptic terminal. The different functional activities of A1Rs in HD mice were associated also to a different intracellular signaling pathway involved in the synaptic effect of CPA. In fact, while the PKA pathway was involved in both genotypes, p38 MAPK inhibitor SB203580 partially prevented synaptic effects of CPA in R6/2, but not in WT, mice; moreover, CPA differently modulated the phosphorylation status of p38 in the two genotypes. In vitro studies confirmed a different behavior of A1Rs in HD: CPA (100 nM for 5h) modulated cell viability in STHdh(Q111/Q111) (mhttHD cells), without affecting the viability of STHdh(Q7/Q7) (wthtt cells). This effect was prevented by the application of SB203580. Our results demonstrate that in the presence of the HD mutation A1Rs undergo profound changes in terms of expression, pharmacology and functional activity. These changes have to be taken in due account when considering A1Rs as a potential therapeutic target for this disease.
Subject(s)
Adenine/analogs & derivatives , Cyclopentanes/pharmacology , Gene Expression Regulation/genetics , Huntington Disease/metabolism , Receptor, Adenosine A1/metabolism , Action Potentials/drug effects , Action Potentials/genetics , Adenine/pharmacology , Adenosine A1 Receptor Antagonists/pharmacokinetics , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Cyclic AMP/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Electric Stimulation , Enzyme Inhibitors/pharmacology , Female , Gene Expression Regulation/drug effects , Glutamic Acid/metabolism , Huntingtin Protein , Huntington Disease/genetics , Huntington Disease/pathology , In Vitro Techniques , Male , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Neurons/drug effects , Neurons/metabolism , Nuclear Proteins/genetics , Potassium Chloride/pharmacology , Protein Binding/drug effects , Signal Transduction/drug effects , Signal Transduction/genetics , Statistics, Nonparametric , Synaptic Transmission/drug effects , Synaptic Transmission/genetics , Synaptosomes/drug effects , Synaptosomes/metabolism , Transfection , Trinucleotide Repeat Expansion/genetics , Tritium/pharmacokinetics , Xanthines/pharmacokineticsABSTRACT
The striatum is a subcortical area involved in sensorimotor, cognitive and emotional processes. Adenosine A(2A) receptors (A(2A)Rs) are highly expressed in the striatum, and their ability to establish functional and molecular interactions with many other receptors attributes to a pivotal role in the modulation and integration of striatal neurotransmission. This review will focus on the interaction between A(2A)Rs and cannabinoid CB(1) receptors (CB(1)Rs), taking it as a paradigmatic example of synaptic integration. Indeed, A(2A)Rs can exert an opposite (permissive vs. inhibitory) influence on CB1-dependent synaptic effect. These apparently irreconcilable functions could depend on a different role of pre- vs. postsynaptic A(2A)Rs, on their interaction with other receptors (namely adenosine A(1), metabotropic glutamate 5 and dopamine D2 receptors), and on whether A(2A)Rs form or not heteromers with CB(1)Rs. Besides providing a good example of the intricate pattern of events taking place in striatal synapses, the A(2A)/CB(1)R interaction proves very informative to understand the physiology of the basal ganglia and the mechanisms of related diseases. This article is part of a Special Issue entitled: Brain Integration.
Subject(s)
Corpus Striatum/physiology , Glutamic Acid/metabolism , Receptor, Adenosine A2A/metabolism , Receptor, Cannabinoid, CB1/metabolism , Synaptic Transmission/physiology , Animals , Cannabinoid Receptor Modulators/pharmacology , Purinergic Agents/pharmacology , Synaptic Transmission/drug effectsABSTRACT
An interaction between adenosine A(2A) receptors (A(2A) Rs) and cannabinoid CB(1) receptors (CB(1) Rs) has been consistently reported to occur in the striatum, although the precise mechanisms are not completely understood. As both receptors control striatal glutamatergic transmission, we now probed the putative interaction between pre-synaptic CB(1) R and A(2A) R in the striatum. In extracellular field potentials recordings in corticostriatal slices from Wistar rats, A(2A) R activation by CGS21680 inhibited CB(1) R-mediated effects (depression of synaptic response and increase in paired-pulse facilitation). Moreover, in superfused rat striatal nerve terminals, A(2A) R activation prevented, while A(2A) R inhibition facilitated, the CB(1) R-mediated inhibition of 4-aminopyridine-evoked glutamate release. In summary, the present study provides converging neurochemical and electrophysiological support for the occurrence of a tight control of CB(1) R function by A(2A) Rs in glutamatergic terminals of the striatum. In view of the key role of glutamate to trigger the recruitment of striatal circuits, this pre-synaptic interaction between CB(1) R and A(2A) R may be of relevance for the pathogenesis and the treatment of neuropsychiatric disorders affecting the basal ganglia.
Subject(s)
Corpus Striatum/physiology , Glutamic Acid/physiology , Neural Inhibition/physiology , Presynaptic Terminals/physiology , Receptor, Adenosine A2A/physiology , Receptor, Cannabinoid, CB1/physiology , Synaptic Transmission/physiology , Animals , Corpus Striatum/metabolism , Male , Presynaptic Terminals/metabolism , Rats , Rats, WistarABSTRACT
In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A(2A) receptors (A(2A)Rs) and brain-derived neurotrophic factor (BDNF). Not only are A(2A)Rs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A(2A)Rs, is involved in such effects. Furthermore, a basal tonus of A(2A)Rs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A(2A)Rs KO mice. The crucial role of adenosine A(2A)Rs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A(2A)Rs seems to play a pathogenetic role.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Brain/physiology , Receptor, Adenosine A2A/physiology , Synaptic Transmission/physiology , Animals , Brain/metabolism , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Humans , Huntington Disease/metabolism , Huntington Disease/physiopathology , Models, Neurological , Receptor, Adenosine A2A/metabolismABSTRACT
Adenosine A(2A), cannabinoid CB(1) and metabotropic glutamate 5 (mGlu(5)) receptors are all highly expressed in the striatum. The aim of the present work was to investigate whether, and by which mechanisms, the above receptors interact in the regulation of striatal synaptic transmission. By extracellular field potentials (FPs) recordings in corticostriatal slices, we demonstrated that the ability of the selective type 1 cannabinoid receptor (CB(1)R) agonist WIN55,212-2 to depress synaptic transmission was prevented by the pharmacological blockade or the genetic inactivation of A(2A)Rs. Such a permissive effect of A(2A)Rs towards CB(1)Rs does not seem to occur pre-synaptically as the ability of WIN55,212-2 to increase the R2/R1 ratio under a protocol of paired-pulse stimulation was not modified by ZM241385. Furthermore, the effects of WIN55,212-2 were reduced in slices from mice lacking post-synaptic striatal A(2A)Rs. The selective mGlu(5)R agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) potentiated the synaptic effects of WIN55,212-2, and such a potentiation was abolished by A(2A)R blockade. Unlike the synaptic effects, the ability of WIN55,212-2 to prevent NMDA-induced toxicity was not influenced by ZM241385. Altogether, these results show that the state of activation of A(2A)Rs regulates the synaptic effects of CB(1)Rs and that A(2A)Rs may control CB(1) effects also indirectly, namely through mGlu(5)Rs.
Subject(s)
Corpus Striatum/metabolism , Receptor, Cannabinoid, CB1/physiology , Receptors, Adenosine A2/physiology , Synapses/physiology , Action Potentials/genetics , Animals , Benzoxazines/pharmacology , Biophysics , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Cerebral Cortex/cytology , Cerebral Cortex/physiology , Corpus Striatum/cytology , Corpus Striatum/embryology , Electric Stimulation/methods , Embryo, Mammalian , Excitatory Amino Acid Agonists/pharmacology , Female , Glycine/analogs & derivatives , Glycine/pharmacology , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Male , Mice , Mice, Knockout , Morpholines/pharmacology , N-Methylaspartate/pharmacology , Naphthalenes/pharmacology , Neurons/drug effects , Neurons/physiology , Phenylacetates/pharmacology , Piperidines/pharmacology , Pregnancy , Pyrazoles/pharmacology , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptors, Adenosine A2/genetics , Synapses/drug effects , Triazines/pharmacology , Triazoles/pharmacologyABSTRACT
Huntington's disease (HD) is an inherited neurodegenerative disorder. Adenosine A(2A) receptors (A(2A)Rs) are involved in excitotoxic/neurodegenerative processes, and A(2A)R ligands may be neuroprotective in models of HD. However, changes in the transcription, expression and function of A(2A)Rs have been reported to occur in HD models. The aim of the present work was to verify whether A(2A)R-mediated effects are altered in the striatum of transgenic HD (R6/2) versus wild-type (WT) mice. Extracellular field potentials (FPs) were recorded in corticostriatal slices from R6/2 mice in early (7-8 weeks) or frankly (12-13 weeks) symptomatic phases, and age-matched WT. In 12-13 weeks aged WT animals, the application of 75 microM NMDA induced a transient disappearance of the FP followed by an almost complete recovery at washout. In slices from HD mice, the mean FP recovery was significantly reduced (P<0.01 versus WT). A(2A)R activation oppositely modulated NMDA-induced toxicity in the striatum of HD versus WT mice. Indeed, the A(2A)R agonist CGS21680 reduced the FP recovery in slices from WT mice, while it significantly increased it in slices from R6/2 mice. In early symptomatic (7-8 weeks) mice, no differences were observed between WT and HD animals in terms of basal synaptic transmission and response to NMDA. At the same age, the behavioural effects elicited by CGS21680 were qualitatively identical in WT and HD mice. These findings may have very important implications for the neuroprotective potential of A(2A)R ligands in HD.
Subject(s)
Adenosine A2 Receptor Agonists , Adenosine/analogs & derivatives , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Huntington Disease/drug therapy , Huntington Disease/metabolism , Neuroprotective Agents/pharmacology , Phenethylamines/pharmacology , Action Potentials/drug effects , Action Potentials/genetics , Adenosine/pharmacology , Adenosine/therapeutic use , Animals , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Corpus Striatum/physiopathology , Disease Models, Animal , Huntington Disease/genetics , Mice , Mice, Transgenic , Neuroprotective Agents/therapeutic use , Neurotoxins/antagonists & inhibitors , Neurotoxins/metabolism , Organ Culture Techniques , Phenethylamines/therapeutic use , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/metabolism , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/genetics , Recovery of Function/drug effects , Recovery of Function/genetics , Species Specificity , Synaptic Transmission/drug effects , Synaptic Transmission/geneticsABSTRACT
This study was designed to test whether chronic treatment with the metabotropic glutamate receptor 5 (mGlu5R) antagonist MPEP showed antiparkinsonian effects in rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA) (a "classic" model of Parkinson's disease, PD), and to evaluate whether chronic MPEP influenced the functional properties and/or the expression of striatal mGlu5Rs. Wistar rats were lesioned with 6-OHDA and then treated with MPEP (3 mg/kg/day, i.p.) or its vehicle over 2 weeks. Chronic MPEP did not induce measurable antiparkinsonian effects, since no differences were found between MPEP- and vehicle-treated animals in the pattern of L-DOPA-induced contralateral rotations. In corticostriatal slices taken from animals chronically treated with MPEP, the functional effects of the mGlu5R agonist CHPG were significantly reduced in the lesioned vs. the intact side, while no changes were found in slices taken from vehicle-treated rats. The binding of [3H]MPEP to striatal membranes showed that neither the maximal number of binding sites (Bmax) nor the dissociation constant (Kd) were changed by the lesion and/or by chronic MPEP. While chronic MPEP did not potentiate L-DOPA-induced turning in a classical model of PD, its ability to reduce mGlu5R-associated signal could help to explain the neuroprotective/antiparkinsonian effects observed in other models of PD.
Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Parkinson Disease/drug therapy , Phenylacetates/pharmacology , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Antiparkinson Agents/pharmacology , Behavior, Animal/drug effects , Corpus Striatum/drug effects , Denervation , Drug Interactions , Excitatory Amino Acid Antagonists/metabolism , Levodopa/pharmacology , Male , Organ Culture Techniques , Oxidopamine , Pyridines/metabolism , Rats , Rats, Wistar , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/agonists , Sympatholytics , TritiumABSTRACT
Adenosine A2A receptor antagonists are regarded as potential neuroprotective drugs, although the mechanisms underlying their effects remain to be elucidated. In this review, quinolinic acid (QA)-induced striatal toxicity was used as a tool to investigate the mechanisms of the neuroprotective effects of A2A receptor antagonists. After having examined the effects of selective A2A receptor antagonists toward different mechanisms of QA toxicity, we conclude that (1) the effect elicited by A2A receptor blockade on QA-induced glutamate outflow may be one of the mechanisms of the neuroprotective activity of A2A receptor antagonists; (2) A2A receptor antagonists have a potentially worsening influence on QA-dependent NMDA receptor activation; and (3) the ability of A2A receptor antagonists to prevent QA-induced lipid peroxidation does not correlate with the neuroprotective effects. These results suggest that A2A receptor antagonists may have either potentially beneficial or detrimental influence in models of neurodegeneration that are mainly due to increased glutamate levels or enhanced sensitivity of NMDA receptors, respectively.
Subject(s)
Adenosine A2 Receptor Antagonists , Neuroprotective Agents/pharmacology , Animals , Brain Chemistry/drug effects , Glutamic Acid/metabolism , Humans , Oxidative Stress/drug effects , Quinolinic Acid/toxicity , Receptors, N-Methyl-D-Aspartate/agonists , Stimulation, ChemicalABSTRACT
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.
Subject(s)
Adenosine/analogs & derivatives , Corpus Striatum/metabolism , Neuroprotective Agents/metabolism , Neurotoxins/metabolism , Receptor, Adenosine A2A/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Synaptic Membranes/metabolism , 4-Aminopyridine/pharmacology , Adenosine/pharmacology , Adenosine A2 Receptor Antagonists , Animals , Calcium/metabolism , Corpus Striatum/drug effects , Corpus Striatum/physiopathology , Dose-Response Relationship, Drug , Glutamic Acid/metabolism , In Vitro Techniques , L-Lactate Dehydrogenase/drug effects , L-Lactate Dehydrogenase/metabolism , Male , Models, Biological , N-Methylaspartate/pharmacology , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/physiopathology , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology , Neurotoxins/antagonists & inhibitors , Phenethylamines/pharmacology , Pyrimidines/pharmacology , Quinolinic Acid/pharmacology , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Synaptic Membranes/drug effects , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Triazines/pharmacology , Triazoles/pharmacologyABSTRACT
The aim of this work was to investigate the potential neuroprotective effects of the metabotropic glutamate receptor 5 (mGlu5R) antagonist 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) towards quinolinic acid (QA)-induced striatal excitoxicity. Intrastriatal MPEP (5 nmol/0.5 micro L) significantly attenuated the body weight loss, the electroencephalographic alterations, the impairment in spatial memory and the striatal damage induced by bilateral striatal injection of QA (210 nmol/0.7 micro L). In a second set of experiments, we aimed to elucidate the mechanisms underlying the neuroprotective effects of MPEP. In microdialysis studies in naive rats MPEP (80-250 micro m through the dialysis probe) significantly reduced the increase in glutamate levels induced by 5 mm QA. In primary cultures of striatal neurons MPEP (50 micro m) reduced the toxicity induced by direct application of glutamate [measured as release of lactate dehydrogenase [LDH]). Finally, we found that 50 micro m MPEP was unable to directly block NMDA-induced effects (namely field potential reduction in corticostriatal slices, as well as LDH release and intracellular calcium increase in striatal neurons). We conclude that: (i) MPEP has neuroprotective effects towards QA-induced striatal excitotoxicity; (ii) both pre- and post-synaptic mechanisms are involved; (iii) the neuroprotective effects of MPEP do not appear to involve a direct blockade of NMDA receptors.
Subject(s)
N-Methylaspartate/pharmacology , Neostriatum/drug effects , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/prevention & control , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Body Weight/drug effects , Calcium/metabolism , Cells, Cultured , Electroencephalography/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/metabolism , Glutamic Acid/toxicity , L-Lactate Dehydrogenase/metabolism , Male , Maze Learning/drug effects , Microdialysis , Neostriatum/pathology , Neostriatum/physiopathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neurotoxicity Syndromes/pathology , Neurotoxicity Syndromes/physiopathology , Neurotoxins/antagonists & inhibitors , Neurotoxins/toxicity , Quinolinic Acid/antagonists & inhibitors , Quinolinic Acid/toxicity , Rats , Rats, Wistar , Receptor, Metabotropic Glutamate 5ABSTRACT
The effects of electroacupuncture (EA) has been studied in a model of global cerebral ischaemia performed in gerbils through the bilateral carotid artery occlusion (BCAO). Animals, under isofluorane anaesthesia, underwent 5 min of BCAO and were killed after 7 days. The effects of EA were evaluated both on functional (with electrophysiological recordings of synaptic potentials in hippocampal slices) and morphological parameters (by counting the number of survived neurons in CA1 area of the hippocampus). The results demonstrated that the treatment of animals with EA (5 min before, during and 20 min after BCAO and 30 min per day in the following 5 days) did not modify either the ischaemia-induced reduction of synaptic potentials amplitude, either ischaemia-induced neuronal loss in the hippocampus. We conclude that, at least in this animal model of cerebral ischaemia, EA does not exert a neuroprotective effect.
Subject(s)
Brain Ischemia/therapy , Disease Models, Animal , Electroacupuncture , Animals , GerbillinaeABSTRACT
The influence of the adenosine A(2A) receptor antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-trizolo[1,5-c] pyrimidine) (50, 200 nM, 1 microM) on quinolinic acid effects has been studied in rat striatal and hippocampal slices. Quinolinic acid induced disappearance of field potentials at concentrations of 500 microM and 2 mM in hippocampal and corticostriatal slices, respectively. We found that 1 microM SCH 58261 prevented quinolinic acid-induced field potential disappearance in corticostriatal but not in hippocampal slices. This finding demonstrates that the peculiar binding profile of SCH 58261 and the predominance in the hippocampus of "atypical" adenosine A(2A) receptor population (not recognized by SCH 58261) could have a functional relevance in the occurrence of region-specific neuroprotective effects.
Subject(s)
Corpus Striatum/drug effects , Hippocampus/drug effects , Purinergic P1 Receptor Antagonists , Pyrimidines/pharmacology , Quinolinic Acid/pharmacology , Triazoles/pharmacology , Animals , Binding Sites , Corpus Striatum/metabolism , Drug Antagonism , Electric Stimulation , Electrophysiology , Hippocampus/metabolism , In Vitro Techniques , Male , Pyrimidines/metabolism , Quinolinic Acid/metabolism , Rats , Rats, Wistar , Receptor, Adenosine A2A , Receptors, Purinergic P1/metabolism , Receptors, Purinergic P1/physiology , Time Factors , Triazoles/metabolismABSTRACT
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.