In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4754-4754
Abstract:
The objective of this study is to study the late-chronic effects of fractionated whole brain irradiation (fWBI) on cognitive impairment and associated cellular and molecular neuro-inflammatory mechanisms using clinically relevant and reliable mouse models. Microglia are recognized as the primary innate immune component of neuroinflammation. However, microglial contributions to radiation-induced cognitive impairment are poorly understood. Here, an athymic nude (Nu/Nu) mouse model was employed to address this issue. Mice were divided into two groups: radiation treatment (XRT) and no-treatment control (CTL). The whole brain of each XRT mouse received 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were assessed for cognitive and behavioral changes at 1, 4, and 6 months posttreatment using the novel object recognition test (for long-term, non-spatial memory), the free running Y-Maze (for short-term, spatial memory) and Barnes Maze (for spatial learning and memory). A significant decline in novel object recognition in the XRT group (P & lt;0.05) was seen at the 4 month time point and continued to persist at 6 months (P & lt;0.05). No significant changes in the Barnes maze or Y-maze were seen at these time points. Expression of neuroinflammatory mediator genes, from both whole brain and isolated microglia, were measured by RT-PCR. We found that markers of the M1-phenotype, which include TNF-α, and MHC II, were significantly upregulated (P & lt;0.05) and markers of the general M2 Phenotype, which include IL-4ra, IL-10ra, and TGF-β, were downregulated (P & lt;0.05) at 1 and 6 month time points. These results indicate that sustained neuroinflammation and microglial M1-polarization are associated with long-term cognitive impairment induced by fWBI. Radiotherapy is the most prevalent treatment for primary and metastatic brain tumors. Whereas previous studies that identified important mechanisms underlying XRT-induced cognitive decline had used treatment regimens that were not clinically relevant ones, we have employed a clinically relevant fractionation scheme to address the cellular and molecular deregulations in association with cognitive impairment. Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati Gulati, Shannon Chen, Jonathan Godbout, Randy J. Nelson, Saikh Haque, Arnab Chakravarti. Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4754. doi:10.1158/1538-7445.AM2017-4754
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-4754
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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