Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling activation

Abstract

Background: P2X7 receptors (P2X7R) are ligand-gated ion channels activated by adenosine 5’-triphosphate (ATP), which are involved in processes that are dysfunctional in stress response and depression, such as neurotransmitter release, and neuroimmune response. Genetic and pharmacological inhibition of the P2X7R induce antidepressant-like effects in animals exposed to stress. However, the effect of P2X7R antagonism in an animal model of depression based on selective breeding has not previously been studied, and the mechanism underling the antidepressant-like effect induced by the P2X7R blockade remains unknown. Aims: The present study aimed to: (1) determine whether P2X7R blockade induces antidepressant-like effects in the Flinders Sensitive Line (FSL) rats and, (2) investigate whether brain-derived neurotrophic factor (BDNF) signalling in the frontal cortex and hippocampus is involved in this effect. Methods: FSL and the control Flinders Resistant Line (FRL) rats were treated with vehicle or the P2X7R antagonist A-804598 (3, 10 or 30 mg/Kg/day) for 1 or 7 days before being exposed to the forced swim test (FST). After the behavioural test, animals were decapitated, their brains were removed and the frontal cortex, ventral and dorsal hippocampus were dissected for BDNF signalling analysis. Results: We found that repeated treatment with A-804598 (30 mg/Kg) reduced the immobility time in the FST and activated the BDNF signalling in the ventral hippocampus of FSL rats. Conclusions: P2X7R blockade induces an antidepressant-like effect associated with increased levels of BDNF-AKT-p70 S6 kinase in the ventral hippocampus, which may be mediated by tropomyosin-related kinase B (TRKB) receptor activation supporting the notion of P2X7R antagonism as a potential new antidepressant strategy.

The P2X7 Receptor: Central Hub of Brain Diseases

“…Mice systemically treated with BBG (50 mg/kg/day) during 8 weeks (Farooq et al, 2018) or rats treated with A-804598, at a dose of 5 mg/kg twice daily for 4 weeks (Iwata et al, 2016), reversed behavioral alterations induced by CUMS exposure. In accordance with these data, 7 days of treatment with BBG (50 mg/kg/day) decreased the number of escape failures induced by inescapable foot shocks application (Ribeiro et al, 2019b). Additionally, 7 days of treatment with A-804598 (30 mg/kg/day) induced antidepressant-like effects in the flinders sensitive line rats, an animal model of depression based on selective breeding (Ribeiro et al, 2019c).…”

“…In another study, paroxetine inhibited, while fluoxetine and clomipramine potentiated ATP-induced dye uptake in HEK-293 cells expressing recombinant human P2X7 receptors ( Dao-Ung et al, 2015 ). In vivo , antidepressant-like effect induced by clemasine ( Su et al, 2018 ), ketamine ( Tan et al, 2017 ) and imipramine ( Ribeiro et al, 2019b ) were associated with diminished P2X7 receptor levels in the hippocampus of stressed animals. These results suggest that P2X7 receptor activity/expression can be modulated by different antidepressants, revealing a potential mechanism by which these drugs may induce their therapeutic effects.…”

Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology

“…Corroborating this hypothesis, antidepressant treatment decreased P2X7 receptor expression in the ventral hippocampus of stressed animals [146]. Moreover, the treatment with a selective P2X7 receptor antagonist (A-804598) induced antidepressant-like effect associated with inflammasome stimulation [147] and BDNF signaling activation [148] in rodent hippocampus. In this context, we propose that the cytokine storm and cell death induced by SARS-CoV-2 infection results in P2X7 receptor-mediated neuroinflammation, leading to the development of neuropsychiatry disorders.…”

Neuroprotective Factors of the Retina and Their Role in Promoting Survival of Retinal Ganglion Cells: A Review

“…Similar to CNTF, BDNF expression may also be influenced by purinergic receptor signaling. P2X7R, mentioned above, has been shown to influence BDNF action: antagonizing P2X7R leads to TrkB activation [67]. BDNF expression can also be modulated by purinergic receptors that belong to the P1 family of metabotropic receptors activated by extracellular adenosine.…”