Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

Abstract

Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7 receptors (P2X7R) and adenosine A2A receptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between P2X7R and A2AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia “activation”) and interleukin-1β (IL1β) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of P2X7R (mRNA) and A2AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P2X7R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, p.o.), which affords neuroprotection through A2AR blockade. Notably, BBG attenuated A2AR upregulation and caffeine attenuated P2X7R upregulation. In microglial N9 cells, the P2X7R agonist BzATP (100 μM) or the A2AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P2X7R antagonist JNJ47965567 (1 μM) and by the A2AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between P2X7R and A2AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.

Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder

“…The authors discovered increased expression of P2X7R and A 2A receptor in the hippocampus and prefrontal cortex. Next, they showed that BBG a P2X7R-selective antagonist and caffeine an A 2A receptor antagonist attenuated the depressive phenotype ( 325 ).…”

Effect of endogenous purines on electrically evoked ACh release at the mouse neuromuscular junction

“…In this regard, Ciruela et al (2006) demonstrated in radioligand‐binding experiments in co‐transfected cells and rat striatum that heteromerization of A 1 and A 2A Rs allows adenosine to exert a fine‐tuning modulation of glutamatergic neurotransmission since activation of A 2A Rs reduces the affinity of the A 1 Rs for agonists. Likewise, there are several examples in different preparations of a functional cross‐talk between P2 and P1 Rs (e.g., Dias et al, 2021; Tonazzini et al, 2007, reviewed by Agostinho et al, 2020). Besides, other factors such as the topographical arrangement of ecto‐enzymes, transporters and other presynaptic Rs may also influence the effects mediated by A 1 , A 3 , or A 2A Rs.…”

Adenosine A2A Receptors as Biomarkers of Brain Diseases

“…A 2A R up-regulation mostly occurs in synapses, in accordance with the involvement of synaptic alterations at the onset of most brain diseases (e.g., Rebola et al, 2005;Kaster et al, 2015;Viana da Silva et al, 2016;Canas et al, 2018), but is also observed in glia cells in the progression of chronic brain diseases (Matos et al, 2012;Orr et al, 2015;Barros-Barbosa et al, 2016;Patodia et al, 2020). It is still unclear if this A 2A R up-regulation only involves an increased readout of A 2A R mRNAs (Canas et al, 2018) or also involves an overexpression of A 2A R mRNA, which has been reported in the dysfunctional or diseased brain (e.g., Costenla et al, 2011;Espinosa et al, 2013;Hu et al, 2016;Dias et al, 2021). In fact, the triggers and mechanisms of this A 2A R up-regulation in the diseased brain are essentially unknown.…”