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Soluble P2X7 Receptor Plasma Levels in Obese Subjects before and after Weight Loss via Bariatric Surgery

by Angelo Di Vincenzo, Marnie Granzotto, Andrea Graziani, Marika Crescenzi, Mirto Foletto, Luca Prevedello, Federico Capone, Roberto Vettor and Marco Rossato

Int. J. Mol. Sci. 2023, 24(23), 16741; https://doi.org/10.3390/ijms242316741 - 25 Nov 2023

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Abstract

Obesity is a systemic disease frequently associated with important complications such as type 2 diabetes and cardiovascular diseases. It has also been proven that obesity is a disease associated with chronic low-grade systemic inflammation and that weight loss improves this low-grade chronic inflammatory [...] Read more.

Obesity is a systemic disease frequently associated with important complications such as type 2 diabetes and cardiovascular diseases. It has also been proven that obesity is a disease associated with chronic low-grade systemic inflammation and that weight loss improves this low-grade chronic inflammatory condition. The P2X7 purinergic receptor (P2X7R), belonging to the family of the receptors for extracellular ATP, is a main player in inflammation, activating inflammasome and pro-inflammatory cytokine production. In this study, we evaluated the plasma levels of soluble P2X7R (sP2X7R) measured in a group of obese patients before and one year after bariatric surgery. Furthermore, we evaluated the relation of sP2X7R to inflammatory marker plasma levels. We enrolled 15 obese patients who underwent laparoscopic sleeve gastrectomy, evaluating anthropometric parameters (weight, height, BMI and waist circumference) before and after surgery. Moreover, we measured the plasma levels of inflammatory markers (CRP, TNFα and IL-6) before and after weight loss via bariatric surgery. The results of our study show that one year after bariatric surgery, obese patients significantly decrease body weight with a significant decrease in CRP, TNF-alfa and IL-6 plasma levels. Similarly, after weight loss, obese subjects showed a significant reduction in sP2X7R plasma levels. Moreover, before surgery, plasma levels of sP2X7R were inversely related with those of CRP, TNF-alfa and IL-6. Given the role of P2X7R in inflammation, we hypothesized that, in obese subjects, sP2X7R could represent a possible marker of chronic low-grade inflammation, hypothesizing a possible role as a mediator of obesity complications. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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14 pages, 2152 KiB

Open AccessArticle

TNAP and P2X7R: New Plasma Biomarkers for Alzheimer’s Disease

by Paloma Aivar, Carolina Bianchi, Caterina Di Lauro, Lucia Soria-Tobar, Beatriz Alvarez-Castelao, Miguel Calero, Miguel Medina and Miguel Diaz-Hernandez

Int. J. Mol. Sci. 2023, 24(13), 10897; https://doi.org/10.3390/ijms241310897 - 30 Jun 2023

Cited by 2 | Viewed by 946

Abstract

Over the last few years, intense research efforts have been made to anticipate or improve the diagnosis of Alzheimer’s disease by detecting blood biomarkers. However, the most promising blood biomarkers identified to date have some limitations, most of them related to the techniques [...] Read more.

Over the last few years, intense research efforts have been made to anticipate or improve the diagnosis of Alzheimer’s disease by detecting blood biomarkers. However, the most promising blood biomarkers identified to date have some limitations, most of them related to the techniques required for their detection. Hence, new blood biomarkers should be identified to improve the diagnosis of AD, better discriminate between AD and mild cognitive impairment (MCI) and identify cognitively unimpaired (CU) older individuals at risk for progression to AD. Our previous studies demonstrated that both the purinergic receptor P2X7 and the tissue-nonspecific alkaline phosphatase ectoenzyme (TNAP) are upregulated in the brains of AD patients. Since both proteins are also present in plasma, we investigated whether plasma P2X7R and TNAP are altered in MCI and AD patients and, if so, their potential role as AD biomarkers. We found that AD but not MCI patients present increased plasma P2X7R levels. Nevertheless, TNAP plasma activity was increased in MCI patients and decreased in the AD group. ROC curve analysis indicated that measuring both parameters has a reasonable discriminating capability to diagnose MCI and AD conditions. In addition to confirming that individuals progressing to MCI have increased TNAP activity in plasma, longitudinal studies also revealed that CU individuals have lower plasma TNAP activity than stable controls. Thus, we propose that P2X7 and TNAP could serve as new plasma biomarkers for MCI and AD. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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20 pages, 4817 KiB

Open AccessArticle

The Pannexin 1 Channel and the P2X7 Receptor Are in Complex Interplay to Regulate the Release of Soluble Ectonucleotidases in the Murine Bladder Lamina Propria

by Mafalda S. L. Aresta Branco, Alejandro Gutierrez Cruz, Lauren E. Peri and Violeta N. Mutafova-Yambolieva

Int. J. Mol. Sci. 2023, 24(12), 9964; https://doi.org/10.3390/ijms24129964 - 09 Jun 2023

Cited by 3 | Viewed by 1068

Abstract

The bladder urothelium releases ATP into the lamina propria (LP) during filling, which can activate P2X receptors on afferent neurons and trigger the micturition reflex. Effective ATP concentrations are largely dependent on metabolism by membrane-bound and soluble ectonucleotidases (s-ENTDs), and the latter are [...] Read more.

The bladder urothelium releases ATP into the lamina propria (LP) during filling, which can activate P2X receptors on afferent neurons and trigger the micturition reflex. Effective ATP concentrations are largely dependent on metabolism by membrane-bound and soluble ectonucleotidases (s-ENTDs), and the latter are released in the LP in a mechanosensitive manner. Pannexin 1 (PANX1) channel and P2X7 receptor (P2X7R) participate in urothelial ATP release and are physically and functionally coupled, hence we investigated whether they modulate s-ENTDs release. Using ultrasensitive HPLC-FLD, we evaluated the degradation of 1,N⁶-etheno-ATP (eATP, substrate) to eADP, eAMP, and e-adenosine (e-ADO) in extraluminal solutions that were in contact with the LP of mouse detrusor-free bladders during filling prior to substrate addition, as an indirect measure of s-ENDTS release. Deletion of Panx1 increased the distention-induced, but not the spontaneous, release of s-ENTDs, whereas activation of P2X7R by BzATP or high concentration of ATP in WT bladders increased both. In Panx1^−/− bladders or WT bladders treated with the PANX1 inhibitory peptide ¹⁰Panx, however, BzATP had no effect on s-ENTDS release, suggesting that P2X7R activity depends on PANX1 channel opening. We concluded, therefore, that P2X7R and PANX1 are in complex interaction to regulate s-ENTDs release and maintain suitable ATP concentrations in the LP. Thus, while stretch-activated PANX1 hinders s-ENTDS release possibly to preserve effective ATP concentration at the end of bladder filling, P2X7R activation, presumably in cystitis, would facilitate s-ENTDs-mediated ATP degradation to counteract excessive bladder excitability. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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Review

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20 pages, 3652 KiB

Open AccessReview

P2X7 Receptor in Dendritic Cells and Macrophages: Implications in Antigen Presentation and T Lymphocyte Activation

by Claudio Acuña-Castillo, Alejandro Escobar, Moira García-Gómez, Vivienne C. Bachelet, Juan Pablo Huidobro-Toro, Daniela Sauma and Carlos Barrera-Avalos

Int. J. Mol. Sci. 2024, 25(5), 2495; https://doi.org/10.3390/ijms25052495 - 21 Feb 2024

Viewed by 726

Abstract

The P2X7 receptor, a member of the P2X purinergic receptor family, is a non-selective ion channel. Over the years, it has been associated with various biological functions, from modulating to regulating inflammation. However, its emerging role in antigen presentation has captured the scientific [...] Read more.

The P2X7 receptor, a member of the P2X purinergic receptor family, is a non-selective ion channel. Over the years, it has been associated with various biological functions, from modulating to regulating inflammation. However, its emerging role in antigen presentation has captured the scientific community’s attention. This function is essential for the immune system to identify and respond to external threats, such as pathogens and tumor cells, through T lymphocytes. New studies show that the P2X7 receptor is crucial for controlling how antigens are presented and how T cells are activated. These studies focus on antigen-presenting cells, like dendritic cells and macrophages. This review examines how the P2X7 receptor interferes with effective antigen presentation and activates T cells and discusses the fundamental mechanisms that can affect the immune response. Understanding these P2X7-mediated processes in great detail opens up exciting opportunities to create new immunological therapies. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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17 pages, 1575 KiB

Open AccessReview

The P2X7 Receptor in Autoimmunity

by Fabio Grassi and Gaia Salina

Int. J. Mol. Sci. 2023, 24(18), 14116; https://doi.org/10.3390/ijms241814116 - 14 Sep 2023

Cited by 1 | Viewed by 997

Abstract

The P2X7 receptor (P2X7R) is an ATP-gated nonselective cationic channel that, upon intense stimulation, can progress to the opening of a pore permeable to molecules up to 900 Da. Apart from its broad expression in cells of the innate and adaptive immune systems, [...] Read more.

The P2X7 receptor (P2X7R) is an ATP-gated nonselective cationic channel that, upon intense stimulation, can progress to the opening of a pore permeable to molecules up to 900 Da. Apart from its broad expression in cells of the innate and adaptive immune systems, it is expressed in multiple cell types in different tissues. The dual gating property of P2X7R is instrumental in determining cellular responses, which depend on the expression level of the receptor, timing of stimulation, and microenvironmental cues, thus often complicating the interpretation of experimental data in comprehensive settings. Here we review the existing literature on P2X7R activity in autoimmunity, pinpointing the different functions in cells involved in the immunopathological processes that can make it difficult to model as a druggable target. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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15 pages, 3059 KiB

Open AccessReview

The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk

by Elena Adinolfi, Elena De Marchi, Marianna Grignolo, Bartosz Szymczak and Anna Pegoraro

Int. J. Mol. Sci. 2023, 24(18), 13906; https://doi.org/10.3390/ijms241813906 - 09 Sep 2023

Cited by 2 | Viewed by 1252

Abstract

The tumor niche is an environment rich in extracellular ATP (eATP) where purinergic receptors have essential roles in different cell subtypes, including cancer, immune, and stromal cells. Here, we give an overview of recent discoveries regarding the role of probably the best-characterized purinergic [...] Read more.

The tumor niche is an environment rich in extracellular ATP (eATP) where purinergic receptors have essential roles in different cell subtypes, including cancer, immune, and stromal cells. Here, we give an overview of recent discoveries regarding the role of probably the best-characterized purinergic receptor in the tumor microenvironment: P2X7. We cover the activities of the P2X7 receptor and its human splice variants in solid and liquid cancer proliferation, dissemination, and crosstalk with immune and endothelial cells. Particular attention is paid to the P2X7-dependent release of microvesicles and exosomes, their content, including ATP and miRNAs, and, in general, P2X7-activated mechanisms favoring metastatic spread and niche conditioning. Moreover, the emerging role of P2X7 in influencing the adenosinergic axis, formed by the ectonucleotidases CD39 and CD73 and the adenosine receptor A2A in cancer, is analyzed. Finally, we cover how antitumor therapy responses can be influenced by or can change P2X7 expression and function. This converging evidence suggests that P2X7 is an attractive therapeutic target for oncological conditions. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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13 pages, 748 KiB

Open AccessReview

The P2X7 Receptor, a Multifaceted Receptor in Alzheimer’s Disease

by Kaitryn E. Ronning, Paul-Alexandre Déchelle-Marquet, Yueshen Che, Xavier Guillonneau, Florian Sennlaub and Cécile Delarasse

Int. J. Mol. Sci. 2023, 24(14), 11747; https://doi.org/10.3390/ijms241411747 - 21 Jul 2023

Cited by 4 | Viewed by 1579

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by impaired episodic memory and two pathological lesions: amyloid plaques and neurofibrillary tangles. In AD, damaged neurons and the accumulation of amyloid β (Aβ) peptides cause a significant release of high amounts of extracellular [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by impaired episodic memory and two pathological lesions: amyloid plaques and neurofibrillary tangles. In AD, damaged neurons and the accumulation of amyloid β (Aβ) peptides cause a significant release of high amounts of extracellular ATP, which acts as a danger signal. The purinergic receptor P2X7 is the main sensor of high concentrations of ATP, and P2X7 has been shown to be upregulated in the brains of AD patients, contributing to the disease’s pathological processes. Further, there are many polymorphisms of the P2X7 gene that impact the risk of developing AD. P2X7 can directly modulate Aβ plaques and Tau protein lesions as well as the inflammatory response by regulating NLRP3 inflammasome and the expression of several chemokines. The significant role of microglial P2X7 in AD has been well established, although other cell types may also be important in P2X7-mediated mechanisms. In this review, we will discuss the different P2X7-dependent pathways involved in the development of AD. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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14 pages, 2179 KiB

Open AccessReview

Untangling Macropore Formation and Current Facilitation in P2X7

by Federico Cevoli, Benoit Arnould, Francisco Andrés Peralta and Thomas Grutter

Int. J. Mol. Sci. 2023, 24(13), 10896; https://doi.org/10.3390/ijms241310896 - 30 Jun 2023

Cited by 3 | Viewed by 886

Abstract

Macropore formation and current facilitation are intriguing phenomena associated with ATP-gated P2X7 receptors (P2X7). Macropores are large pores formed in the cell membrane that allow the passage of large molecules. The precise mechanisms underlying macropore formation remain poorly understood, but recent evidence suggests [...] Read more.

Macropore formation and current facilitation are intriguing phenomena associated with ATP-gated P2X7 receptors (P2X7). Macropores are large pores formed in the cell membrane that allow the passage of large molecules. The precise mechanisms underlying macropore formation remain poorly understood, but recent evidence suggests two alternative pathways: a direct entry through the P2X7 pore itself, and an indirect pathway triggered by P2X7 activation involving additional proteins, such as TMEM16F channel/scramblase. On the other hand, current facilitation refers to the progressive increase in current amplitude and activation kinetics observed with prolonged or repetitive exposure to ATP. Various mechanisms, including the activation of chloride channels and intrinsic properties of P2X7, have been proposed to explain this phenomenon. In this comprehensive review, we present an in-depth overview of P2X7 current facilitation and macropore formation, highlighting new findings and proposing mechanistic models that may offer fresh insights into these untangled processes. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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13 pages, 966 KiB

Open AccessReview

P2X₇ Receptor and Extracellular Vesicle Release

by Maria Teresa Golia, Martina Gabrielli and Claudia Verderio

Int. J. Mol. Sci. 2023, 24(12), 9805; https://doi.org/10.3390/ijms24129805 - 06 Jun 2023

Cited by 2 | Viewed by 1338

Abstract

Extensive evidence indicates that the activation of the P2X₇ receptor (P2X₇R), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2X₇R-expressing cells regulate non-classical [...] Read more.

Extensive evidence indicates that the activation of the P2X₇ receptor (P2X₇R), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2X₇R-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2X₇R activation on extracellular vesicle release and their activities. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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11 pages, 604 KiB

Open AccessReview

The Coming of Age of the P2X7 Receptor in Diagnostic Medicine

by Francesco Di Virgilio, Valentina Vultaggio-Poma, Simonetta Falzoni and Anna Lisa Giuliani

Int. J. Mol. Sci. 2023, 24(11), 9465; https://doi.org/10.3390/ijms24119465 - 30 May 2023

Cited by 5 | Viewed by 1812

Abstract

The discovery of the P2X7 receptor (P2X7R, originally named P2Z) in immune cells, its cloning, and the identification of its role in a multiplicity of immune-mediated diseases raised great hopes for the development of novel and more potent anti-inflammatory medicaments. Unfortunately, such hopes [...] Read more.

The discovery of the P2X7 receptor (P2X7R, originally named P2Z) in immune cells, its cloning, and the identification of its role in a multiplicity of immune-mediated diseases raised great hopes for the development of novel and more potent anti-inflammatory medicaments. Unfortunately, such hopes were partially deluded by the unsatisfactory results of most early clinical trials. This failure substantially reduced the interest of the pharmaceutical and biotech industries in the clinical development of P2X7R-targeted therapies. However, recent findings ushered in a second life for the P2X7R in diagnostic medicine. New P2X7R radioligands proved to be very reliable tools for the diagnosis of neuroinflammation in preclinical and clinical studies, and detection and measurement of free P2X7 receptor (or P2X7 subunit) in human blood suggested its potential use as a circulating marker of inflammation. Here we provide a brief review of these novel developments. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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15 pages, 1274 KiB

Open AccessReview

The Role of P2X7 Purinoceptors in the Pathogenesis and Treatment of Muscular Dystrophies

by Krzysztof Zabłocki and Dariusz C. Górecki

Int. J. Mol. Sci. 2023, 24(11), 9434; https://doi.org/10.3390/ijms24119434 - 29 May 2023

Cited by 2 | Viewed by 1726

Abstract

Muscular dystrophies are inherited neuromuscular diseases, resulting in progressive disability and often affecting life expectancy. The most severe, common types are Duchenne muscular dystrophy (DMD) and Limb-girdle sarcoglycanopathy, which cause advancing muscle weakness and wasting. These diseases share a common pathomechanism where, due [...] Read more.

Muscular dystrophies are inherited neuromuscular diseases, resulting in progressive disability and often affecting life expectancy. The most severe, common types are Duchenne muscular dystrophy (DMD) and Limb-girdle sarcoglycanopathy, which cause advancing muscle weakness and wasting. These diseases share a common pathomechanism where, due to the loss of the anchoring dystrophin (DMD, dystrophinopathy) or due to mutations in sarcoglycan-encoding genes (LGMDR3 to LGMDR6), the α-sarcoglycan ecto-ATPase activity is lost. This disturbs important purinergic signaling: An acute muscle injury causes the release of large quantities of ATP, which acts as a damage-associated molecular pattern (DAMP). DAMPs trigger inflammation that clears dead tissues and initiates regeneration that eventually restores normal muscle function. However, in DMD and LGMD, the loss of ecto-ATPase activity, that normally curtails this extracellular ATP (eATP)-evoked stimulation, causes exceedingly high eATP levels. Thus, in dystrophic muscles, the acute inflammation becomes chronic and damaging. The very high eATP over-activates P2X7 purinoceptors, not only maintaining the inflammation but also tuning the potentially compensatory P2X7 up-regulation in dystrophic muscle cells into a cell-damaging mechanism exacerbating the pathology. Thus, the P2X7 receptor in dystrophic muscles is a specific therapeutic target. Accordingly, the P2X7 blockade alleviated dystrophic damage in mouse models of dystrophinopathy and sarcoglycanopathy. Therefore, the existing P2X7 blockers should be considered for the treatment of these highly debilitating diseases. This review aims to present the current understanding of the eATP-P2X7 purinoceptor axis in the pathogenesis and treatment of muscular dystrophies. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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16 pages, 761 KiB

Open AccessReview

The Role of IL-18 in P2RX7-Mediated Antitumor Immunity

by Serena Janho dit Hreich, Paul Hofman and Valérie Vouret-Craviari

Int. J. Mol. Sci. 2023, 24(11), 9235; https://doi.org/10.3390/ijms24119235 - 25 May 2023

Cited by 5 | Viewed by 1759

Abstract

Cancer is the leading cause of death worldwide despite the variety of treatments that are currently used. This is due to an innate or acquired resistance to therapy that encourages the discovery of novel therapeutic strategies to overcome the resistance. This review will [...] Read more.

Cancer is the leading cause of death worldwide despite the variety of treatments that are currently used. This is due to an innate or acquired resistance to therapy that encourages the discovery of novel therapeutic strategies to overcome the resistance. This review will focus on the role of the purinergic receptor P2RX7 in the control of tumor growth, through its ability to modulate antitumor immunity by releasing IL-18. In particular, we describe how the ATP-induced receptor activities (cationic exchange, large pore opening and NLRP3 inflammasome activation) modulate immune cell functions. Furthermore, we recapitulate our current knowledge of the production of IL-18 downstream of P2RX7 activation and how IL-18 controls the fate of tumor growth. Finally, the potential of targeting the P2RX7/IL-18 pathway in combination with classical immunotherapies to fight cancer is discussed. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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31 pages, 963 KiB

Open AccessReview

Animal Models for the Investigation of P2X7 Receptors

by Ronald Sluyter, Sahil Adriouch, Stephen J. Fuller, Annette Nicke, Reece A. Sophocleous and Debbie Watson

Int. J. Mol. Sci. 2023, 24(9), 8225; https://doi.org/10.3390/ijms24098225 - 04 May 2023

Cited by 4 | Viewed by 2744

Abstract

The P2X7 receptor is a trimeric ligand-gated cation channel activated by extracellular adenosine 5′-triphosphate. The study of animals has greatly advanced the investigation of P2X7 and helped to establish the numerous physiological and pathophysiological roles of this receptor in human health and disease. [...] Read more.

The P2X7 receptor is a trimeric ligand-gated cation channel activated by extracellular adenosine 5′-triphosphate. The study of animals has greatly advanced the investigation of P2X7 and helped to establish the numerous physiological and pathophysiological roles of this receptor in human health and disease. Following a short overview of the P2X7 distribution, roles and functional properties, this article discusses how animal models have contributed to the generation of P2X7-specific antibodies and nanobodies (including biologics), recombinant receptors and radioligands to study P2X7 as well as to the pharmacokinetic testing of P2X7 antagonists. This article then outlines how mouse and rat models have been used to study P2X7. These sections include discussions on preclinical disease models, polymorphic P2X7 variants, P2X7 knockout mice (including bone marrow chimeras and conditional knockouts), P2X7 reporter mice, humanized P2X7 mice and P2X7 knockout rats. Finally, this article reviews the limited number of studies involving guinea pigs, rabbits, monkeys (rhesus macaques), dogs, cats, zebrafish, and other fish species (seabream, ayu sweetfish, rainbow trout and Japanese flounder) to study P2X7. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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21 pages, 793 KiB

Open AccessReview

The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy

by Tobias Engel

Int. J. Mol. Sci. 2023, 24(6), 5410; https://doi.org/10.3390/ijms24065410 - 12 Mar 2023

Cited by 5 | Viewed by 2252

Abstract

Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with [...] Read more.

Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with no molecular biomarker in routine clinical use. Moreover, treatment based on anti-seizure medications (ASMs) remains ineffective in 30% of patients, and, even if seizure-suppressive, lacks disease-modifying potential. Current epilepsy research is, therefore, mainly focussed on the identification of new drugs with a different mechanism of action effective in patients not responding to current ASMs. The vast heterogeneity of epilepsy syndromes, including differences in underlying pathology, comorbidities and disease progression, represents, however, a particular challenge in drug discovery. Optimal treatment most likely requires the identification of new drug targets combined with diagnostic methods to identify patients in need of a specific treatment. Purinergic signalling via extracellularly released ATP is increasingly recognized to contribute to brain hyperexcitability and, consequently, drugs targeting this signalling system have been proposed as a new therapeutic strategy for epilepsy. Among the purinergic ATP receptors, the P2X7 receptor (P2X7R) has attracted particular attention as a novel target for epilepsy treatment, with P2X7Rs contributing to unresponsiveness to ASMs and drugs targeting the P2X7R modulating acute seizure severity and suppressing seizures during epilepsy. In addition, P2X7R expression has been reported to be altered in the brain and circulation in experimental models of epilepsy and patients, making it both a potential therapeutic and diagnostic target. The present review provides an update on the newest findings regarding P2X7R-based treatments for epilepsy and discusses the potential of P2X7R as a mechanistic biomarker. Full article

(This article belongs to the Special Issue The Role of P2X7 Receptor in Human Health and Diseases)

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