A GSK-3β inhibitor protects against radiation necrosis in mouse brain.

Abstract

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 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: Xiaoyu Jiang, Carlos J Perez-Torres, Dinesh Thotala, John A Engelbach, Liya Yuan, Jeremy Cates, Feng Gao, Robert E Drzymala, Keith M Rich, Robert E Schmidt, Joseph J H Ackerman, Dennis E Hallahan, Joel R Garbow
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 89 Issue 4 Pg. 714-21 (Jul 15 2014) ISSN: 1879-355X [Electronic] United States
• PMID: 24969790 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
• Aminophenols
• Maleimides
• Neuroprotective Agents
• Radiation-Protective Agents
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3
• Dimethyl Sulfoxide

Topics

• Aminophenols (pharmacology)
• Analysis of Variance
• Animals
• Brain (pathology, radiation effects)
• Colony-Forming Units Assay (methods)
• Dimethyl Sulfoxide (pharmacology)
• Female
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Magnetic Resonance Imaging (methods)
• Maleimides (pharmacology)
• Mice
• Mice, Inbred BALB C
• Necrosis (prevention & control)
• Neuroprotective Agents (pharmacology)
• Radiation Dosage
• Radiation Injuries, Experimental (mortality, pathology, prevention & control)
• Radiation-Protective Agents (pharmacology)
• Radiosurgery (adverse effects)
• Survival Analysis