Radiation and Cancer Biology

SS 19 - Biology 4 - Normal Tissue Radiobiology

148 - Hippocampal Sparing Fractionated Whole Brain Irradiation Attenuates Microglia Activation and Preserves Immature Neurons Two Months After Treatment

Tuesday, October 23
8:15 AM - 8:25 AM
Location: Room 008

Hippocampal Sparing Fractionated Whole Brain Irradiation Attenuates Microglia Activation and Preserves Immature Neurons Two Months After Treatment
B. Johnson1, S. Kanji1, P. Gulati1, K. Witcher1, J. Godbout1, E. H. Bell2, S. J. Haque3, and A. Chakravarti4; 1The Ohio State University, Columbus, OH, 2The Ohio State University Comprehensive Cancer Center, Columbus, OH, 3Ohio State University, Columbus, OH, 4Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH

Purpose/Objective(s): In RTOG-0933 Hippocampal Sparing fractionated Whole Brain Irradiation (HS-fWBI) was shown to preserve memory function when compared to historical controls. Our primary goal was to develop a clinically relevant mouse model of HS-fWBI to study the cellular and molecular mechanisms of this effect

Materials/Methods: C57BL/6J mice were divided into four groups (n=3): Sham radiated control, fractionated Whole Brain Irradiation (fWBI), Hippocampal Sparing 1 (HS1) and Hippocampal Sparing 2 (HS2). The irradiation protocols were performed using the image-guided target localization capabilities of the small animal radiation research platform (SARRP, Xstrahl, Surrey, UK). fWBI mice received a single beam of 3Gy to the entire brain. HS1 mice received a 3Gy dose each day resulted in an irradiation field covering the ventral part of the brain, avoiding the hippocampus. HS2 mice received two additional beams of 3gy to the cortex superior to the hippocampus along the dorsal part of the brain. All mice received a total of 30Gy in 10 fractions over 12 days. For both HS1 and HS2 the 10 percent isodose fell adjacent to the hippocampus for all beams; this implies a total dose of less than 3Gy for HS1 and 9Gy for HS2 for the entire protocol to the hippocampus. Two months after completion of treatment mice were euthanized and brain tissues were harvested and prepared for immunohistochemical analysis.

Results: Immunohistochemical analysis of fWBI mice showed a decreased number of immature neurons (P<0.05) and increased number of microglia displaying activated morphology compared to control mice. In contrast, both HS1 and HS2 mice showed reduced number of activated microglia (P<0.05) in the hippocampus compared to fWBI mice. A reduced number of activated microglia were observed in the cortex of HS1 (P<0.05) compared to fWBI and HS2 mice. The number of immature neurons were higher in the dentate gyrus of the HS1 and HS2 mice compared to fWBI mice, but only HS2 mice were significantly different (P<0.05).

Conclusion: This study demonstrated that hippocampal sparing fWBI prevents microglia activation in the hippocampus. Microglia activation occurred only in regions of the brain receiving direct exposure to radiation. Additionally, this study demonstrated that a clinically relevant dosing and fractionation schedule with hippocampal sparing can prevent the loss of immature neurons in the hippocampus. This clinically relevant mouse model could be a useful tool to study the cellular and molecular mechanisms of radiation induced cognitive decline.

Author Disclosure: B. Johnson: None. S. Kanji: None. P. Gulati: None. A. Chakravarti: None.

Benjamin Johnson, BA

Disclosure:
Employment
The Ohio State University: Research Assitant: Employee

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