Stroke and multiple sclerosis involve oxygen and nutrient deprivation in the brain as well as inflammation, all of which lead to the release of glutamate and ATP. These compounds can cause excitotoxicity, contributing to neuronal and glial damage. Purinergic signaling, mediated by ATP and adenosine, regulates neuroinflammatory and neuroprotective mechanisms, playing a pivotal role in CNS injury. Key elements such as pannexin-1 hemichannels, calcium homeostasis modulator-1 (CalHM1), purinergic P2X7 receptors, and downstream intermediaries of ATP release contribute to neurotoxicity and inflammatory processes. Notably, P2X7 and P2X4 receptors are critical targets for reducing neuronal damage caused by microglia-mediated inflammation and repair, respectively. Additionally, the interaction between purinergic signaling and GABA type A (GABA_A) receptors opens new therapeutic possibilities by potentially promoting a balance in neurotransmission modulation and mitigating excitotoxicity. Experimental evidence and recent pharmacological developments, including P2X7 antagonists, P2X4 positive allosteric modulators, P1 agonists, and modulators of GABA_A receptors, offer promising avenues for translating preclinical findings into effective therapies for cerebrovascular diseases. Further clinical investigations are necessary to validate these interventions to attenuate tissue damage and foster repair in multiple sclerosis lesions and post-ischemic penumbra.

2025-12-01·BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

P2X7 receptor contributes to DNA damage repair and acquisition of malignant phenotypes in irradiated human glioblastoma cells

Article

作者: Tanuma, Sei-ichi ; Kitabatake, Kazuki ; Uchiumi, Fumiaki ; Tsukimoto, Mitsutoshi ; Seki, Hiromu

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.

2025-12-01·JOURNAL OF AFFECTIVE DISORDERS

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

Article

作者: 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.

项与 P2X7 receptor antagonists(Gwangju Institute of Science & Technology) 相关的新闻（医药）

2023-07-25

·Pharmaceutical Technology

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.