title: A GSK-3β inhibitor protects against radiation necrosis in mouse brain.
abstract: OBJECTIVE
  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
  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 concert 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.
authors: Department of Chemistry, Washington University, St. Louis, Missouri.
authors: Xiaoyu
authors: X
authors: Jiang
authors: Department of Radiology, Washington University, St. Louis, Missouri.
authors: Carlos J
authors: CJ
authors: Perez-Torres
authors: Department of Radiation Oncology, Washington University, St. Louis, Missouri.
authors: Dinesh
authors: D
authors: Thotala
authors: Department of Radiology, Washington University, St. Louis, Missouri.
authors: John A
authors: JA
authors: Engelbach
authors: Department of Neurosurgery, Washington University, St. Louis, Missouri.
authors: Liya
authors: L
authors: Yuan
authors: Department of Radiation Oncology, Washington University, St. Louis, Missouri.
authors: Jeremy
authors: J
authors: Cates
authors: Division of Biostatistics, Washington University, St. Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors: Feng
authors: F
authors: Gao
authors: Department of Radiation Oncology, Washington University, St. Louis, Missouri; Department of Neurosurgery, Washington University, St. Louis, Missouri.
authors: Robert E
authors: RE
authors: Drzymala
authors: Department of Radiation Oncology, Washington University, St. Louis, Missouri; Department of Neurosurgery, Washington University, St. Louis, Missouri.
authors: Keith M
authors: KM
authors: Rich
authors: Department of Neuropathology, Washington University, St. Louis, Missouri.
authors: Robert E
authors: RE
authors: Schmidt
authors: Department of Chemistry, Washington University, St. Louis, Missouri; Department of Radiology, Washington University, St. Louis, Missouri; Department of Internal Medicine, Washington University, St. Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors: Joseph J H
authors: JJ
authors: Ackerman
authors: Department of Radiation Oncology, Washington University, St. Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors: Dennis E
authors: DE
authors: Hallahan
authors: Department of Radiology, Washington University, St. Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University, St. Louis, Missouri. Electronic address: garbow@wustl.edu.
authors: Joel R
authors: JR
authors: Garbow
mesh_terms: D000627:Aminophenols / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology* / Q000528:radiation effects*; D003114:Colony-Forming Units Assay / Q000379:methods; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D008279:Magnetic Resonance Imaging / Q000379:methods; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D016634:Radiosurgery / Q000009:adverse effects; D016019:Survival Analysis
chemical_list: C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; D018696:Neuroprotective Agents; D011837:Radiation-Protective Agents; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004121:Dimethyl Sulfoxide