Radiation therapy for cancer takes advantage of the higher sensitivity of tumor cells to radiation compared to normal tissue, but some cancers, such as glioblastoma (GBM) and malignant melanoma, acquire radiation resistance (radioresistance), rendering treatment ineffective. Radioresistance is characterized by strong activation of DNA repair mechanisms in response DNA damage induced by radiation, together with possession of malignant property such as enhanced invasiveness and metastasis, though the molecular mechanisms involved remain to be fully established. Here, we show that P2X7 receptor-specific inhibitors suppress the γ-irradiation-induced DNA damage response (DDR) and enhance cell death of A172 GBM cells. In contrast, ATP, a P2X7 receptor ligand, promotes the DDR and suppresses cell death. Irradiation immediately induced ATP release from cells, and P2X7 receptor inhibitor suppressed the release of ATP. Furthermore, P2X7 receptor inhibitors suppress the release of high mobility group box 1 (HMGB1), which is known to promote cancer cell migration. Inhibitors of the receptor for advanced glycation end products (RAGE) also suppress ATP-induced cell motility, indicating that the P2X7-HMGB1-RAGE pathway contributes to radiation-induced malignant transformation. These data indicate firstly that the P2X7 receptor promotes the γ-irradiation-induced DDR, leading to increased resistance of GBM cells to γ-radiation-induced death, and secondly that the P2X7 receptor and extracellular ATP may be involved in the γ-irradiation-induced acquisition of malignant property such as cytoskeletal changes and enhanced motility in GBM cells.

01 Dec 2025·JOURNAL OF AFFECTIVE DISORDERS

A P2X7 receptor antagonist alleviates PTSD-like behaviors in adolescent rats through gut microbiota modulation and hippocampal transcriptomic remodeling

Article

Author: Pan, Liangke ; Xu, Jingjing ; Zhang, Yang ; Wang, Xinqi ; Gao, Jin ; Xu, Wangwang ; Chen, Shuwen

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder that frequently manifests during adolescence, a critical neurodevelopmental period. Although the P2X7 receptor is implicated in the pathophysiology of PTSD, its role in adolescent-onset PTSD, particularly concerning gut microbiota dysbiosis and hippocampal transcriptomic alterations, remains unclear. This study investigated the effects of the P2X7 receptor antagonist Brilliant Blue G (BBG) on PTSD-like behaviors, gut microbiota, and hippocampal transcriptomic profiles in adolescent rats subjected to single prolonged stress and electric foot shock (SPS&S). BBG treatment significantly ameliorated SPS&S-induced fear- and anxiety-like behaviors and spatial working memory deficits. Metagenomic analysis revealed that BBG partially reversed SPS&S-induced gut microbiota dysbiosis, significantly enriching key bacterial taxa (e.g., Bacteroidota) and modulating functional pathways related to immunity and metabolism. Hippocampal transcriptomic analysis demonstrated that BBG normalized a majority of SPS&S-induced differentially expressed genes; these corrected genes were significantly enriched in pathways for extracellular matrix organization, neural differentiation, and PI3K-Akt signaling pathway. Integrated multi-omics correlation analyses revealed significant correlations among key microbial abundances, hippocampal gene expression, and behavioral outcomes, supporting a gut-brain axis mechanism underlying the therapeutic effects of BBG. These findings position the P2X7 receptor as a promising therapeutic target for adolescent PTSD and highlight the crucial role of gut microbiota in modulating stress-related neuropathology via the gut-brain axis.

01 Oct 2025·British Journal of Pharmacology

Pharmacological evaluation of non‐nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury

Article

Author: Giner‐García, Javier ; Decouty‐Pérez, Céline ; Rodríguez‐Domínguez, Víctor ; Pastor‐Martínez, Andrea ; Valencia, Inés ; de los Ríos, Cristóbal ; Palpán‐Flores, Alexis J. ; Hernández‐García, Borja J. ; Álvarez‐Rubal, María ; Rodríguez de Cía, Javier ; Zamorano‐Fernández, Jorge ; Calzaferri, Francesco ; Lopez‐Rodriguez, Ana Belen ; Ramos, Eva ; Egea, Javier ; Romero, Alejandro

Background and purpose:

Traumatic brain injury (TBI) is considered to be a leading cause of mortality and disability worldwide. After TBI, innate immunity is rapidly activated in response to damage‐associated molecular patterns, such as ATP release, recognised by P2X7 receptors. The P2X7‐NLRP3 inflammasome axis has been identified as one of the main players in neuroinflammation. This study aimed to validate P2X7 receptors as therapeutic target for traumatic brain injury.

Experimental approach:

P2X7 receptors were studied by genetic and pharmacological approaches. Six non‐nucleotide purine derivatives were evaluated as P2X7 antagonists. Compounds that prevented LPS + ATP‐induced IL‐1β release from primary glial cultures were investigated in the closed‐head injury TBI model in vivo in male mice. Finally, we evaluated soluble (s)P2X7 receptor plasmatic levels in a cohort of TBI patients.

Key results:

P2rx7−/− mice showed an exaggerated inflammatory response 24 h post‐TBI compared to control mice. However, animals treated with the selective P2X7 antagonist JNJ‐47965567 (30 mg kg−1 i.p.) 30 min post‐TBI showed improved neurological and inflammatory parameters. The purine derivative ITH15004 was the most potent compound reducing IL‐1β production in vitro. When administered in vivo 30 min post‐TBI, ITH15004 (1 mg kg−1 i.p.) improved both neuro‐behavioural and inflammatory markers at 24 h. In TBI patients, we showed a tendency towards increase in circulating sP2X7 receptor levels at 24 and 72 h post‐TBI.

Conclusions and implications:

These results highlight the importance of P2X7 receptors in the acute phase of TBI and present ITH15004 as a promising pharmacological tool to counteract P2X7 receptor‐dependent neuroinflammation in vivo.

News (Medical) associated with P2X7 receptor antagonists(Gwangju Institute of Science & Technology)

25 Jul 2023

·www.pharmaceutical-technology.com

Golgi and Breye partner to develop P2X7 receptor antagonist programme

Diabetic retinopathy is one of the main reasons for blindness among working-age adults. Credit: Alexander Grey from Pixabay. Golgi Neurosciences has joined forces with Breye Therapeutics for the development of a P2X7 receptor antagonist programme. The receptor, a vital inflammation switch, is an adenosine triphosphate (ATP) gated ion channel found in several cell types. Recommended Reports Reports Beta 2 Adrenergic Receptor (Beta 2 Adrenoreceptor or ADRB2) Drugs in Development by Therapy Areas... GlobalData Reports D2 Dopamine Receptor (Dopamine D2 Receptor or DRD2) Drugs in Development by Therapy Areas and Ind... GlobalData View all Companies Intelligence Breye Therapeutics ApS View all The oral P2X7 receptor antagonists offer a new treatment approach for both early-stage diabetic retinopathy (DR) and dry age-related macular degeneration (dry AMD). Golgi Neurosciences managing director Chiara Liberati said: “With leading experts on the Scientific Advisory Board, Breye is led by a strong and seasoned Management team, supported by a highly-regarded syndicate of investors, making Breye the ideal partner to facilitate the next steps in advancing our P2X7 receptor antagonist program towards developing innovative approaches for retinal disorders.” DR impacts around 30% of individuals with diabetes and is one of the main reasons for blindness among working-age adults. AMD is a significant factor contributing to the loss of vision, especially among individuals aged 60 years and older. Breye Therapeutics CEO Ulrik Mouritzen said: “The Golgi incubator has fantastic expertise in neurosciences, and we are pleased to collaborate to advance the P2X7 receptor antagonist programme for retinal disorders, where there is a large unmet medical need for more effective and less burdensome therapies.” Based in Milan, Italy, Golgi is involved in the discovery and development of small molecule-based therapies for neurodegenerative diseases. Breye is focused on the development of novel, oral ophthalmology drugs for DR and AMD.

100 Deals associated with P2X7 receptor antagonists(Gwangju Institute of Science & Technology)

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Solid Tumor	Preclinical	South Korea	Gwangju Institute of Science & Technology	25 Aug 2016

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