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A Synthetic Steroid 5α-Androst-3β, 5, 6β-triol Alleviates Radiation-Induced Brain Injury in Mice via Inhibiting GBP5/NF-κB/NLRP3 Signal Axis

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Abstract

Radiotherapy for head and neck tumors can lead to a severe complication known as radiation-induced brain injury (RIBI). However, the underlying mechanism of RIBI development remains unclear, and limited prevention and treatment options are available. Neuroactive steroids have shown potential in treating neurological disorders. 5α-Androst-3β, 5, 6β-triol (TRIOL), a synthetic neuroprotective steroid, holds promise as a treatment candidate for RIBI patients. However, the neuroprotective effects and underlying mechanism of TRIOL on RIBI treatment are yet to be elucidated. In the present study, our findings demonstrate TRIOL’s potential as a neuroprotective agent against RIBI. In gamma knife irradiation mouse model, TRIOL treatment significantly reduced brain necrosis volume, microglial activation, and neuronal loss. RNA-sequencing, immunofluorescence, real-time quantitative polymerase chain reaction, siRNA transfection, and western blotting techniques revealed that TRIOL effectively decreased microglial activation, proinflammatory cytokine release, neuron loss, and guanylate-binding protein 5 (GBP5) expression, along with its downstream signaling pathways NF-κB and NLRP3 activation in vitro. In summary, TRIOL effectively alleviate RIBI by inhibiting the GBP5/NF-κB/NLRP3 signal axis, reducing microglia activation and pro-inflammation cytokines release, rescuing neuron loss. This study highlights the potential of TRIOL as a novel and promising therapy drug for RIBI treatment.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Guangzhou Cellprotek Pharmaceutical Co. Ltd who provide the TRIOL.

Funding

This study was supported by the National Natural Science Foundation of China (no. 81925031 and 81820108026), Guangzhou Science and Technology Program Key Projects (202007030001), and STI 2030 Major Projects (2022ZD0211600) to Y.T.; National Natural Science Foundation of China (no. 82103775) and China Postdoctoral Science Foundation (2022M723589) to Z.S.; and Guang Dong Basic and Applied Basic Research Foundation (2022A1515110189) to K.Z.

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Author notes

  1. Ke Zhong, Kejia Liu, and Yu Song contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Ke Zhong, Kejia Liu, Yu Song, Sitai Chen, **a Hu, Ruiqi Xue, Xueying Ma, Shaojian Li, **gwen Yang, Zhenhong Deng, **aoqiu Zhu, Yamei Tang & Zhongshan Shi

  2. Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Ke Zhong

  3. Guangzhou Cellprotek Pharmaceutical Co., Ltd., H Building F/1, 3 Juquan Road, Science City, Guangzhou, 510670, China

    Mingjun Yuan, Yijun Huang, Wei Yin & Yupin Chen

  4. Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Yamei Tang

  5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Yamei Tang

  6. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China

    Yamei Tang

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  1. Ke Zhong
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Contributions

ZK designed this study, performed the experiments, and drafted the manuscript. LKJ and SY performed the experiments, carried out extra data analysis, and revised the manuscript. CST performed high-throughput sequencing analysis. HX and XRQ assisted in gamma ray irradiation and MR imaging. MXY, LSJ, and YJW assisted in tissue processing and IF experiments. ZXQ and YMJ assisted in drug administration of animals. HYJ and YW revised the manuscript. CYP, TYM, and SZS revised the manuscript, and supervised the design of the study and conceived the manuscript. All authors reviewed and approved the final version of this paper.

Corresponding authors

Correspondence to Yupin Chen, Yamei Tang or Zhongshan Shi.

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This study was approved by the Ethics Committee of Sun Yat-sen University (SYXK 2022–0289).

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Supplementary file1 (DOCX 19 KB)

12035_2023_3831_MOESM2_ESM.tif

Supplementary file2 (TIF 11774 KB) TRIOL alleviated radiation-induced myelin loss and astrocyte activation. (A) Representative images of MAG immunofluorescent staining in the thalamus of sham mice and two irradiated mice at 8 weeks post irradiation. Red: MAG, blue: DAPI. Quantification of the average fluorescence intensity number of MAG in the thalamus from immunofluorescent images. (B) Representative images of GFAP immunofluorescent staining in thalamus from sham mice and two irradiated mice at 8 weeks post irradiation. Red: GFAP, blue: DAPI. Quantification of the number of GFAP+ cells in the thalamus sections. n= 5 mice per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc analysis. All other groups were compared with the control group. Scale bar = 50 μm. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001

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Zhong, K., Liu, K., Song, Y. et al. A Synthetic Steroid 5α-Androst-3β, 5, 6β-triol Alleviates Radiation-Induced Brain Injury in Mice via Inhibiting GBP5/NF-κB/NLRP3 Signal Axis. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03831-9

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