On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson’s Disease (original) (raw)
Related papers
Targeting adenosine A 2A receptors in Parkinson's disease
Trends in Neurosciences, 2006
The adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5 and adenosine A1 receptors. Blockade of the adenosine A2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard ‘dopamine replacement’ treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.
An Update on Adenosine A2A Receptors as Drug Target in Parkinson's Disease
CNS & Neurological Disorders - Drug Targets, 2011
Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiological functions of adenosine. In the central nervous system adenosine A 2A receptors (A 2A Rs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D 2 receptor (D 2 R). Furthermore, it is assumed that the formation of balanced A 2A R/D 2 R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A 2A R activation reduces the affinity of striatal D 2 R for dopamine and the blockade of A 2A R with specific antagonists facilitates function of the D 2 R. Thus, it may be postulated that A 2A R antagonists are pro-dopaminergic agents.
Molecular Pharmacology, 2020
In medium-size, spiny striatal neurons of the direct pathway, dopamine D 1-and adenosine A 1-receptors are coexpressed and are mutually antagonistic. Recently, a mutation in the gene encoding the A 1-receptor (A 1 R), A 1 R-G279S 7.44 , was identified in an Iranian family: two affected offspring suffered from earlyonset L-DOPA-responsive Parkinson's disease. The link between the mutation and the phenotype is unclear. Here, we explored the functional consequence of the G279S substitution on the activity of the A 1-receptor after heterologous expression in HEK293 cells. The mutation did not affect surface expression and ligand binding but changed the susceptibility to heat denaturation: the thermodynamic stability of A 1 R-G279S 7.44 was enhanced by about 2 and 8 K when compared with wildtype A 1-receptor and A 1 R-Y288A 7.53 (a folding-deficient variant used as a reference), respectively. In contrast, the kinetic stability was reduced, indicating a lower energy barrier for conformational transitions in A 1 R-G279S 7.44 (73 6 23 kJ/mol) than in wild-type A 1 R (135 6 4 kJ/mol) or in A 1 R-Y288A 7.53 (184 6 24 kJ/mol). Consistent with this lower energy barrier, A 1 R-G279S 7.44 was more effective in promoting guanine nucleotide exchange than wild-type A 1 R. We detected similar levels of complexes formed between D 1-receptors and wild-type A 1 R or A 1 R-G279S 7.44 by coimmunoprecipitation and bioluminescence resonance energy transfer. However, lower concentrations of agonist were required for half-maximum inhibition of dopamine-induced cAMP accumulation in cells coexpressing D 1-receptor and A 1 R-G279S 7.44 than in those coexpressing wild-type A 1 R. These observations predict enhanced inhibition of dopaminergic signaling by A 1 R-G279S 7.44 in vivo, consistent with a pathogenic role in Parkinson's disease. SIGNIFICANCE STATEMENT Parkinson's disease is caused by a loss of dopaminergic input from the substantia nigra to the caudate nucleus and the putamen. Activation of the adenosine A 1-receptor antagonizes responses elicited by dopamine D 1-receptor. We show that this activity is more pronounced in a mutant version of the A 1receptor (A 1 R-G279S 7.44), which was identified in individuals suffering from early-onset Parkinson's disease. This work is part of a dissertation submitted in partial fulfillment of the requirements of the Ph.D. degree. This work was supported by the doctoral program Cell Communication in Health and Disease funded the Austrian Science Fund/FWF [Grant W1205] and by the Medical University of Vienna. The authors declare that they have no conflicts of interest with the contents of this article.
British Journal of Pharmacology, 2019
Background and Purpose: Parkinson's disease (PD) involves an initial loss of striatal dopamine terminals evolving into degeneration of dopamine neurons in substantia nigra (SN), which can be modeled by 6-hydroxydopamine (6-OHDA) administration. Adenosine A2A receptor (A2AR) blockade attenuates PD features in animal models, but the source of the adenosine responsible for A2AR over-activation is unknown. Since ATP is a stress signal, we now tested if the extracellular catabolism of adenine nucleotides into adenosine (through ecto-5'nucleotidase or CD73) is responsible for A2AR over-activation in PD. Experimental Approach: We tested the impact of blocking CD73 with ,-methylene ADP (AOPCP) in 6-OHDA-exposed rats and dopamine-differentiated neuroblastoma SH-SY5Y cells. Key Results: 6-OHDA bolstered ATP release and its extracellular conversion into adenosine through CD73 up-regulation in SH-SY5Y cells. Removing extracellular adenosine with adenosine deaminase, blocking CD73 with AOPCP or blocking A2AR with SCH58261 were equieffective to prevent 6-OHDA-induced damage of SH-SY5Y cells. In vivo striatal exposure to 6-OHDA increased ATP release and the extracellular formation of adenosine from adenosine nucleotides and up-regulated CD73 and A2AR in striatal synaptosomes. Intracerebroventricular administration of AOPCP phenocopied the effect of SCH58261, attenuating 6-OHDA-induced: 1-increase of contralateral rotations in the apomorphine test; 2reduction of dopamine content in striatum and SN; 3-loss of tyrosine hydroxylase staining in striatum and SN; 4-motor dysfunction in the cylinder test; 5-short-term memory impairment in the object recognition test. Conclusion and Implications: This indicates that increased ATP-derived adenosine formation is responsible for A2AR over-activation in PD, prompting CD73 as a new target to manage PD.
The FASEB Journal, 2010
Parkinson's disease (PD). The primary aim of this study was to investigate the expression, affinity, and density of A 1 , A 2A , A 2B , and A 3 adenosine receptors (ARs) and D 2 dopamine receptors (D 2 Rs) in PD. An increase in A 2A AR density in putamen was found. The presence and functionality of ARs in human lymphocyte and neutrophil membranes from patients with PD revealed a specific A 2A AR alteration compared with healthy subjects. A statistically significant linear correlation among the A 2A AR density, functionality, or tumor necrosis factor-␣ (TNF-␣) levels and Unified Parkinson's Disease Rating Scale (UPDRS) motor score was reported. Adenosine concentration and TNF-␣ levels were increased in plasma of patients with PD. In rat adrenal pheochromocytoma (PC12) cells, a widely useful model, adenosine antagonists decreased dopamine uptake, and an opposite effect was mediated by A 2A agonists. This is the first report showing the presence of an A 2A AR alteration in putamen in PD that mirrors a similar up-regulation in human peripheral blood cells. Moreover, the correlation found between A 2A AR density or A 2A agonist potency and UPDRS motor score highlights the central role of A 2A ARs in the pharmacological treatment of PD.-Varani, K., Vincenzi, F., Tosi, A., Gessi, S., Casetta, I., Granieri, G., Fazio, P., Leung, E., MacLennan, S., Granieri, E., Borea, P. A. A 2A adenosine receptor overexpression and functionality, as well as TNF-␣ levels, correlate with motor symptoms in Parkinson's disease. FASEB J. 24, 587-598 (2010). www.fasebj.org Key Words: D 2 dopamine receptors ⅐ human putamen ⅐ human lymphocytes and neutrophils
British Journal of Pharmacology, 2019
Background and Purpose: Parkinson's disease (PD) involves an initial loss of striatal dopamine terminals evolving into degeneration of dopamine neurons in substantia nigra (SN), which can be modeled by 6-hydroxydopamine (6-OHDA) administration. Adenosine A2A receptor (A2AR) blockade attenuates PD features in animal models, but the source of the adenosine responsible for A2AR over-activation is unknown. Since ATP is a stress signal, we now tested if the extracellular catabolism of adenine nucleotides into adenosine (through ecto-5'nucleotidase or CD73) is responsible for A2AR over-activation in PD. Experimental Approach: We tested the impact of blocking CD73 with ,-methylene ADP (AOPCP) in 6-OHDA-exposed rats and dopamine-differentiated neuroblastoma SH-SY5Y cells. Key Results: 6-OHDA bolstered ATP release and its extracellular conversion into adenosine through CD73 up-regulation in SH-SY5Y cells. Removing extracellular adenosine with adenosine deaminase, blocking CD73 with AOPCP or blocking A2AR with SCH58261 were equieffective to prevent 6-OHDA-induced damage of SH-SY5Y cells. In vivo striatal exposure to 6-OHDA increased ATP release and the extracellular formation of adenosine from adenosine nucleotides and up-regulated CD73 and A2AR in striatal synaptosomes. Intracerebroventricular administration of AOPCP phenocopied the effect of SCH58261, attenuating 6-OHDA-induced: 1-increase of contralateral rotations in the apomorphine test; 2reduction of dopamine content in striatum and SN; 3-loss of tyrosine hydroxylase staining in striatum and SN; 4-motor dysfunction in the cylinder test; 5-short-term memory impairment in the object recognition test. Conclusion and Implications: This indicates that increased ATP-derived adenosine formation is responsible for A2AR over-activation in PD, prompting CD73 as a new target to manage PD.
Frontiers in neuroscience, 2017
Parkinson's disease (PD) is one of the most prevalent neurodegenerative disease displaying negative impacts on both the health and social ability of patients and considerable economical costs. The classical anti-parkinsonian drugs based in dopaminergic replacement are the standard treatment, but several motor side effects emerge during long-term use. This mini-review presents the rationale to several efforts from pre-clinical and clinical studies using adenosine receptor antagonists as a non-dopaminergic therapy. As several studies have indicated that the monotherapy with adenosine receptor antagonists reaches limited efficacy, the usage as a co-adjuvant appeared to be a promising strategy. The formulation of multi-targeted drugs, using adenosine receptor antagonists and other neurotransmitter systems than the dopaminergic one as targets, have been receiving attention since Parkinson's disease presents a complex biological impact. While pharmacological approaches to cure or ...
Neurotoxicity Research, 2001
The most effective treatment of Parkinson's disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenyl-alanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term, effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A2A receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A2A antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-l,2,4-triazolo(1,5-c)pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Foslike-immunoreactivity in neurons of the lesioned striatum. Likewise, other A2A receptor antagonists such as (3,7-dimethyl-l-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-l,3-dipropyl-7-methylxanthine] (KF 17837) and [E-1,3-dietyl-8(3,4-dimethoxystyryl-7-methyl-3,7-dhydro-lH-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in nonhuman primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTPtreated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A2A receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A2A antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) (MPTP) model of PD. Adenosine A2A receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.
Archives of Medical Science
Introduction: In Parkinson's disease (PD), compelling data indicate a functional link between adenosine/dopamine receptors and the progression of the neurodegenerative process. The present study was carried out to evaluate the effect of the non-selective adenosine receptor (ADR) antagonist caffeine, as well as the selective antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an ADRsA 1 antagonist, and ((E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002), an ADRsA 2A antagonist, on the prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice. Material and methods: Mice were allocated to five groups: group I-control group; group II: MPTP group, received four injections of MPTP (20 mg/kg, i.p.) at 2 h intervals; groups III, IV, V: received MPTP and i.p. caffeine (20 mg/kg/ day) or DPCPX (5 mg/kg/day) or KW-6002 (10 mg/kg/day) starting one week before MPTP injection and continuing for 2 weeks. Results: Therapy with caffeine or KW-6002 not only led to the reversibility of movement dysfunction and increased the concentrations of dopamine and ATP levels (p < 0.05), but also, ameliorates the dopaminergic neuron loss and restored the mtDNA and nDNA integrity (p < 0.05). Furthermore, in passive avoidance test, caffeine and DPCPX significantly (p < 0.05) reversed the MPTP-induced memory deficits, whereas the specific ADRsA2A antagonist did not. Conclusions: The current results provide evidence that blockade of both ADRsA 1 and ADRsA 2A has therapeutic implications in alleviating MPTP-induced motor and cognitive dysfunction and might be a promising candidate for treatment of PD.
Targeting Adenosine Receptors in Neurological Diseases
Cellular Reprogramming, 2021
Adenosine plays a significant role in neurotransmission process by controlling the blood pressure, while adenosine triphosphate (ATP) acts as a neuromodulator and neurotransmitter and by activation of P2 receptors, regulates the contractility of the heart. Adenosine signaling is essential in the process of regeneration by regulating proliferation, differentiation, and apoptosis of stem cells. In this review, we have selected neurological disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy) with clinical trials using antagonists and epigenetic tools targeting adenosine receptor as a therapeutic approach in the treatment of these disorders. Promising results have been reported from many clinical trials. It has been found that higher expression levels of A2A and P2X7 receptors in neurological disorders further complicate the disease condition. Therefore, modulations of these receptors by using antagonists of these receptors or SAM (S-adenosylmethionine) therapy as an epigenetic tool could be useful in reversing the complications of these disorders. Finally, we suggest that modulation of adenosine receptors in neurological disorders can increase the regenerative phase by increasing the rate of proliferation and differentiation in the damaged tissues.