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Cited by 129Adenosine and Purinergic SignalingTryptophan and brain disordersTreatment of Major Depression

P2X7 Receptor Signaling in Stress and Depression

Open access
Ribeiro, Deidiane Elisa, Roncalho, Aline Lulho, Glaser, Talita, Ulrich, Henning, Wegener, Gregers, Joca, Sâmia·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20112778PMC PMC6600521
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Abstract

Stress exposure is considered to be the main environmental cause associated with the development of depression. Due to the limitations of currently available antidepressants, a search for new pharmacological targets for treatment of depression is required. Recent studies suggest that adenosine triphosphate (ATP)-mediated signaling through the P2X7 receptor (P2X7R) might play a prominent role in regulating depression-related pathology, such as synaptic plasticity, neuronal degeneration, as well as changes in cognitive and behavioral functions. P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system (CNS), playing a crucial role in neuron-glia signaling. P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide (NO) and glutamate. Moreover, P2X7R stimulation in microglia modulates the innate immune response by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, consistent with the neuroimmune hypothesis of MDD. Importantly, blockade of P2X7R leads to antidepressant-like effects in different animal models, which corroborates the findings that the gene encoding for the P2X7R is located in a susceptibility locus of relevance to depression in humans. This review will discuss recent findings linked to the P2X7R involvement in stress and MDD neuropathophysiology, with special emphasis on neurochemical, neuroimmune, and neuroplastic mechanisms.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that ATP-gated P2X7 receptor signaling links stress exposure to depression-related neurochemical, neuroimmune, and neuroplastic changes, and that P2X7R blockade produces antidepressant-like effects in animal models. It synthesizes human genetic and preclinical evidence while highlighting unresolved questions about neuronal P2X7R expression and clinical translation.

Key findings

  • P2X7R is a low-affinity ATP-gated cation channel activated by high ATP concentrations (>100 μM; EC50 ≥100 µmol·L−1); its gene is at chromosomal region 12q24.31, and SNP rs2230912 (Gln460Arg) has been associated with MDD/mood disorders, though meta-analyses show conflicting results.
  • Stress and antidepressants modulate hippocampal P2X7R: CUMS/CRS increased P2X7R in hippocampus and medial prefrontal cortex, while imipramine, desipramine, clemastine, and ketamine were associated with decreased P2X7R levels; other studies report no change or reduced P2X7R after restraint stress.
  • Genetic and pharmacological P2X7R blockade is antidepressant-like: P2X7R KO mice show reduced immobility in FST/TST and enhanced neurogenesis; antagonists such as BBG (50 mg/kg/day) or fluoxetine (15 mg/kg/day) for 7 weeks, A-804598 (5 mg/kg twice daily for 28 days; 30 mg/kg i.p. for 7 days), and hippocampal BBG (1 pM) or A-438079 (1.75 nM) reverse stress-induced behavioral alterations.
  • Mechanistically, P2X7R stimulation promotes glutamate/GABA release and reduces their uptake, modulates 5-HT, NA, and NO signaling, activates the NLRP3 inflammasome via K+ efflux to release IL-1β, IL-18, and TNF-α, and impairs neurogenesis/synaptogenesis partly through reduced BDNF.

Methods

  • Design: critical/narrative review of evidence associating P2X7R with stress and depression, emphasizing neurochemical, neuroimmune, and neuroplastic mechanisms.
  • Data/sample: human genetic association studies (e.g., rs2230912) and preclinical in vitro, knockout, pharmacological, and rodent stress-model studies; no primary experimental data were generated.
  • Analysis: narrative synthesis of cited literature, including tables summarizing stress/antidepressant effects and P2X7R manipulations; no systematic search or meta-analysis is described.

Limitations

  • Stated: human studies are scarce and inconclusive, and rs2230912 findings are controversial, with two meta-analyses reaching different conclusions.
  • Stated: neuronal P2X7R expression is debated; antibody specificity and possible glial contamination are concerns, and in vivo reproducibility remains to be established.
  • Stated/evident: divergent preclinical results may arise from different techniques, doses, administration routes, and models; as a narrative review, it does not systematically assess bias or quantify pooled effects.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms20112778

Cites

201 of 201 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 266 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Repeated treatments with imipramine or desipramine attenuated P2X7R levels in the ventral hippocampus of rats exposed to a paradigm of inescapable foot shocks.

    “Similarly, we recently observed that the antidepressant-like effects induced by repeated treatments with imipramine or desipramine attenuated P2X7R levels in the ventral hippocampus of rats exposed to a paradigm of inescapable foot shocks [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Ribeiro, 2019, P2X7 receptors are involved in stress-related behaviours and antidepressant effect, Eur. Neuropsychopharmacol. source

      Not checked in the free run.

  • Premisecitation

    The gene encoding P2X7R is located in a susceptibility locus of relevance to depression in humans.

    “which corroborates the findings that the gene encoding for the P2X7R is located in a susceptibility locus of relevance to depression in humans.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Shink, 2005, A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12, Mol. Psychiatry source

      Not checked in the free run.

    • cites [70] Li, 2018, Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder, Neuropsychopharmacology source

      Not checked in the free run.

  • Premisecitation

    Purinergic signaling is involved in several psychiatric disorders, including MDD.

    “Purinergic signaling is involved in several psychiatric disorders, including MDD [25,26,27,28], and is mediated by nucleoside and nucleotide actions on P1 (P1R) and P2 (P2R) receptors.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [25] Sperlagh, 2012, The role of purinergic signaling in depressive disorders, Neuropsychopharmacol. Hung.

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    • cites [26] Cheffer, 2018, Purinergic system in psychiatric diseases, Mol. Psychiatry source

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    • cites [27] Burnstock, 2017, Purinergic Signalling and Neurological Diseases: An Update, CNS Neurol. Disord. Drug Targets source

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    • cites [28] Illes, 2014, P2X7 receptor: An emerging target in central nervous system diseases, Trends Pharmacol. Sci. source

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  • Interpretationnone given

    P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide, and glutamate.

    “P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide (NO) and glutamate.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Stress exposure is considered to be the main environmental cause associated with the development of depression.

    “Stress exposure is considered to be the main environmental cause associated with the development of depression.”
    • Also stated in: § 1. Introduction · plain
      “Stress exposure is considered to be the main environmental cause of mental health disorders, such as major depressive disorder (MDD) [1,2,3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Kendler, 2006, Toward a comprehensive developmental model for major depression in men, Am. J. Psychiatry source

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    • cites [2] Kendler, 2002, Toward a comprehensive developmental model for major depression in women, Am. J. Psychiatry source

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    • cites [3] Post, 1992, Transduction of psychosocial stress into the neurobiology of recurrent affective disorder, Am. J. Psychiatry source

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  • May combine two claims. 69
  • Classified as probably not a substantial claim. 22

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    Premisecitation

    P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system and plays a crucial role in neuron-glia signaling.

    “P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system (CNS), playing a crucial role in neuron-glia signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Sluyter, 2017, The P2X7 receptor, Advances in Experimental Medicine and Biology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Current hypotheses propose that MDD results from the interplay and interaction between genetic and environmental factors, leading to neuroendocrine imbalance, neurochemical alterations, and decreased neuroplasticity.

    “Current hypotheses propose that MDD results from the interplay and interaction between genetic and environmental factors, leading to neuroendocrine imbalance, neurochemical alterations (including impaired monoaminergic neurotransmission, enhanced glutamate release and neuroimmune response), as well as decreased neuroplasticity (e.g., synaptogenesis and neurogenesis) [1,17] (Figure 1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Kendler, 2006, Toward a comprehensive developmental model for major depression in men, Am. J. Psychiatry source

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    • cites [17] Dean, 2017, The neurobiology of depression: An integrated view, Asian J. Psychiatr. source

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    Premisecitation

    Clinical diagnosis of MDD is based on symptom identification, with no biological marker currently available.

    “Clinical diagnoses of MDD is based on symptom identification, with no biological marker currently available.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders: DSM-5, American Psychiatric Association. source

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    Premisecitation

    P2X7R is widely distributed in different brain regions and is found both in neurons and in glial cells.

    “The P2X7R is widely distributed in different brain regions, found both in neurons and in glial cells [49,55,65].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [49] Sim, 2004, Reanalysis of P2X7 Receptor Expression in Rodent Brain, J. Neurosci. source

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    • cites [55] Metzger, 2017, Genetically dissecting P2rx7 expression within the central nervous system using conditional humanized mice, Purinergic Signal. source

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    • cites [65] Jimenez-Mateos, E.M., Smith, J., Nicke, A., and Engel, T. (2019). Regulation of P2X7 receptor expression and function in the brain. Brain Res. Bull. source

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  • Classified as probably not a substantial claim.

    Premisecitation

    P2X7R has been suggested as a putative target for therapeutic intervention in mood disorders.

    “Among the purinergic receptors, the P2X7R has been suggested as a putative target for therapeutic intervention in mood disorders [33] (Figure 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Deussing, 2018, P2X7 Receptor: A Potential Therapeutic Target for Depression?, Trends Mol. Med. source

      Not checked in the free run.

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    Premisecitation

    P2X7R stimulation in microglia modulates the innate immune response by activating the NLRP3 inflammasome, consistent with the neuroimmune hypothesis of MDD.

    “Moreover, P2X7R stimulation in microglia modulates the innate immune response by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, consistent with the neuroimmune hypothesis of MDD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Iwata, 2016, Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor, Biol. Psychiatry source

      Not checked in the free run.

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    Premisecitation

    P2X7R has only low affinity for ATP (>100 μM), requiring exceptionally high concentrations to be activated, which can be observed during conditions of stress.

    “Interestingly, P2X7R have only low affinity for ATP (>100 μM), requiring exceptionally high concentrations in order to be activated, which can be observed during conditions of 2stress [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Namovic, 2009, Mammalian P2X7 receptor pharmacology: Comparison of recombinant mouse, rat and human P2X7 receptors, Br. J. Pharmacol. source

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    Interpretationcitation

    The characteristic response following P2X7R stimulation has been demonstrated in cultured neurons or synaptosomes by electrophysiological recordings, intracellular Ca2+ measurements, and activation of intracellular signaling cascades, supporting the hypothesis of P2X7R expression in neurons.

    “On the other hand, the characteristic response following stimulation of this receptor has been demonstrated in cultured neurons or synaptosomes by electrophysiological recordings, intracellular Ca2+ measurements and activation of intracellular signaling cascades [50,60,61,62,63,64], which supports the hypothesis of P2X7R expression in neurons.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [50] Deuchars, 2001, Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems, J. Neurosci. source

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    • cites [60] Anderson, 2006, Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons, Trends Neurosci. source

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    • cites [61] Carrasquero, 2009, P2X7 and P2Y13 purinergic receptors mediate intracellular calcium responses to BzATP in rat cerebellar astrocytes, J. Neurochem. source

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    • cites [62] Lucas, 2008, Inhibition of the ATP-gated P2X7 receptor promotes axonal growth and branching in cultured hippocampal neurons, J. Cell Sci. source

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    • cites [63] 2003, Coexpression of functional P2X and P2Y nucleotide receptors in single cerebellar granule cells, J. Neurosci. Res. source

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    • cites [64] Ortega, 2009, P2X7 Nucleotide Receptor is Coupled to GSK-3 Inhibition and Neuroprotection in Cerebellar Granule Neurons, Neurotox. Res. source

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    Premisecitation

    P2X7R is an ion channel activated by high concentrations of ATP, which can be observed following stress exposure.

    “The P2X7 receptor (P2X7R) is an ion channel activated by high concentrations of ATP, which for example can be observed following stress exposure [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Sluyter, 2017, The P2X7 receptor, Advances in Experimental Medicine and Biology source

      Not checked in the free run.

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    Premisecitation

    P2X7R has been involved in impaired monoaminergic neurotransmission, increased glutamatergic neurotransmission, stimulation of a neuroinflammatory response, and reduced neuroplasticity in MDD.

    “The P2X7R has been involved in several process observed in MDD, such as impaired monoaminergic neurotransmission [19,20,21], increased glutamatergic neurotransmission [22], stimulation of a neuroinflammatory response [23] as well as reduced neuroplasticity [20,24].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [19] Baranyi, 2017, Regulation of Hippocampal 5-HT Release by P2X7 Receptors in Response to Optogenetic Stimulation of Median Raphe Terminals of Mice, Front. Mol. Neurosci. source

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    • cites [20] Csölle, C., Baranyi, M., Zsilla, G., Kittel, A., Gölöncsér, F., Illes, P., Papp, E., Vizi, E.S., and Sperlágh, B. (2013). Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors. PLoS ONE, 8. source

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    • cites [21] Papp, 2004, P2X Receptor Activation Elicits Transporter-Mediated Noradrenaline Release from Rat Hippocampal Slices, J. Pharmacol. Exp. Ther. source

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    • cites [22] Mayhew, 2018, Purinergic modulation of glutamate transmission: An expanding role in stress-linked neuropathology, Neurosci. Biobehav. Rev. source

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    • cites [23] Iwata, 2016, Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor, Biol. Psychiatry source

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    Premisecitation

    Most antidepressants induce therapeutic effects only after 3 or 4 weeks of continuous treatment and also induce several side effects.

    “Moreover, most antidepressants induce therapeutic effects only after 3 or 4 weeks of continuous treatment [13,14], while also inducing several side effects [15].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Blier, 2003, The pharmacology of putative early-onset antidepressant strategies, Eur. Neuropsychopharmacol. source

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    • cites [14] Baumann, 2010, The timing of antidepressant effects: A comparison of diverse pharmacological and somatic treatments, Pharmaceuticals source

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    • cites [15] Santarsieri, 2015, Antidepressant efficacy and side-effect burden: A quick guide for clinicians, Drugs Context source

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    Premisecitation

    P2X7R knockout mice present reduced immobility time in both the forced swim test and the tail suspension test.

    “Additional studies further corroborated these initial findings, with observations that P2X7R KO mice presents reduced immobility time in both the FST [85] and the TST [20,85].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Kittel, 2013, The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice, Int. J. Neuropsychopharmacol. source

      Not checked in the free run.

    • cites [20] Csölle, C., Baranyi, M., Zsilla, G., Kittel, A., Gölöncsér, F., Illes, P., Papp, E., Vizi, E.S., and Sperlágh, B. (2013). Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors. PLoS ONE, 8. source

      Not checked in the free run.

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    Premisecitation

    The human P2X7R gene is located on chromosomal region 12q24.31, a region related to bipolar disorder and depression.

    “The human P2X7R gene is located on the chromosomal region 12q24.31, a region related to bipolar disorder (BD) and depression [69,70].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Shink, 2005, A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12, Mol. Psychiatry source

      Not checked in the free run.

    • cites [70] Li, 2018, Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder, Neuropsychopharmacology source

      Not checked in the free run.

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    Premisecitation

    Paroxetine inhibited while fluoxetine and clomipramine potentiated ATP-induced dye uptake in HEK-293 cells expressing recombinant human P2X7R.

    “In another study, antidepressants demonstrated differential effects on human P2X7R-mediated responses, as paroxetine inhibited while fluoxetine and clomipramine potentiated ATP-induced dye uptake in HEK-293 cells expressing recombinant human P2X7R [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Skarratt, 2015, Paroxetine suppresses recombinant human P2X7 responses, Purinergic Signal. source

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    Premisecitation

    SNP rs2230912 is associated with mood disorders and longer episodes of depression.

    “Corroborating the primary study of Lucae and coworkers, it was later found that SNP rs2230912 is associated with mood disorders and longer episodes of depression [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Soronen, 2011, P2RX7 gene is associated consistently with mood disorders and predicts clinical outcome in three clinical cohorts, Am. J. Med. Genet. Part B Neuropsychiatr. Genet. source

      Not checked in the free run.

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    Premisecitation

    Heterozygous mice for both P2X7R variants exhibited attenuated function of P2X7R and impaired sleep, which was also observed in healthy heterozygous human subjects.

    “Interestingly, heterozygous mice for both variants exhibited attenuated function of P2X7R and impaired sleep, which was also observed in healthy heterozygous human subjects [77].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Metzger, 2017, Heterozygosity for the mood disorder-associated variant Gln460Arg alters P2X7 receptor function and sleep quality, J. Neurosci. source

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    Premisecitation

    The magnitude of the P2X7R reduction was significantly greater during chronic stress compared to the acute stress group, with a gradual normalization of P2X7R expression in animals allowed to recover for 7 days following stress sessions.

    “Interestingly, a comparative analysis of normalized data indicates that the magnitude of the P2X7R reduction was significantly greater during chronic stress compared to the acute stress group, with a gradual normalization of the expression of P2X7R in animals that were allowed to recover for 7 days following stress sessions [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Kongsui, 2014, Chronic stress induces prolonged suppression of the P2X7 receptor within multiple regions of the hippocampus: A cumulative threshold spectra analysis, Brain. Behav. Immun. source

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    Interpretationcitation

    Data from P2X7R knockout mice indicate that absence of the P2X7R results in increased resilience to stress and a phenotype showing less depression-like characteristics.

    “Altogether, data from P2X7R KO mice indicates that absence of the P2X7R results in increased resilience to stress, and a phenotype showing less depression-like characteristics.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Basso, 2009, Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: Relevance for neuropsychiatric disorders, Behav. Brain Res. source

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    • cites [85] Kittel, 2013, The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice, Int. J. Neuropsychopharmacol. source

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    • cites [86] Boucher, 2011, Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test, Neuroscience source

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    • Rests on an assumption: Animal models of stress and depression (e.g., forced swim test, tail suspension test, chronic unpredictable mild stress, social defeat) are predictive of human depression and antidepressant effects.

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    Premisecitation

    The included studies differed between the two meta-analyses, with the latter more recent one including more validated studies.

    “However, as discussed in the latter study [76], it is noteworthy that the included studies differed between the two metaanalyses, with the latter more recent one including more validated studies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Czamara, 2018, The P2RX7 polymorphism rs2230912 is associated with depression: A meta-analysis, Prog. Neuro-Psychopharmacol. Biol. Psychiatry source

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    Interpretationcitation

    P2X7R knockout mice show a less depressive-like phenotype, suggesting an antidepressant-like effect of the genetic manipulation.

    “These mice present increased active behaviors in these tests, without changes in spontaneous locomotor activity, which can be interpreted as less depressive-like phenotype, suggesting an antidepressant-like effect of the genetic manipulation [84].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Basso, 2009, Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: Relevance for neuropsychiatric disorders, Behav. Brain Res. source

      Not checked in the free run.

    • Rests on an assumption: Animal models of stress and depression (e.g., forced swim test, tail suspension test, chronic unpredictable mild stress, social defeat) are predictive of human depression and antidepressant effects.

  • May combine two claims.

    Interpretationcitation

    Absence of P2X7R-mediated signaling can facilitate behavioral adaptation upon repeated stress exposure, preventing development of depressive-like behaviors following a single exposure to the stressful condition.

    “indicating that absence of P2X7R-mediated signaling can facilitate behavioral adaptation upon repeated stress exposure, preventing development of depressive-like behaviors, following a single exposure to the stressful condition [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Boucher, 2011, Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test, Neuroscience source

      Not checked in the free run.

    • Rests on an assumption: Animal models of stress and depression (e.g., forced swim test, tail suspension test, chronic unpredictable mild stress, social defeat) are predictive of human depression and antidepressant effects.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Stress may trigger excessive ATP release, followed by activation of P2X7R signaling in the hippocampus, which may impair mechanisms involved in behavioral adaptation to chronic aversive situations and facilitate the development of depressive-like behaviors.

    “It can therefore be hypothesized that stress may trigger excessive ATP release, followed by activation of P2X7R signaling in the hippocampus. This may subsequently impair mechanisms involved in behavioral adaptation to chronic aversive situations, and facilitate the development of depressive-like behaviors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Yue, 2017, Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors, J. Neuroinflamm. source

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    Interpretationcitation

    P2X7R activation in glial cells could also have elicited the observed responses in brain slices.

    “However, as these analyses were performed in brain slices, in which glial cells were also present in the preparation, it cannot be excluded that P2X7R activation in glial cells also could have elicited the observed responses [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Angulo, 2004, Glutamate Released from Glial Cells Synchronizes Neuronal Activity in the Hippocampus, J. Neurosci. source

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    Interpretationcitation

    Stimulation of P2X7R in hippocampal nerve terminals induces glutamate release, which may lead to kainate receptor-mediated GABA efflux from interneurons.

    “Altogether, these results suggest that stimulation of the P2X7R in hippocampal nerve terminals induce glutamate release, which may leads to kainate receptor-mediated GABA efflux from interneurons [51].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Deuchars, 2002, Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus, J. Neurochem. source

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  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Interpretationcitation

    P2X7R stimulation could inhibit 5-HT and NA release upon stress exposure and impair behavioral adaptation; blockade of P2X7R-mediated signaling could disinhibit 5-HT and NA release in limbic brain regions and promote stress coping behaviors.

    “Based on that, it is plausible to suggest that P2X7R stimulation could inhibit 5-HT and NA release upon stress exposure and impair behavioral adaptation. Similarly, blockade of P2X7R-mediated signaling could disinhibit 5-HT and NA release in limbic brain regions and promote stress coping behaviors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Diniz, 2017, Monoamine involvement in the antidepressant-like effect induced by P2 blockade, Brain Res. source

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    Premisecitation

    Genetic deletion of P2X7R in mice inhibits glutamate release and downregulates AMPA and metabotropic glutamate receptor subunits and upregulates the NR2B subunit of NMDA receptors in the amygdala.

    “This is in line with studies showing that genetic deletion of P2X7R in mice inhibits glutamate release and downregulates AMPA and metabotropic glutamate receptor subunits and upregulates the NR2B subunit of N-methyl-D-aspartate (NMDA) receptors in the amygdala of P2X7R deficient mice [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Csölle, C., Baranyi, M., Zsilla, G., Kittel, A., Gölöncsér, F., Illes, P., Papp, E., Vizi, E.S., and Sperlágh, B. (2013). Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors. PLoS ONE, 8. source

      Not checked in the free run.

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    Premisecitation

    Median raphe nuclei are activated in response to stress, and increased 5-HT release in the hippocampus promotes stress adaptation.

    “As it is well documented that the median raphe nuclei are activated in response to stress, increased 5-HT release in the hippocampus to promote stress adaptation is a notable consequence [92,95].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Fujino, 2002, Increased serotonin release in mice frontal cortex and hippocampus induced by acute physiological stressors, Neurosci. Lett. source

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    • cites [95] Adell, 1988, Chronic Stress Increases Serotonin and Noradrenaline in Rat Brain and Sensitizes Their Responses to a Further Acute Stress, J. Neurochem. source

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    Premisecitation

    Exogenously applied P2R agonists may be hydrolyzed to adenosine, which is known to induce glutamate release.

    “Another issue is that exogenously applied P2R agonists may be hydrolyzed to adenosine [102], which is known to induce glutamate release [103,104,105].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [102] Kukley, 2004, Ecto-Nucleotidases and Nucleoside Transporters Mediate Activation of Adenosine Receptors on Hippocampal Mossy Fibers by P2X7 Receptor Agonist 2′-3′-O-(4-Benzoylbenzoyl)-ATP, J. Neurosci. source

      Not checked in the free run.

    • cites [103] Popoli, 2003, Modulation of glutamate release and excitotoxicity by adenosine A2A receptors, Neurology source

      Not checked in the free run.

    • cites [104] Inoue, 1992, Extracellular adenosine 5′-triphosphate-evoked glutamate release in cultured hippocampal neurons, Neurosci. Lett. source

      Not checked in the free run.

    • cites [105] Popoli, 1995, Adenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats, Eur. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P2X7R stimulation by ATP analogues elicited a concentration-dependent GABA efflux from rat hippocampal slices, which was reduced by treatment with TTX or kainate receptor antagonists but not with an NMDA antagonist or AMPA receptor blocker.

    “Moreover, P2X7R stimulation by ATP analogues elicited a concentration-dependent GABA efflux from rat hippocampal slices, which was reduced by treatment with the voltage-dependent sodium (Na+) channel blocker (tetrodotoxin, TTX) or kainate receptor antagonists (gadolinium or 6-cyano-7-nitroquinoxaline-2,3-dione, CNQX), but not with the NMDA antagonist (AP-5) or AMPA receptor blocker (GYKI 53655) [5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Deuchars, 2002, Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus, J. Neurochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P2X7R knockout mice present increased hippocampal 5-HT levels, increased 5-HT transporter binding sites and 5-HT uptake, along with behavioral adaptation to stress.

    “In another study, however, P2X7R KO mice presents with increased hippocampal 5-HT levels, increased 5-HT transporter binding sites and 5-HT uptake, along with behavioral adaptation to stress [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Csölle, C., Baranyi, M., Zsilla, G., Kittel, A., Gölöncsér, F., Illes, P., Papp, E., Vizi, E.S., and Sperlágh, B. (2013). Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors. PLoS ONE, 8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic treatment with BBG or fluoxetine during 7 weeks in mice exposed to CUMS reversed the behavioral alterations induced by chronic stress exposure, suggesting an antidepressant-like effect of both interventions.

    “In line with these observations, systemic treatment with BBG (50 mg/kg, per day) or fluoxetine (15 mg/kg, per day) during 7 weeks in mice exposed to CUMS reversed the behavioral alterations induced by the chronic stress exposure, strongly suggesting an antidepressant-like effect of both interventions in the model [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Farooq, 2018, A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice, Psychoneuroendocrinology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NLRP3 is the most studied and best-characterized inflammasome and belongs to the nucleotide-binding oligomerization domain-like receptors.

    “The most studied and best-characterized inflammasome is the NLR family pyrin domain containing 3 (NLRP3), which belongs to the nucleotide-binding oligomerization domain (NOD) - like receptors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Broz, 2016, Inflammasomes: Mechanism of assembly, regulation and signalling, Nat. Rev. Immunol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intra-nasal administration of ketamine was approved for treatment-resistant depression.

    “Recently, the intra-nasal administration of ketamine was approved for treatment resistant-depression [127].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Targum, 2019, Comparability of blinded remote and site-based assessments of response to adjunctive esketamine or placebo nasal spray in patients with treatment resistant depression, J. Psychiatr. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The inflammasome is a high-molecular-weight complex present in the cytosol of immune cells.

    “Among the different types of PRRs, the newest described is the inflammasome, a high-molecular-weight complex, present in the cytosol of immune cells [132].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Martinon, 2002, The Inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-β, Mol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic administration of PPADS or iso-PPADS induced an antidepressant-like effect in mice associated with decreased NO levels in the prefrontal cortex.

    “Our research group observed that systemic administration of PPADS or iso-PPADS induced antidepressant-like effect in mice associated with decreased NO levels in prefrontal cortex [87].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Pereira, 2013, Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: Involvement of nitric oxide, Eur. Neuropsychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Regardless of their specific location, P2X7R stimulation increases the release of glutamate and GABA, as well as decreases the uptake/clearing of these transmitters.

    “However, regardless of their specific location, P2X7R stimulation increase the release of glutamate and GABA, as well as decrease the uptake/clearing of these transmitters.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [51] Deuchars, 2002, Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus, J. Neurochem. source

      Not checked in the free run.

    • cites [99] Papp, 2004, Lack of ATP-evoked GABA and glutamate release in the hippocampus of P2X7 receptor-/- mice, Neuroreport source

      Not checked in the free run.

    • cites [112] Lobo, 2015, P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes, Neuroscience source

      Not checked in the free run.

    • cites [113] Fonseca, 2016, Up-regulation of P2X7 receptor-mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex, Epilepsia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation and assembly of the inflammasome begin with the release of PAMPs and DAMPs, causing an opening in NLRP3, which allows the interaction between the PYD domain in NLRP3 and ASC.

    “The activation and assembly of the inflammasome begin with the release of PAMPs and DAMPs, causing an opening in NLRP3, which allows the interaction between the PYD domain in NLRP3 and ASC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Broz, 2016, Inflammasomes: Mechanism of assembly, regulation and signalling, Nat. Rev. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P2X7R stimulation decreased GABA and glutamate uptake by nerve terminals from rat and human cerebral cortex as well as glutamate uptake and glutamine synthetase activity in astrocyte cultures.

    “P2X7R stimulation decreased GABA and glutamate uptake by nerve terminals from rat and human cerebral cortex [112,113] as well as glutamate uptake and glutamine synthetase activity in astrocyte-cultures [114].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [112] Lobo, 2015, P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes, Neuroscience source

      Not checked in the free run.

    • cites [113] Fonseca, 2016, Up-regulation of P2X7 receptor-mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex, Epilepsia source

      Not checked in the free run.

    • cites [114] Lo, 2008, Activation of P2X7 receptors decreases glutamate uptake and glutamine synthetase activity in RBA-2 astrocytes via distinct mechanisms, J. Neurochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased glutamate levels are observed in the brains of animals exposed to stress and in depressed individuals.

    “As increased glutamate levels are observed in the brains of animals exposed to stress [118,119] and in depressed individuals [120,121], understanding the importance of the regulation of glutamatergic neurotransmission in stress and depression are crucial.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [118] Musazzi, L., Milanese, M., Farisello, P., Zappettini, S., Tardito, D., Barbiero, V.S., Bonifacino, T., Mallei, A., Baldelli, P., and Racagni, G. (2010). Acute Stress Increases Depolarization-Evoked Glutamate Release in the Rat Prefrontal/Frontal Cortex: The Dampening Action of Antidepressants. PLoS ONE, 5. source

      Not checked in the free run.

    • cites [119] Rada, 2003, Glutamate release in the nucleus accumbens is involved in behavioral depression during the Porsolt swim test, Neuroscience source

      Not checked in the free run.

    • cites [120] Hashimoto, 2007, Increased Levels of Glutamate in Brains from Patients with Mood Disorders, Biol. Psychiatry source

      Not checked in the free run.

    • cites [121] Levine, 2000, Increased cerebrospinal fluid glutamine levels in depressed patients, Biol. Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The NLRP3 inflammasome presents a tripartite domain organization: a C-terminal LRR domain, a central NACTH domain, and an N-terminal PYD that recruits ASC/PYCARD.

    “Structurally, the NLRP3 inflammasome presents a tripartite domain organization: a C-terminal domain with regulatory functions composed by leucine-rich repeats (LRR), a nucleotide binding-and-oligomerization domain (NACTH) centrally located that regulate the self-oligomerization, and an N-terminal pyrin domain (PYD) that recruits an adaptor molecule called apoptosis-associated speck-like protein”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Broz, 2016, Inflammasomes: Mechanism of assembly, regulation and signalling, Nat. Rev. Immunol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The innate immune response consists of the recognition of PAMPs or DAMPs by pattern-recognition receptors expressed in innate immune and inflammatory cells such as macrophages, microglia, monocytes, neutrophils, and dendritic cells.

    “The innate immune response consists of the recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern-recognition receptors (PRRs), expressed in innate immune and inflammatory cells such as macrophages, microglia, monocytes, neutrophils and dendritic cells [131].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Newton, 2012, Signaling in innate immunity and inflammation, Cold Spring Harb. Perspect. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    There is substantial evidence that P2X7R modulates 5-HT, NA, glutamate, GABA, and NO release, which are mechanisms consistently involved in stress and depression.

    “Altogether, there are substantial evidence that P2X7R modulates 5-HT, NA, glutamate, GABA and NO release, which are mechanisms consistently involved in stress and depression [123,129,130].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [123] Sanacora, 2012, Towards a glutamate hypothesis of depression An emerging frontier of neuropsychopharmacology for mood disorders, Neuropharmacology source

      Not checked in the free run.

    • cites [129] Joca, S.R.L., Sartim, A.G., Roncalho, A.L., Diniz, C.F.A., and Wegener, G. (2019). Nitric oxide signalling and antidepressant action revisited. Cell Tissue Res. source

      Not checked in the free run.

    • cites [130] Luscher, 2011, The GABAergic deficit hypothesis of major depressive disorder, Mol. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLRP3 inflammasome formation elicits self-cleavage of procaspase-1, generating active caspase-1 and converting IL-1β and IL-18 to active forms that are secreted from activated immune cells.

    “Formation of this complex elicit the self-cleavage of procaspase-1, generating the active caspase 1 and inducing the conversion of proinflammatory cytokines such as interleukin 1 beta (IL-1β) and interleukin 18 (IL-18) in their active forms, that will be secreted from activated immune cells (Figure 3B) [134,135].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [134] Schroder, 2010, The Inflammasomes, Cell source

      Not checked in the free run.

    • cites [135] Wu, 2007, The pyroptosome: A supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation, Cell Death Differ. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BBG treatment blocked increase in TNF-α levels in serum and induced antidepressant-like effect in LPS-treated mice.

    “In another study, BBG treatment blocked increase in TNF-α levels in serum and induced antidepressant-like effect in LPS-treated mice [155].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Ma, 2014, Effects of Brilliant Blue G on Serum Tumor Necrosis Factor-alpha Levels and Depression-like Behavior in Mice after Lipopolysaccharide Administration, Clin. Psychopharmacol. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice submitted to 4 weeks of CUMS present higher serum levels of IL-1β and enhanced hippocampal NLRP3, caspase-1 and active IL-1β protein levels.

    “Mice submitted to 4 weeks of CUMS presents with higher serum levels of IL-1β, along with enhanced hippocampal NLRP3, caspase-1 and active IL-1β protein levels [149].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Zhang, 2015, NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation, Int. J. Neuropsychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Differentiation is triggered to replace dead cells; quiescent NPCs exit the dormant state, re-enter the cell proliferation cycle, and new-born cells are determined to neuronal vs glial fate, migrate, maturate and integrate to the neuronal circuitry.

    “The differentiation process is triggered in order to replace dead cells, which for example are controlling the retrieval of memories. Therefore, quiescent NPCs exit the dormant state, and re-enter in the cell proliferation cycle. The new-born cells are then determined to neuronal vs glial fate, migrate, maturate and integrate to the neuronal circuitry [166].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Toni, 2016, Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus, Cold Spring Harb. Perspect. Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    New extensions connect to existing neurons, creating new synapses (synaptogenesis).

    “These new extensions will connect to existing neurons, creating new synapses (synaptogenesis) [168].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Toni, 2007, Synapse formation on neurons born in the adult hippocampus, Nat. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P2X7R is activated only by high concentrations of ATP (EC50 ≥ 100 μmol·L−1), which occurs after stress exposure.

    “Interestingly, P2X7R is activated only by high concentrations of ATP (EC50 ≥ 100 µmol·L−1), which occurs after stress exposure [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Surprenant, 1996, The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7), Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CUS increased ATP levels and promoted activation of the hippocampal NLRP3 inflammasomal pathway.

    “This proposal is further substantiated in a study where CUS increased ATP levels and promoted activation of the hippocampal NLRP3 inflammasomal pathway [53]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Yue, 2017, Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors, J. Neuroinflamm. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In untreated depressive patients, blood levels of NLRP3 and caspase-1 are increased along with increased serum levels of IL-1β and IL-18.

    “A clinical report published in 2014 showed that the levels of NLRP3 and caspase-1 were increased in the blood of untreated depressive patients along with increased serum levels of IL-1β and IL-18 [145].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Cordero, 2014, NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder, Brain Behav. Immun. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    New cells gain archetypical morphology by extending neurites (neuritogenesis), which further matures to dendrites and axons.

    “Meanwhile, the new cells gain the archetypical morphology by extending projections - neurites (neuritogenesis), which further matures to dendrites and axons [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Sun, 2013, Seamless reconstruction of intact adult-born neurons by serial end-block imaging reveals complex axonal guidance and development in the adult hippocampus, J. Neurosci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In mammals there are two canonical neurogenic regions, the subventricular zone (SVZ) and subgranular zone (SGZ) at the dentate gyrus of the hippocampus.

    “In mammals there are two canonical regions, the subventricular zone (SVZ) and subgranular zone (SGZ) at the dentate gyrus of the hippocampus [159,161].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [159] Gage, 2000, Mammalian neural stem cells, Science source

      Not checked in the free run.

    • cites [161] Lim, 2016, The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis, Cold Spring Harb. Perspect. Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neural progenitor cells may generate neurons and glial cells by differentiation, as well as self-renew to maintain the original pool of parent cells.

    “Neural progenitor cells (NPCs) may generate cells of the neural lineage, neurons and glial cells by differentiation, as well as self-renewal in order to maintain the original pool of parent cells [159,160].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [159] Gage, 2000, Mammalian neural stem cells, Science source

      Not checked in the free run.

    • cites [160] Bonaguidi, 2011, In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics, Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other regions like neocortex, striatum, amygdala, hypothalamus, substantia nigra, cerebellum and brain stem may also have sporadic neurogenesis.

    “However, other regions like neocortex, striatum, amygdala, hypothalamus, substantia nigra, cerebellum and brain stem may also have sporadic neurogenesis [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Feliciano, 2015, Noncanonical Sites of Adult Neurogenesis in the Mammalian Brain, Cold Spring Harb. Perspect. Biol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These neurogenic regions are important for cognitive functions like learning and memory, emotion control, anxiety and stress response.

    “These regions are important for cognitive functions like learning and memory, emotion control, anxiety and stress response [163,164,165].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [163] Lieberwirth, 2016, Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory, Brain Res. source

      Not checked in the free run.

    • cites [164] Knoth, R., Singec, I., Ditter, M., Pantazis, G., Capetian, P., Meyer, R.P., Horvat, V., Volk, B., and Kempermann, G. (2010). Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE, 5. source

      Not checked in the free run.

    • cites [165] Eriksson, 1998, Neurogenesis in the adult human hippocampus, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of NLRP3 reduces serum and hippocampal levels of IL-1β and attenuates depressive-like behaviors induced by stress.

    “inhibition of the NLRP3 was able to reduce the serum and hippocampal levels of IL-1β, while attenuating the depressive-like behaviors induced by stress [149].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Zhang, 2015, NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation, Int. J. Neuropsychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P2X7R KO mice showed a less depression-like phenotype after a challenge with LPS, associated with inability to release IL-1β.

    “while P2X7R KO mice showed a less depression-like phenotype after a challenge with LPS. These findings were associated with inability to release IL-1β [20,84].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Csölle, C., Baranyi, M., Zsilla, G., Kittel, A., Gölöncsér, F., Illes, P., Papp, E., Vizi, E.S., and Sperlágh, B. (2013). Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors. PLoS ONE, 8. source

      Not checked in the free run.

    • cites [84] Basso, 2009, Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: Relevance for neuropsychiatric disorders, Behav. Brain Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Neurogenesis in the adult brain takes place at sites in which the pool of NPCs is active, called neurogenic niches.

    “Neurogenesis in the adult brain may therefore takes place at the sites in which the pool of NPCs is active, called neurogenic niches.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [159] Gage, 2000, Mammalian neural stem cells, Science source

      Not checked in the free run.

    • cites [161] Lim, 2016, The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis, Cold Spring Harb. Perspect. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Increased ATP levels induced by stress exposure may stimulate P2X7R, leading to diminished intracellular K+ concentration, subsequent NLRP3 inflammasome activation and secretion of pro-inflammatory cytokines.

    “Altogether, these data support the notion that increased ATP levels induced by stress exposure may stimulate P2X7R leading to diminished intracellular K+ concentration, with subsequent NLRP3 inflammasome activation and secretion of pro-inflammatory cytokines [93,154].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] 2017, The NLRP3 and pyrin inflammasomes: Implications in the pathophysiology of autoinflammatory diseases, Front. Immunol.

      Not checked in the free run.

    • cites [154] Bhattacharya, 2018, Emerging role of the P2X7-NLRP3-IL1β pathway in mood disorders, Psychoneuroendocrinology source

      Not checked in the free run.

    • Rests on an assumption: Activated P2X7R allows Ca2+ and Na+ influx as well as K+ efflux from cells.

  • May combine two claims.

    Interpretationreasoning

    The relationship between stress, depression and inflammation does not occur in a single direction; the three elements act on each other.

    “suggesting that the relationship between stress, depression and inflammation does not occur in a single direction, but that the three elements of this equation act on each other.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The antidepressant-like effect induced by ketamine attenuated LPS-induced depressive-like behavior together with hippocampal over-expression of IL-1β and NLRP3.

    “a recent study reported that the antidepressant-like effect induced by ketamine, attenuated the LPS-induced depressive-like behavior together with hippocampal over-expression of IL-1β and NLRP3 [156].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Li, 2019, Ketamine may exert antidepressant effects via suppressing NLRP3 inflammasome to upregulate AMPA receptors, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of A-804598 (25 mg/kg) in rats through intubation only partially attenuated the increase in IL-1β and CD14 mRNA in the paraventricular nucleus, and failed to reverse the behavioral changes induced by stress.

    “However, administration of A-804598 (25 mg/kg) in rats through intubation only partially attenuated the increase in IL-1β and CD14 mRNA in the paraventricular nucleus, and failed to reverse the behavioral changes induced by stress [91].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Catanzaro, 2014, The impact of the P2X7 receptor antagonist A-804598 on neuroimmune and behavioral consequences of stress, Behav. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking adult hippocampal neurogenesis are not more susceptible to stress or do not present more depressive-related behavior.

    “mice lacking adult hippocampal neurogenesis are not more susceptible to stress [174] or do not present more depressive-related behavior [175,176].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [174] Santarelli, 2003, Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science source

      Not checked in the free run.

    • cites [175] Airan, 2007, High-speed imaging reveals neurophysiological links to behavior in an animal model of depression, Science source

      Not checked in the free run.

    • cites [176] Holick, 2008, Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During embryo development, P2X7R expression could be detected in immature neurons of the SGZ and in brain neural stem cells (NSCs) of SVZ and SGZ.

    “during embryo development, it has been reported that P2X7R expression could be detected in immature neurons of the SGZ [193] and in brain neural stem cells (NSCs) of SVZ and SGZ [194,195].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [193] Tsao, 2013, PKC-dependent ERK phosphorylation is essential for P2X7 receptor-mediated neuronal differentiation of neural progenitor cells, Cell Death Dis. source

      Not checked in the free run.

    • cites [194] Lledo, 2006, Adult neurogenesis and functional plasticity in neuronal circuits, Nat. Rev. Neurosci. source

      Not checked in the free run.

    • cites [195] Mu, 2010, Signaling in adult neurogenesis, Curr. Opin. Neurobiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Together, neuritogenesis and synaptogenesis are main neuroplasticity processes in the CNS, which are adaptations to the surrounding environment.

    “Together, neuritogenesis and synaptogenesis are main neuroplasticity processes in the CNS, which are adaptations to the surrounding environment of the organism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    P2X7R stimulation would shift the homeostasis of the NPC pool, leading to increased cell death or inhibition of neurogenesis, which could contribute to the establishment of depressive behavior.

    “Therefore, P2X7R stimulation would shift the homeostasis of the NPC pool, leading to increased cell death or inhibition of neurogenesis, which could contribute to the establishment of the depressive behavior.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Administration of BzATP caused a decrease in BDNF levels, which was reversed by BBG treatment.

    “Intriguingly, administration of BzATP caused a decrease in BDNF levels, which could be reversed by BBG treatment, suggesting that this response was mediated by P2X7R [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Csölle, C., Baranyi, M., Zsilla, G., Kittel, A., Gölöncsér, F., Illes, P., Papp, E., Vizi, E.S., and Sperlágh, B. (2013). Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors. PLoS ONE, 8. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    According to the neuroplasticity hypothesis of depression, mood alterations, cognition, learning and memory impairments induced by stress or depressive conditions are a result of dysfunctional neuroplasticity, which can be observed as affected neurogenesis and/or synaptogenesis.

    “According to that, mood alterations, cognition, learning and memory impairments induced by stress or depressive conditions are a result of dysfunctional neuroplasticity, which can be observed as affected neurogenesis and/or synaptogenesis [184].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Liu, 2017, The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex, Neural Plast. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Throughout life, the brain acquires and registers information to better adapt to environment, inducing establishment of new cognitive blocks, like emotional control.

    “In addition, throughout life, the brain acquires and registers information in order to better adapt to environment, inducing the establishment of new cognitive blocks, like emotional control [170].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Opendak, 2015, Adult neurogenesis: A substrate for experience-dependent change, Trends Cogn. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Stimulation of P2X7R and NMDA receptors leads to enhanced K+ efflux resulting in NLRP3 inflammasome activation and secretion of inflammatory cytokines (e.g., IL-1β, IL-18, TNF-α) from astrocytes and microglia.

    “Stimulation of these receptors leads to: 1. enhanced K+ efflux resulting in NLRP3 inflammasome activation and secretion of inflammatory cytokines (e.g., IL-1β, IL-18, TNF-α) from astrocytes and microglia;”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Activated P2X7R allows Ca2+ and Na+ influx as well as K+ efflux from cells.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neurogenesis has been reported to be required for antidepressant response, although many of these studies are controversial and lack replication.

    “However, neurogenesis have been reported to be required for antidepressant response [174,175,177,178], although many of these studies are controversial and lacks replication.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [174] Santarelli, 2003, Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science source

      Not checked in the free run.

    • cites [175] Airan, 2007, High-speed imaging reveals neurophysiological links to behavior in an animal model of depression, Science source

      Not checked in the free run.

    • cites [177] Sahay, 2007, Adult hippocampal neurogenesis in depression, Nat. Neurosci. source

      Not checked in the free run.

    • cites [178] Vaidya, 2007, Regulation of adult hippocampal neurogenesis: Relevance to depression, Expert Rev. Neurother. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Under condition of stress, high levels of ATP, glutamate and pro-inflammatory cytokines are maintained by a regenerative circuit, even after stress stimulus termination, leading to diminished BDNF levels, decreased synapto-/neuro-genesis and damage of brain circuits important for emotional/mood regulation.

    “Under condition of stress, high levels of ATP, glutamate and pro-inflammatory cytokines are maintained by a regenerative circuit, even after stress stimulus termination, leading to diminished BDNF levels, decreased synapto-/neuro-genesis and damage of brain circuits important for emotional/mood regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    P2X7R expressed in cultured NPCs prepared from the adult mouse SVZ can trigger apoptosis through activation of caspase 3, which can be of particular relevance during pathological conditions such as stress exposure which is known to increase ATP release.

    “studies indicate that P2X7R expressed in cultured NPCs prepared from the adult mouse SVZ, can trigger apoptosis through activation of caspase 3, which can be of particular relevance during pathological conditions, such as stress exposure which is known to increase ATP release [198].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Messemer, 2013, P2X7 receptors at adult neural progenitor cells of the mouse subventricular zone, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stress diminishes the number of dendritic spines and synapses, causes dendritic atrophy, and leads to reduced glial cells (both in number and size) in structures related to development of depression, such as hippocampus and prefrontal cortex.

    “stress—which also is a crucial environmental factor in the pathology of depression—diminish the number of dendritic spines and synapses [185], cause dendritic atrophy [186,187] and leads to reduced glial cells (both in number and size) [188,189] in structures related to development of depression, such as hippocampus and prefrontal cortex.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [185] Qiao, 2016, Dendritic Spines in Depression: What We Learned from Animal Models, Neural Plast. source

      Not checked in the free run.

    • cites [186] Jia, 2010, Prenatal stress causes dendritic atrophy of pyramidal neurons in hippocampal CA3 region by glutamate in offspring rats, Dev. Neurobiol. source

      Not checked in the free run.

    • cites [187] Magarinos, 1996, Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews, J. Neurosci. source

      Not checked in the free run.

    • cites [188] Han, 2015, Loss of Glial Cells of the Hippocampus in a Rat Model of Post-traumatic Stress Disorder, Neurochem. Res. source

      Not checked in the free run.

    • cites [189] Noorafshan, 2015, Stress changes the spatial arrangement of neurons and glial cells of medial prefrontal cortex and sertraline and curcumin prevent it, Psychiatry Investig. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    New neurons that are still maturing can sense information and fine-tune synapses, promoting synaptic plasticity, leading to increased sensitivity and potentiation upon cognitive demands, environmental stimuli, and behavioral or sensory experiences.

    “New neurons that are still maturing possess an intriguing capability to sense information and fine-tune synapses, promoting synaptic plasticity, leading to increased sensitivity and potentiation upon cognitive demands, environmental stimuli, and behavioral or sensory experiences [166,169].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166] Toni, 2016, Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus, Cold Spring Harb. Perspect. Biol. source

      Not checked in the free run.

    • cites [169] Bergami, 2015, A critical period for experience-dependent remodeling of adult-born neuron connectivity, Neuron source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Stimulation of these receptors leads to increased Ca2+ influx leading to ATP and glutamate release from nerve terminals and astrocytes, which is responsible for excitotoxicity.

    “2. increased Ca2+ influx leading to ATP and glutamate release from nerve terminals and astrocytes, which is responsible to excitotoxicity;”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Stimulation of these receptors leads to NMDA-mediated nNOS activation and subsequent NO formation in nerve terminals, also contributing to excitotoxicity.

    “3. NMDA-mediated nNOS activation and subsequent NO formation in nerve terminals, also contributing to excitotoxicity process;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Stimulation of P2X7R induced cell death of NPCs, which subsequently during development may adjust the number of neurons in the organism.

    “Moreover, stimulation of P2X7R induced cell death of NPCs [196], which subsequently during the development may adjust the number of neurons in the organism [197].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [196] Delarasse, 2009, Neural progenitor cell death is induced by extracellular ATP via ligation of P2X7 receptor, J. Neurochem. source

      Not checked in the free run.

    • cites [197] Ulrich, 2014, P2X receptors in maintenance and differentiation of neural progenitor cells, Neural Regen. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Increased neurogenesis and synaptogenesis could reverse depressive-related behaviors induced by chronic stress.

    “Since increased neurogenesis and synaptogenesis could reverse depressive-related behaviors induced by chronic stress”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Stress exposure, the main environmental cause of MDD, elicits massive ATP and glutamate release from neurons and glial cells with subsequent stimulation of P2X7R and NMDA receptor.

    “Stress exposure, the main environmental cause of MDD, elicits a massive ATP and glutamate release from neurons and glial cells with subsequent stimulation of the P2X7R and NMDA receptor (Figure 4).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Stress exposure is the main environmental cause of MDD.

  • May combine two claims.

    Premisecitation

    P2X7R KO also shows reduction in the spine synapse number in DG of hippocampus, associated with improved performance in the learned helplessness model of depression.

    “Furthermore, P2X7R KO also shows reduction in the spine synapse number in DG of hippocampus, associated with improved performance in the learned helplessness model of depression [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Otrokocsi, 2017, P2X7 receptors drive spine synapse plasticity in the learned helplessness model of depression, Int. J. Neuropsychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    P2X7R has been proposed to be a potential target for therapeutic intervention in mental disorders, due to its activity in neuroinflammatory processes, which are significantly involved in MDD, schizophrenia, epilepsy and neurodegenerative diseases.

    “P2X7R has been proposed to be a potential target for therapeutic intervention in mental disorders, due to its activity in neuroinflammatory processes, which are significantly involved in MDD, schizophrenia, epilepsy and neurodegenerative diseases (e.g., multiple sclerosis, Huntington, Parkinson’s and Alzheimer’s disease) [66,67,68].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Burnstock, 2018, The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression, Purinergic Signal. source

      Not checked in the free run.

    • cites [67] Bhattacharya, 2016, The microglial ATP-gated ion channel P2X7 as a CNS drug target, Glia source

      Not checked in the free run.

    • cites [68] Bhattacharya, 2018, Recent advances in CNS P2X7 physiology and pharmacology: Focus on neuropsychiatric disorders, Front. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies suggest that decreased neurogenesis is not a major contributor to MDD development, but it may be associated with cognitive impairments induced by stress and observed in patients with depression.

    “There are studies suggesting that decreased neurogenesis is not a major contributor to the MDD development, but it may be associated to cognitive impairments induced by stress and observed in patients with depression [172,173].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] Fang, J., Demic, S., and Cheng, S. (2018). The reduction of adult neurogenesis in depression impairs the retrieval of new as well as remote episodic memory. PLoS ONE, 13. source

      Not checked in the free run.

    • cites [173] Schoenfeld, T.J., Rhee, D., Martin, L., Smith, J.A., Sonti, A.N., Padmanaban, V., and Cameron, H.A. (2019). New neurons restore structural and behavioral abnormalities in a rat model of PTSD. Hippocampus. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P2X7R blockade with A-804598 reverted the depressive-like behavior exhibited by FSL rats, an effect associated with activation of the BDNF signaling pathway in ventral hippocampus.

    “it was also observed by our group that P2X7R blockade with A-804598, reverted the depressive-like behavior exhibited by FSL rats, an effect which also was associated with activation of the BDNF signaling pathway in ventral hippocampus [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Ribeiro, 2019, P2X7 receptors are involved in stress-related behaviours and antidepressant effect, Eur. Neuropsychopharmacol. source

      Not checked in the free run.

84 of 84

  • The paper relies on this without support.

    Animal models of stress and depression (e.g., forced swim test, tail suspension test, chronic unpredictable mild stress, social defeat) are predictive of human depression and antidepressant effects.

    “Evidence from pharmacological studies have further corroborated this hypothesis, since treatment with P2X7R antagonists induce antidepressant-like effects in various animal models.”
    “Altogether, both pharmacological and genetic evidence strongly suggest that P2X7R stimulation during stress increase the vulnerability and subsequent development of behavioral adversities associated with the neurobiology of depression (Table 2).”

  • The paper relies on this without support.

    Findings on P2X7R expression and function in rodents and cell models can be generalized to human MDD pathophysiology.

    “This review will discuss recent findings linked to the P2X7R involvement in stress and MDD neuropathophysiology, with special emphasis on neurochemical, neuroimmune, and neuroplastic mechanisms.”
    “These results indicate that heterozygotic individuals may be more susceptible to development of depression through interaction between genetic predisposition and stress exposure [77].”

  • The paper relies on this without support.

    Stress exposure is the main environmental cause of MDD.

    “Stress exposure, the main environmental cause of MDD”

  • The paper relies on this without support.

    Patients with high inflammatory disease burden may not respond to current available treatments.

    “which may not respond to current available treatments.”

  • The paper relies on this without support.

    There is a high incidence of patients resistant to conventional monoaminergic antidepressants.

    “given the high incidence of patients resistant to conventional monoaminergic antidepressants”

  • The paper relies on this without support.

    Activated P2X7R allows Ca2+ and Na+ influx as well as K+ efflux from cells.

    “The activated P2X7R allows Ca2+ and Na+ influx as well as potassium (K+) efflux from cells.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Inhibition of the P2X7 receptor might decrease pathological traits mediated by the RAAS pressor axis and protect against brain and lung injury in COVID-19 patients.

    “Since the P2X7 receptor is also involved in lung damage [87–89], neurodegenerative and psychiatric disorders [92, 95, 118], the hypothesis is reasonable that inhibition of this receptor might decrease pathological traits mediated by the RAAS pressor axis and protect against brain and lung injury in COVID-19 patients.”

    From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [118]

  • The role of the P2X7 receptor in neuroinflammatory processes in neuropsychiatric and neurodegenerative diseases is widely studied.

    “The role of the P2X7 receptor in neuroinflammatory processes in neuropsychiatric and neurodegenerative diseases is widely studied [95, 118].”

    From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [118]

  • Neuroinflammation and increased levels of ATP are observed in neuropsychiatry disorders, supposedly correlated with P2X7 receptor activation.

    “Neuroinflammation and increased levels of ATP are observed in neuropsychiatry disorders, supposedly correlated with P2X7 receptor activation [118, 145].”

    From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [118]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Knight, G.E. (2010). Purinergic Receptors. Encyclopedia of Neuroscience, Elsevier.

Cited by

Sorted by citations

Related

Authors
Ribeiro, D. E., Roncalho, A. L., Glaser, T., Ulrich, H., Wegener, G., & Joca, S.
Affiliations
  • Universidade de São Paulo (BR)
  • Aarhus University (DK)
Corresponding author
  • Ribeiro, Deidiane Elisa
  • Joca, Sâmia
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-06-06
Volume
20
Issue
11
Pages
2778
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms20112778
PMC
PMC6600521
OpenAlex
W2948329699
Semantic Scholar
e7440574cae057ba14879e247ec731d81d29e7be
Cited by
129
References
201
Citations by year
2026: 11 · 2025: 18 · 2024: 17 · 2023: 19 · 2022: 26 · 2021: 16 · 2020: 18 · 2019: 1 · 2018: 2
FWCI
2.17
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Scopus (Elsevier) (submittedVersion, cc-by)
Funders
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/13345-1; 2012/50880-4; 2018/08426-0)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (304780/2018-9)
  • Danmarks Frie Forskningsfond (8020-00310B)
  • Horizon 2020 (754513)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
P2X7 receptor, major depressive disorder, stress, depression, ATP signaling, NLRP3 inflammasome, microglia, synaptic plasticity, neurodegeneration, monoamines, glutamate, nitric oxide, antidepressant targets, genetic susceptibility loci, neuron-glia signaling
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Brain, Depression, Humans, Stress, Psychological, Signal Transduction, Neurotransmitter Agents, Receptors, Purinergic P2X7

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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