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Enhanced ATP release and CD73-mediated adenosine formation sustain adenosine A2A receptor over-activation in a rat model of Parkinson's disease.

ABSTRACT: 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 modelled by 6-hydroxydopamine (6-OHDA) administration. Adenosine A2A receptor blockade attenuates PD features in animal models, but the source of the adenosine causing A2A receptor over-activation is unknown. As ATP is a stress signal, we have tested if extracellular catabolism of adenine nucleotides into adenosine (through ecto-5'-nucleotidase or CD73) leads to A2A receptor over-activation in PD. EXPERIMENTAL APPROACH:Effects of blocking CD73 with ?,?-methylene ADP (AOPCP) were assayed in 6-OHDA-treated rats and dopamine-differentiated neuroblastoma SH-SY5Y cells. KEY RESULTS:6-OHDA increased ATP release and extracellular conversion into adenosine through CD73 up-regulation in SH-SY5Y cells. Removing extracellular adenosine with adenosine deaminase, blocking CD73 with AOPCP, or blocking A2A receptors with SCH58261 were equi-effective in preventing 6-OHDA-induced damage in SH-SY5Y cells. In vivo striatal exposure to 6-OHDA increased ATP release and extracellular formation of adenosine from adenosine nucleotides and up-regulated CD73 and A2A receptors in striatal synaptosomes. Intracerebroventricular administration of AOPCP phenocopied effects of SCH58261, attenuating 6-OHDA-induced (a) increase of contralateral rotations after apomorphine, (b) reduction of dopamine content in striatum and SN, (c) loss of TH staining in striatum and SN, (d) motor dysfunction in the cylinder test, and (e) short-term memory impairment in the object recognition test. CONCLUSION AND IMPLICATIONS:Our data indicate that increased ATP-derived adenosine formation is responsible for A2A receptor over-activation in PD, suggesting CD73 as a new target to manage PD.

SUBMITTER: Carmo M

PROVIDER: S-EPMC6715785 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Enhanced ATP release and CD73-mediated adenosine formation sustain adenosine A<sub>2A</sub> receptor over-activation in a rat model of Parkinson's disease.

Carmo Marta M Gonçalves Francisco Q FQ Canas Paula M PM Oses Jean-Pierre JP Fernandes Francisco D FD Duarte Filipe V FV Palmeira Carlos M CM Tomé Angelo R AR Agostinho Paula P Andrade Geanne M GM Cunha Rodrigo A RA

British journal of pharmacology 20190801 18

<h4>Background and purpose</h4>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 modelled by 6-hydroxydopamine (6-OHDA) administration. Adenosine A<sub>2A</sub> receptor blockade attenuates PD features in animal models, but the source of the adenosine causing A<sub>2A</sub> receptor over-activation is unknown. As ATP is a stress signal, we have tested if extracellular catabolism o ...[more]

PMID: 31220343

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Project description:Background and purposeLrp4 (low-density lipoprotein receptor-related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4's function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis.MethodsThe brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured.ResultsLrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER's protective effect.ConclusionsThe astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.

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Enhanced ATP release and CD73-mediated adenosine formation sustain adenosine A2A receptor over-activation in a rat model of Parkinson's disease.

Publications

Enhanced ATP release and CD73-mediated adenosine formation sustain adenosine A<sub>2A</sub> receptor over-activation in a rat model of Parkinson's disease.

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