Enhanced ATP release and CD73‐mediated adenosine formation sustain adenosine A_2A 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 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 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.

Deletion of CD73 increases exercise power in mice

“…This stems from the lack of evident peripheral changes in CD73-KO mice typified by the lack of altered blood pressure [22], cardiac output and ejection fraction [22], on running wheels during the light and dark phase of circadian rhythm [23], oxygen saturation erythrocytic and pH [23], blood glucose and 2,3-biphosphoglycerate levels [23]. This is in accordance with the presently observed lack of differences in the submaximal and maximum in a graded exercise test between CD73-KO mice and their WT littermates and the lack of alteration of spontaneous locomotion either in CD73-KO mice [12,15,24] or upon administration of the CD73 inhibitor α,β-methylene-ADP (AOPCP) [14]. Kulesskay et al [25] observed a hyperlocomotion in CD73-KO mice but attributed this difference to their isolation in cages with running wheels, contrasting with the collective housing in the present study.…”

“…Moreover, the ergogenicity of CD73-KO mice phenocopies the ergogenic profile of forebrain A 2A R-KO mice [8]. Indeed, CD73 and A 2A R are functionally coupled in different brain regions [12–15], namely, in basal ganglia [12,14], A 2A R antagonism with SCH58261 is ergogenic [8], and the hyperlocomotion stimulated by SCH-58261 is reduced in CD73-KO mice [12].…”

A New Side-effect of Sufentanil: Increased Monocyte-endothelial Adhesion

“…The enzymes involved are CD39, which converts ATP to AMP, and CD73, which converts AMP to ADO. From the available evidence, this pathway, which protects against cell adhesion, is robust in endothelial cells [34,35]. As previously reported, in addition to Cx43 channels, both connexin37 (Cx37) channels and pannexin1 are potential pathways for ATP release.…”

Aluminum-Induced Alterations in Purinergic System Parameters of BV-2 Brain Microglial Cells

“…A coordinated upregulation of 5′-NT and purinoceptor expression, particularly A2AR expression, has been suggested by previous reports such as in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE) [ 44 ], in a rat model of Parkinson's disease [ 45 ], and in a rat model of AD [ 46 ]. However, although our results regarding the A2AR receptor are in agreement with these previous reports, the decrease in 5′-NT activity was also indicated when neurospheres were treated with Al 3+ [ 13 ].…”