期刊
NEUROSCIENCE
卷 463, 期 -, 页码 204-215出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2021.03.034
关键词
radiation; cognitive dysfunction; p5-TAT; Cdk5; neurogenesis
资金
- National Natural Science Foundation of China [81773223, 81372411]
- Jiangsu Province's Key Medical Department in 2011
- Suzhou Science and Technology Development Program
- Jiangsu Provincial Special Program of Clinical Medical Science [BL2014040]
- Suzhou Medical Center of Radiotherapy and Oncology [Szzxj201503]
- Medicine Outstanding Leader of Suzhou program
- Practice Innovation Program for College Graduates of Jiangsu Province [SJZZ15 0153]
- Suzhou Science and Technology Project [SYS201651]
- Jiangsu Provincial Medical Youth Talent program [QNRC2016234]
- Project of Jiangsu Natural Science Foundation [BK20171224]
- Suzhou Cancer Clinical Medical Center [Szzx201506]
- Preresearch Program of the Second Affiliated Hospital of Soochow University [SDFEYBS2010, SDFEYQN2004]
- Science Program of Suzhou City [SYSD2020106]
This study investigated the protective effects of inhibiting the Cdk5/caspase-3 pathway on radiation-induced cognitive dysfunction using p5-TAT, which was found to reduce Cdk5 hyperactivity, prevent inhibition of hippocampal neurogenesis and proliferation, and improve cognitive function.
cognitive dysfunction is a common complication associated with cranial radiation therapy. Inhibition of hippocampal neurogenesis and proliferation plays a critical role in this complication. Relieving hippocampal apoptosis may significantly protect hippocampal neurogenesis and proliferation. Previous studies have demonstrated that hyperactivity of cyclin-dependent kinase 5 (Cdk5) is closely related to apoptosis. The exact molecular changes and function of Cdk5 in radiation-induced cognitive dysfunction are still not clear. Whether inhibition of Cdk5 and the relevant caspase-3 could improve hippocampal neurogenesis and ameliorate radiationinduced cognitive dysfunction needs further exploration. We hypothesized that inhibition of the Cdk5/caspase-3 pathway by p5-TAT could protect hippocampal neurogenesis and alleviate radiation-induced cognitive dysfunction. In our study, we reported that radiation induced hyperactivity of Cdk5 accompanied by elevation of the levels of cleaved caspase-3, a marker of neuronal apoptosis. Inhibition of hippocampal neurogenesis and proliferation as well as cognitive dysfunction was also observed. p5-TAT, a specific inhibitor of Cdk5, decreased the overactivation of Cdk5 without affecting the levels of Cdk5 activators. Additionally, this treatment suppressed the expression of cleaved caspase-3. We further demonstrated that p5-TAT treatment reduced hippocampal dysfunction and improved behavioral performance. Therefore, Cdk5 inhibition by the small peptide p5-TAT is a promising therapeutic strategy for radiation-induced cognitive dysfunction. ? 2021 IBRO. Published by Elsevier Ltd. All rights reserved.
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