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Title: A GSK-3β Inhibitor Protects Against Radiation Necrosis in Mouse Brain

Purpose: To quantify the effectiveness of SB415286, a specific inhibitor of GSK-3β, as a neuroprotectant against radiation-induced central nervous system (brain) necrosis in a mouse model. Methods and Materials: Cohorts of mice were treated with SB415286 or dimethyl sulfoxide (DMSO) prior to irradiation with a single 45-Gy fraction targeted to the left hemisphere (brain) using a gamma knife machine. The onset and progression of radiation necrosis (RN) were monitored longitudinally by noninvasive in vivo small-animal magnetic resonance imaging (MRI) beginning 13 weeks postirradiation. MRI-derived necrotic volumes for SB415286- and DMSO-treated mice were compared. MRI results were supported by correlative histology. Results: Mice treated with SB415286 showed significant protection from radiation-induced necrosis, as determined by in vivo MRI with histologic validation. MRI-derived necrotic volumes were significantly smaller at all postirradiation time points in SB415286-treated animals. Although the irradiated hemispheres of the DMSO-treated mice demonstrated many of the classic histologic features of RN, including fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, and tissue loss, the irradiated hemispheres of the SB415286-treated mice consistently showed only minimal tissue damage. These studies confirmed that treatment with a GSK-3β inhibitor dramatically reduced delayed time-to-onset necrosis in irradiated brain. Conclusions: The unilateral cerebral hemispheric stereotactic radiation surgery mouse model in concertmore » with longitudinal MRI monitoring provided a powerful platform for studying the onset and progression of RN and for developing and testing new neuroprotectants. Effectiveness of SB415286 as a neuroprotectant against necrosis motivates potential clinical trials of it or other GSK-3β inhibitors.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [4] ;  [3] ;  [5] ;  [6] ; ;  [3] ;  [6] ;  [7] ;  [1] ;  [6] ;  [6] ;  [6] ;  [3] ;  [6] ;  [2] ;  [6]
  1. Department of Chemistry, Washington University, St. Louis, Missouri (United States)
  2. Department of Radiology, Washington University, St. Louis, Missouri (United States)
  3. Department of Radiation Oncology, Washington University, St. Louis, Missouri (United States)
  4. Department of Neurosurgery, Washington University, St. Louis, Missouri (United States)
  5. Division of Biostatistics, Washington University, St. Louis, Missouri (United States)
  6. (United States)
  7. Department of Neuropathology, Washington University, St. Louis, Missouri (United States)
Publication Date:
OSTI Identifier:
22420357
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 89; Journal Issue: 4; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BRAIN; CLINICAL TRIALS; DMSO; HEMORRHAGE; IN VIVO; MICE; NECROSIS; NMR IMAGING; SURGERY