The P2X7 receptor: a new therapeutic target in Alzheimer’s disease

Illéš, Peter; Rubini, Patrizia; Huang, Lumei; Tang, Yong

doi:10.1080/14728222.2019.1575811

Cited by 40 publications

(40 citation statements)

References 157 publications

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“…A particularly intensively discussed issue is the transition of the cationic channel to a large membrane pore, because it appears to be essential for cytokine production and secretion (Illes et al, 2019;Martin et al, 2019). Originally, it was suggested based on equilibrium potential (V rev ) measurements with the whole-cell patch-clamp technique that the ion conducting pathway shows progressive dilation (Virginio et al, 1999).…”

Section: Purinergic P2x7 Receptormentioning

confidence: 99%

“…The preferential location of P2X7Rs in the CNS is on the microglia, the resident macrophages of the brain (Bhattacharya and Jones, 2018). Microglia are equipped with a battery of pattern recognition receptors that stereotypically detect pathogenassociated molecules (PAMPs) such as lipopolysaccharide (LPS) from bacterial infection or danger-associated molecular patterns (DAMPs), such as ATP (Figure 1; Shao et al, 2015;Young and Górecki, 2018;Illes et al, 2019;Martin et al, 2019). Activation of microglia stimulates the release of interleukin-1β (IL-1β) in a two-step process: the first being the stimulation of toll-like receptor 4 (TLR4) by LPS, leading to accumulation of cytoplasmic pro-IL-1β, and the second being the ATP-dependent stimulation of P2X7Rs, promoting nucleotidebinding, leucine-rich repeat, pyrin domain containing 3 (NLRP3) inflammasome-mediated caspase-1 activation and secretion of IL-1β (Perregaux and Gabel, 1998;Ferrari et al, 2006).…”

Section: Purinergic P2x7 Receptormentioning

confidence: 99%

“…Microglia are the resident immunocytes of the CNS; unlike other tissue macrophages, they persist for the life of the organism with negligible turnover rates at steady state (Tay et al, 2016;Anderson and Vetter, 2019). Microglia are instrumental in the maintenance of biochemical homeostasis, neuronal circuit maturation during development, and experience-dependent remodeling of neuronal circuits in the adult brain (Szepesi et al, 2018;Anderson and Vetter, 2019;Illes et al, 2019). The cellular processes of quiescent or ''resting'' microglia are highly mobile (extension and withdrawal) by scanning the environment for disruptions of brain homeostasis (Davalos et al, 2005).…”

Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

“…Microglia establish close contact with both neurons (Eyo and Wu, 2013) and astrocytes (Jha et al, 2019), supplementing the ''tripartite synapse'' (see below) with a microglial component (''quadripartite synapse''; Schafer et al, 2013;Illes et al, 2019). An important regulator of this interaction is ATP/ADP, which is released from neurons and astrocytes/microglia by exocytotic and non-exocytotic mechanisms (Calovi et al, 2019).…”

Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

“…Astrocytes to a large extent define synaptic connectivity. Indirect effects are exerted by changes in astrocytic functions due to modifications in K + uptake and redistribution; Cl − and water fluxes; Na + /K + , Na + /Ca 2+ , or Na + /HCO 3 − exchange; neurotransmitter uptake; etc (Verkhratsky et al, 2017;Mederos et al, 2018;Illes et al, 2019). Astrocytes also directly modify synaptic transmission, because they contact and partially ensheathe synapses with their perisynaptic processes (Allen and Eroglu, 2017).…”

Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

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Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R-or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans.

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Section: Purinergic P2x7 Receptormentioning

confidence: 99%

Section: Purinergic P2x7 Receptormentioning

confidence: 99%

Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

Section: Microglial and Astroglial Functions; Cell Death And Prolifermentioning

confidence: 99%

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Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists

et al. 2020

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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan‐1‐yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand‐based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two‐electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl‐cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2‐chloro‐N‐[1‐(3‐(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μM.

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Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

Yin

Wei

Caseley

et al. 2023

Medicinal Research Reviews

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The P2X7 receptor is an exceptional member of the P2X purinergic receptor family, with its activation requiring high concentrations of extracellular adenosine 5ʹ‐triphosphate (ATP) that are often associated with tissue damage and inflammation. In the central nervous system (CNS), it is highly expressed in glial cells, particularly in microglia. In this review, we discuss the role and mechanisms of the P2X7 receptor in mediating neuroinflammation and other pathogenic events in a variety of traumatic CNS damage conditions, which lead to loss of neurological and cognitive functions. We raise the perspective on the steady progress in developing CNS‐penetrant P2X7 receptor‐specific antagonists that leverage the ATP‐P2X7 receptor signaling axis as a potential therapeutic strategy to alleviate traumatic CNS damage and related complications.

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The P2X7 receptor: a new therapeutic target in Alzheimer’s disease

Cited by 40 publications

References 157 publications

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists

Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

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