title: Extracellular ATP enhances radiation-induced brain injury through microglial activation and paracrine signaling via P2X7 receptor.
abstract: Activation of purinergic receptors by extracellular ATP (eATP) released from injured cells has been implicated in the pathogenesis of many neuronal disorders. The P2X7 receptor (P2X7R), an ion-selective purinergic receptor, is associated with microglial activation and paracrine signaling. However, whether ATP and P2X7R are involved in radiation-induced brain injury (RBI) remains to be determined. Here, we found that the eATP level was elevated in the cerebrospinal fluid (CSF) of RBI patients and was associated with the clinical severity of the disorder. In our experimental model, radiation treatment increased the level of eATP in the supernatant of primary cultures of neurons and glial cells and in the CSF of irradiated mice. In addition, ATP administration activated microglia, induced the release of the inflammatory mediators such as cyclooxygenase-2, tumor necrosis factor α and interleukin 6, and promoted neuronal apoptosis. Furthermore, blockade of ATP-P2X7R interaction using P2X7 antagonist Brilliant Blue G or P2X7 knockdown suppressed radiation-induced microglial activation and proliferation in the hippocampus, and restored the spatial memory of irradiated mice. Finally, we found that the PI3K/AKT and nuclear factor κB mediated pathways were downstream of ATP-P2X7R signaling in RBI. Taken together, our results unveiled the critical role of ATP-P2X7R in brain damage in RBI, suggesting that inhibition of ATP-P2X7R axis might be a potential strategy for the treatment of patients with RBI.
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Yongteng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Pan
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: Madhuvika
authors.initials: M
authors.lastname: Murugan
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: yameitang@hotmail.com.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000255:Adenosine Triphosphate / Q000009:adverse effects* / Q000134:cerebrospinal fluid; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000209:etiology / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D019899:Paracrine Communication; D011832:Radiation Injuries / Q000134:cerebrospinal fluid / Q000150:complications / Q000378:metabolism*; D011878:Radiotherapy / Q000009:adverse effects*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
chemical_list: D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate
keywords: BBG; COX-2; Extracellular ATP; IL-6; Inflammation; Microglia; P2X7R; Radiation-induced brain injury; TNF-α