Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A 2A receptor over‐activation in a rat model of Parkinson's disease (original) (raw)
Related papers
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.
Molecular Neurobiology, 2022
Extracellular ATP can be a danger signal, but its role in striatal circuits afflicted in Parkinson's disease (PD) is unclear and was now investigated. ATP was particularly released at high stimulation intensities from purified striatal nerve terminals of mice, which were endowed with different ATP-P2 receptors (P2R), although P2R antagonists did not alter corticostriatal transmission or plasticity. Instead, ATP was extracellularly catabolized into adenosine through CD73 to activate adenosine A 2A receptors (A 2A R) modulating corticostriatal long-term potentiation (LTP) in mice. In the presymptomatic phase of a 6-hydroxydopamine rat model of PD, ATP release from striatal nerve terminals was increased and was responsible for a greater impact of CD73 and A 2A R on corticostriatal LTP. These observations identify increased ATP release and ATP-derived formation of extracellular adenosine bolstering A 2A R activation as a key pathway responsible for abnormal synaptic plasticity in circuits involved in the onset of PD motor symptoms. The translation of these findings to humans prompts extending the use of A 2A R antagonists from only co-adjuvants of motor control in Parkinsonian patients to neuroprotective drugs delaying the onset of motor symptoms.
Journal of Neuroscience, 2013
Adenosine is a neuromodulator acting through inhibitory A 1 receptors (A 1 Rs) and facilitatory A 2A Rs, which have similar affinities for adenosine. It has been shown that the activity of intracellular adenosine kinase preferentially controls the activation of A 1 Rs, but the source of the adenosine activating A 2A Rs is unknown. We now show that ecto-5Ј-nucleotidase (CD73), the major enzyme able to convert extracellular AMP into adenosine, colocalizes with A 2A Rs in the basal ganglia. In addition to astrocytes, striatal CD73 is prominently localized to postsynaptic sites. Notably, CD73 coimmunoprecipitated with A 2A Rs and proximity ligation assays confirmed the close proximity of CD73 and A 2A Rs in the striatum. Accordingly, the cAMP formation in synaptosomes as well as the hypolocomotion induced by a novel A 2A R prodrug that requires CD73 metabolization to activate A 2A Rs were observed in wild-type mice, but not in CD73 knock-out (KO) mice or A 2A R KO mice. Moreover, CD73 KO mice displayed increased working memory performance and a blunted amphetamineinduced sensitization, mimicking the phenotype of global or forebrain-A 2A R KO mice, as well as upon pharmacological A 2A R blockade. These results show that CD73-mediated formation of extracellular adenosine is responsible for the activation of striatal A 2A R function. This study points to CD73 as a new target that can fine-tune A 2A R activity, and a novel therapeutic target to manipulate A 2A R-mediated control of striatal function and neurodegeneration.
Experimental Brain Research, 2005
In Parkinson's disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A 2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A 2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A 2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A 2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.
Adenosine A2A receptor gene expression in the normal striatum and after 6-OH-dopamine lesion
Journal of Neural Transmission, 2000
Adenosine A 2A receptors are present on enkephalinergic medium sized striatal neurons in the rat and have an important function in the modulation of striatal output. In order to establish more accurately whether adenosine transmission is a generalized phenomenon in mammalian striatum we compared the A 2A R expression in the mouse, rat, cat and human striatum. Secondly we compared the modulation of enkephalin gene expression and A 2A receptor gene expression in rat striatal neurons after 6-OH-dopamine lesion of the substantia nigra. Hybridization histochemistry was performed with a 35 Slabelled radioactive oligonucleotide probe. The results showed high expression of A 2A adenosine receptor genes only in the medium-sized cells of the striatum in all examined species. In the rat striatum, expression of A 2A receptors was not significantly altered after lesion of the dopaminergic pathways with 6-OHdopamine even though enkephalin gene expression was up-regulated. The absence of a change in A 2A receptor gene expression after 6-OH-dopamine treatment speaks against a dependency on dopaminergic innervation. The maintained inhibitory function of A 2A R on motor activity in spite of dopamine depletion could be partly responsible for the depression of locomotor activity observed in basal ganglia disorders such as Parkinson's disease.
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.
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.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
The striatum is the major input region of the basal ganglia, playing a pivotal role in the selection, initiation, and coordination of movement both physiologically and in pathophysiological situations such as Parkinson's disease. In the present study, we characterize interactions between NMDA receptors, adenosine receptors, and cAMP signaling within the striatum. Both NMDA (100 micrometer) and the adenosine A(2a) receptor agonist CPCA (3 micrometer) increased cAMP levels (218.9 +/- 19.9% and 395.7 +/- 67.2%, respectively; cf. basal). The NMDA-induced increase in cAMP was completely blocked when slices were preincubated with either the NMDA receptor antagonist 7-chlorokynurenate or the adenosine A(2) receptor antagonist DMPX (100 micrometer), suggesting that striatal NMDA receptors increase cAMP indirectly via stimulation of adenosine A(2a) receptors. Thus, NMDA receptors and adenosine A(2a) receptors might share a common signaling pathway within the striatum. In striatal slices ...