Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation
Abstract Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed....
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-12293-3 |
| _version_ | 1811258846062051328 |
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| author | Natsuko Kondo Yoshinori Sakurai Takushi Takata Kuniyuki Kano Kyo Kume Munetoshi Maeda Nobuhiko Takai Shugo Suzuki Fumihiro Eto Kenji Kikushima Hideki Wanibuchi Shin-Ichi Miyatake Takayuki Kajihara Shoji Oda Mitsutoshi Setou Junken Aoki Minoru Suzuki |
| author_facet | Natsuko Kondo Yoshinori Sakurai Takushi Takata Kuniyuki Kano Kyo Kume Munetoshi Maeda Nobuhiko Takai Shugo Suzuki Fumihiro Eto Kenji Kikushima Hideki Wanibuchi Shin-Ichi Miyatake Takayuki Kajihara Shoji Oda Mitsutoshi Setou Junken Aoki Minoru Suzuki |
| author_sort | Natsuko Kondo |
| collection | DOAJ |
| description | Abstract Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed. In inflammation, lysophospholipids (LPLs) are produced by phospholipase A2 and function as bioactive lipids involved in sterile inflammation in atherosclerosis or brain disorders. To elucidate its underlying mechanisms, we investigated the possible associations between lysophospholipids (LPLs) and RN development in terms of microglial activation with the purinergic receptor P2X purinoceptor 4 (P2RX4). We previously developed a mouse model of RN and in this study, measured phospholipids and LPLs in the brains of RN model by liquid chromatography tandem mass spectrometry (LC–MS/MS) analyses. We immune-stained microglia and the P2RX4 in the brains of RN model with time-course. We treated RN model mice with ivermectin, an allosteric modulator of P2RX4 and investigate the effect on microglial activation with P2RX4 and LPLs’ production, and resulting effects on overall survival and working memory. We revealed that LPLs (lysophosphatidylcholine (LPC), lysophosphatidyl acid, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylglycerol) remained at high levels during the progression of RN with microglial accumulation, though phospholipids elevations were limited. Both microglial accumulation and activation of the P2RX4 were attenuated by ivermectin. Moreover, the elevation of all LPLs except LPC was also attenuated by ivermectin. However, there was limited prolongation of survival time and improvement of working memory disorders. Our findings suggest that uncontrollable increased LPC, even with ivermectin treatment, promoted the development of RN and working memory disorders. Therefore, LPC suppression will be essential for controlling RN and neurocognitive disorder after radiation therapy. |
| first_indexed | 2024-04-12T18:20:36Z |
| format | Article |
| id | doaj.art-65ef210142224300834ab4848e0233ed |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T18:20:36Z |
| publishDate | 2022-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-65ef210142224300834ab4848e0233ed2022-12-22T03:21:26ZengNature PortfolioScientific Reports2045-23222022-05-0112111410.1038/s41598-022-12293-3Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activationNatsuko Kondo0Yoshinori Sakurai1Takushi Takata2Kuniyuki Kano3Kyo Kume4Munetoshi Maeda5Nobuhiko Takai6Shugo Suzuki7Fumihiro Eto8Kenji Kikushima9Hideki Wanibuchi10Shin-Ichi Miyatake11Takayuki Kajihara12Shoji Oda13Mitsutoshi Setou14Junken Aoki15Minoru Suzuki16Particle Radiation Oncology Center, Institute for Integrated Radiation and Nuclear Science, Kyoto UniversityParticle Radiation Oncology Center, Institute for Integrated Radiation and Nuclear Science, Kyoto UniversityParticle Radiation Oncology Center, Institute for Integrated Radiation and Nuclear Science, Kyoto UniversityDepartment of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of TokyoProton Medical Research Division, Research and Development Department, The Wakasa Wan Energy Research CenterProton Medical Research Division, Research and Development Department, The Wakasa Wan Energy Research CenterDepartment of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Nagasaki International UniversityDepartment of Molecular Pathology, Osaka Metropolitan University Graduate School of MedicineDepartment of Cellular and Molecular Anatomy and International Mass Imaging Center, Hamamatsu University School of MedicineDepartment of Cellular and Molecular Anatomy and International Mass Imaging Center, Hamamatsu University School of MedicineDepartment of Molecular Pathology, Osaka Metropolitan University Graduate School of MedicineCancer Center, Osaka Medical and Pharmaceutical UniversityDepartment of Integrated Biosciences, Graduate School of Frontier Sciences, The University of TokyoDepartment of Integrated Biosciences, Graduate School of Frontier Sciences, The University of TokyoDepartment of Cellular and Molecular Anatomy and International Mass Imaging Center, Hamamatsu University School of MedicineDepartment of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of TokyoParticle Radiation Oncology Center, Institute for Integrated Radiation and Nuclear Science, Kyoto UniversityAbstract Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed. In inflammation, lysophospholipids (LPLs) are produced by phospholipase A2 and function as bioactive lipids involved in sterile inflammation in atherosclerosis or brain disorders. To elucidate its underlying mechanisms, we investigated the possible associations between lysophospholipids (LPLs) and RN development in terms of microglial activation with the purinergic receptor P2X purinoceptor 4 (P2RX4). We previously developed a mouse model of RN and in this study, measured phospholipids and LPLs in the brains of RN model by liquid chromatography tandem mass spectrometry (LC–MS/MS) analyses. We immune-stained microglia and the P2RX4 in the brains of RN model with time-course. We treated RN model mice with ivermectin, an allosteric modulator of P2RX4 and investigate the effect on microglial activation with P2RX4 and LPLs’ production, and resulting effects on overall survival and working memory. We revealed that LPLs (lysophosphatidylcholine (LPC), lysophosphatidyl acid, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylglycerol) remained at high levels during the progression of RN with microglial accumulation, though phospholipids elevations were limited. Both microglial accumulation and activation of the P2RX4 were attenuated by ivermectin. Moreover, the elevation of all LPLs except LPC was also attenuated by ivermectin. However, there was limited prolongation of survival time and improvement of working memory disorders. Our findings suggest that uncontrollable increased LPC, even with ivermectin treatment, promoted the development of RN and working memory disorders. Therefore, LPC suppression will be essential for controlling RN and neurocognitive disorder after radiation therapy.https://doi.org/10.1038/s41598-022-12293-3 |
| spellingShingle | Natsuko Kondo Yoshinori Sakurai Takushi Takata Kuniyuki Kano Kyo Kume Munetoshi Maeda Nobuhiko Takai Shugo Suzuki Fumihiro Eto Kenji Kikushima Hideki Wanibuchi Shin-Ichi Miyatake Takayuki Kajihara Shoji Oda Mitsutoshi Setou Junken Aoki Minoru Suzuki Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation Scientific Reports |
| title | Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation |
| title_full | Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation |
| title_fullStr | Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation |
| title_full_unstemmed | Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation |
| title_short | Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation |
| title_sort | persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by p2rx4 activation |
| url | https://doi.org/10.1038/s41598-022-12293-3 |
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