A GSK-3尾 Inhibitor Protects Against Radiation Necrosis in Mouse Brain

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• 作者：Xiaoyu Jiang ; PhD^&lowast ; ; Carlos J. Perez-Torres ; PhD^&dagger ; ; Dinesh Thotala ; PhD^&Dagger ; ; John A. Engelbach ; AS^&dagger ; ; Liya Yuan ; PhD^§ ; ; Jeremy Cates ; BS^&Dagger ; ; Feng Gao ; MD ; PhD^# ; ^&lowast ; &lowast ; ; Robert E. Drzymala ; PhD^&Dagger ; ; ^§ ; ; Keith M. Rich ; MD^&Dagger ; ; ^§ ; ; Robert E. Schmidt ; MD ; PhD^|| ; Joseph J.H. Ackerman ; PhD^&lowast ; ; ^&dagger ; ; ^¶ ; ; ^&lowast ; &lowast ; ; Dennis E. Hallahan ; MD^&Dagger ; ; ^&lowast ; &lowast ; ; Joel R. Garbow ; PhD^&dagger ; ; ^&lowast ; &lowast ; ; ^{garbow@wustl.edu" class="auth_mail}
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：15 July 2014
• 年：2014
• 卷：89
• 期：4
• 页码：714-721
• 全文大小：1072 K

文摘

To quantify the effectiveness of SB415286, a specific inhibitor of GSK-3尾, 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-3尾 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-3尾 inhibitors.