P2X7R antagonists in chronic stress-based depression models: a review

Abstract

Depression affects around 320 million people worldwide. Growing evidence proposes the immune system to be the core interface between psychosocial stress and the neurobiological and behavioural features of depression. Many studies have identified purinergic signalling via the P2X7 receptor (P2X7R) to be of great importance in depression genesis yet only a few have evaluated P2X7R antagonists in chronic stress-based depression models. This review summarizes their findings and analyses their methodology. The four available studies used three to nine weeks of unpredictable, chronic mild stress or unpredictable, chronic stress in male mice or rats. Stress paradigm composition varied moderately, with stimuli being primarily psychophysical rather than psychosocial. Behavioural testing was performed during or after the last week of stress application and resulted in depressive-like behaviours, immune changes (NLRP3 assembly, interleukin-1β level increase, microglia activation) and neuroplasticity impairment. During the second half of each stress paradigm, a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was applied. Studies differed with regard to antagonist dosage and application timing. Nonetheless, all treatments attenuated the stress-induced neurobiological changes and depressive-like behaviours. The evidence at hand underpins the importance of P2X7R signalling in chronic stress and depression. However, improvements in study planning and reporting are necessary to minimize experimental bias and increase data purview. To achieve this, we propose adherence to the Research Domain Criteria and the STRANGE framework.

High, in Contrast to Low Levels of Acute Stress Induce Depressive-like Behavior by Involving Astrocytic, in Addition to Microglial P2X7 Receptors in the Rodent Hippocampus

“…In the following experiments, we compared the current amplitudes induced by NMDA (100 µM) and Bz-ATP (300, 1000 µM), in very young (12)(13)(14) and young (23)(24)(25) day old rat astrocytes. Interestingly, both NMDA and Bz-ATP showed effects that depended on the age of the animals.…”

“…(2) The genetic deletion of P2X7Rs in mice results in decreased behavioral despair and, consequently, reduced immobility in FST and TST, indicating an antidepressive phenotype [17,18]. (3) Especially, chronic stress models in rodents have convincingly born out the participation of P2X7Rs in depressive-like behaviors, in combination with immune changes (NLRP3 inflammasome assembly and activation, IL-1β release, microglia activation) and neuroplasticity impairments [19][20][21][22][23] (see also Section 3). In all of these studies, unpredictable, chronic mild stress or unpredictable, chronic stress was applied for the duration of a few weeks, and for the second half of each stress paradigm a P2X7R antagonist (Brilliant Blue G, A-438079, A-804598) was administered.…”

P2X7 Receptor-Related Genetic Mouse Models – Tools for Translational Research in Psychiatry

“…Once activated, P2X7R adopts an open conformation, allowing K + efflux and Na + and Ca 2+ influx ( Habermacher et al, 2016 ; Di Virgilio et al, 2018 ), triggering the assembly of the intracellular NLR family pyrin domain containing 3 (NLRP3) inflammasome and subsequent activation of caspase-1. This stimulates cell metabolism via glycolysis and upregulation of oxidative phosphorylation and causes IL-1β, IL-6, TNFα, and IL-18 release, eliciting a neuroinflammatory response ( Di Virgilio et al, 2017 ; von Muecke-Heim et al, 2021 ). P2X7R activation also potentiates the innate immune response by inducing proliferation, recruitment and activation of microglia, macrophages, and lymphocytes ( Dubyak, 2012 ; Monif et al, 2016 ; Colonna and Butovsky, 2017 ).…”

“…Translational research in rodents has shown that chronic stress causes extracellular ATP increase and P2X7R activation in the brain, which results in depressive-like behavior and impaired neuroplasticity ( Iwata et al, 2016 ; Wohleb et al, 2016 ; Metzger et al, 2017b ; von Muecke-Heim et al, 2021 ). Vice versa, blockage along the P2X7R -NLRP3-IL-1β cascade has been shown to promote stress resilience with microglia and monocytes playing an important part ( Schiweck et al, 2020 ; von Muecke-Heim et al, 2021 ). These studies point out P2X7R’s signaling role as an important interface between chronic stress and the behavioral features of clinical depression.…”

“…Meanwhile, psychosocial stress, the main environmental risk factor for depression, was linked to changes in adenosine triphosphate (ATP) mediated P2X7 receptor (P2X7R) signaling and related to neuroinflammation ( Kendler et al, 1999 ; Iwata et al, 2013 ; Rohleder, 2014 ; Calcia et al, 2016 ; Nelson et al, 2017 ; Maydych, 2019 ; Ribeiro et al, 2019 ; Kim et al, 2020 ). Therefore, innate, and adaptive immunity involving P2X7R is currently deemed a key player in stress-induced depression ( Wohleb et al, 2016 ; Leday et al, 2018 ; Giollabhui et al, 2020 ; Illes et al, 2020 ; Troubat et al, 2020 ; von Muecke-Heim et al, 2021 ). However, the role of P2X7R in this disorder still needs to be fully unraveled ( Medina-Rodriguez et al, 2018 ).…”