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• W2953308945 endingPage "3680" @default.
• W2953308945 startingPage "3666" @default.
• W2953308945 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 A 2A receptor blockade attenuates PD features in animal models, but the source of the adenosine causing A 2A 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 A 2A receptor over‐activation in PD. Experimental Approach Effects of blocking CD73 with α,β‐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 A 2A 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 A 2A 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 A 2A receptor over‐activation in PD, suggesting CD73 as a new target to manage PD." @default.
• W2953308945 created "2019-06-27" @default.
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• W2953308945 date "2019-08-01" @default.
• W2953308945 modified "2023-10-06" @default.
• W2953308945 title "Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A _2A receptor over‐activation in a rat model of Parkinson's disease" @default.
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• W2953308945 doi "https://doi.org/10.1111/bph.14771" @default.
• W2953308945 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6715785" @default.
• W2953308945 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31220343" @default.
• W2953308945 hasPublicationYear "2019" @default.
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