Hengyi Fan1, Wolfgang Sievert2, Julian Hofmann3, Selina J Keppler3, Katja Steiger4, Xènia Puig-Bosch5, Bernhard Haller6, Gerhard Rammes5, Gabriele Multhoff7. 1. Department of Radiation Oncology, Klinikum rechts der Isar; Central Institute for Translational Cancer Research, TranslaTUM, Klinikum rechts der Isar. Electronic address: hengyi.fan@tum.de. 2. Department of Radiation Oncology, Klinikum rechts der Isar; Central Institute for Translational Cancer Research, TranslaTUM, Klinikum rechts der Isar. 3. Central Institute for Translational Cancer Research, TranslaTUM, Klinikum rechts der Isar; Inflammation and Immunity Lab, Institute for Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar. 4. Comparative Experimental Pathology, Institute Pathology. 5. Department of Anaesthesiology and Intensive Care Medicine, Klinikum rechts der Isar. 6. Institute of Medical Informatics, Statistics and Epidemiology, Technische Universität München, Munich, Germany. 7. Department of Radiation Oncology, Klinikum rechts der Isar; Central Institute for Translational Cancer Research, TranslaTUM, Klinikum rechts der Isar. Electronic address: gabriele.multhoff@tum.de.
Abstract
PURPOSE: Radiation-induced cognitive deficits have a severe negative impact on pediatric brain tumor patients. The severity of cognitive symptoms is related to the age of the child when radiation was applied, with the most severe effects seen in the youngest. Previous studies using whole-brain irradiation in mice confirmed these findings. To understand ipsilateral and contralateral changes in the hippocampus after partial-brain radiation therapy (PBRT) of the left hemisphere, we assessed the neuroplasticity and changes in the microvasculature of the irradiated and nonirradiated hippocampus in juvenile mice. METHODS AND MATERIALS: The left hemispheres of 5-week-old mice were irradiated with 2, 8, and 20 Gy and a fractionated dose of 8 Gy in 2 fractions using a computed tomography image guided small animal radiation research platform. Long-term potentiation (LTP) has been monitored ex vivo in the hippocampal cornu ammonis 1 (CA1) region and was assessed 3 days and 5 and 10 weeks after PBRT in both hemispheres and compared to a sham group. Irradiation effects on the hippocampus microvasculature were quantified by efficient tissue clearing and multiorgan volumetric imaging. RESULTS: LTP in irradiated hippocampal slices of juvenile mice declines 3 days after radiation, lasts up to 10 weeks in the irradiated part of the hippocampus, and correlates with a significantly reduced microvasculature length. Specifically, LTP inhibition is sustained in the irradiated (20 Gy, 8 Gy in 2 fractions, 8 Gy, 2 Gy) hippocampus, whereas the contralateral hippocampus remains unaffected after PBRT. LTP inhibition in the irradiated hemisphere after PBRT might be associated with an impaired microvascular network. CONCLUSION: PBRT induces a long-lasting impairment in neuroplasticity and the microvessel network of the irradiated hippocampus, whereas the contralateral hippocampus remains unaffected. These findings provide insight into the design of PBRT strategies to better protect the young developing brain from cognitive decline.
PURPOSE: Radiation-induced cognitive deficits have a severe negative impact on pediatric brain tumor patients. The severity of cognitive symptoms is related to the age of the child when radiation was applied, with the most severe effects seen in the youngest. Previous studies using whole-brain irradiation in mice confirmed these findings. To understand ipsilateral and contralateral changes in the hippocampus after partial-brain radiation therapy (PBRT) of the left hemisphere, we assessed the neuroplasticity and changes in the microvasculature of the irradiated and nonirradiated hippocampus in juvenile mice. METHODS AND MATERIALS: The left hemispheres of 5-week-old mice were irradiated with 2, 8, and 20 Gy and a fractionated dose of 8 Gy in 2 fractions using a computed tomography image guided small animal radiation research platform. Long-term potentiation (LTP) has been monitored ex vivo in the hippocampal cornu ammonis 1 (CA1) region and was assessed 3 days and 5 and 10 weeks after PBRT in both hemispheres and compared to a sham group. Irradiation effects on the hippocampus microvasculature were quantified by efficient tissue clearing and multiorgan volumetric imaging. RESULTS: LTP in irradiated hippocampal slices of juvenile mice declines 3 days after radiation, lasts up to 10 weeks in the irradiated part of the hippocampus, and correlates with a significantly reduced microvasculature length. Specifically, LTP inhibition is sustained in the irradiated (20 Gy, 8 Gy in 2 fractions, 8 Gy, 2 Gy) hippocampus, whereas the contralateral hippocampus remains unaffected after PBRT. LTP inhibition in the irradiated hemisphere after PBRT might be associated with an impaired microvascular network. CONCLUSION: PBRT induces a long-lasting impairment in neuroplasticity and the microvessel network of the irradiated hippocampus, whereas the contralateral hippocampus remains unaffected. These findings provide insight into the design of PBRT strategies to better protect the young developing brain from cognitive decline.
Authors: Maxim O Politko; Alexandra Y Tsidulko; Oxana A Pashkovskaya; Konstantin E Kuper; Anastasia V Suhovskih; Galina M Kazanskaya; Lyubov S Klyushova; Dmitry K Sokolov; Alexander M Volkov; Evgenii E Kliver; Alexander A Zheravin; Svetlana V Aidagulova; Elvira V Grigorieva Journal: Int J Mol Sci Date: 2021-12-12 Impact factor: 5.923