Hyperforin promotes post-stroke functional recovery through interleukin (IL)-17A-mediated angiogenesis.
Hyperforin, the main active ingredient of the medicinal plant Hypericum perforatum, has been shown to be neuroprotective against acute ischemic stroke. However, the long-term actions of hyperforin on the post-stroke functional recovery and underlying mechanisms have not been investigated. C57BL/6 wild-type mice or interleukin (IL)-17A knock-out mice underwent middle cerebral artery occlusion (60min) followed by reperfusion for 28 days. Here, we found that delayed treatment with hyperforin significantly promoted functional recovery and increased IL-17A expression in the ischemic hemisphere at 28 days post-ischemia (dpi). IL-17A knock-out or anti-IL-17A monoclonal antibody (mAb) treatment significantly attenuated the promoting effects of hyperforin on functional recovery. After screening for neurotrophic factors, we revealed that blocking IL-17A significantly decreased, whereas recombinant mouse IL-17A (rIL-17A) treatment significantly increased vascular endothelial growth factor (VEGF) expression. Our data also showed that rIL-17A treatment significantly increased CD34 expression and promoted functional recovery at 28dpi, and the promoting effects were attenuated by VEGF neutralizing antibody treatment. Furthermore, hyperforin treatment significantly increased the expression of VEGF and CD34 in the ischemic hemisphere at 28dpi, and the effects were attenuated by blocking IL-17A. Furthermore, VEGF neutralizing antibody significantly attenuated the promoting role of hyperforin on the cerebral CD34 expression. Thus, our results suggest that, in addition to the acute neuroprotection when delivered immediately after ischemic stroke, hyperforin could also promote functional recovery when delivered in the later phases of stroke recovery. Our results also reveal a previously uncharacterized property of IL-17A/VEGF signaling-induced angiogenesis in hyperforin-mediated functional recovery.
Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Jiancheng
J
Zhang
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Chengye
C
Yao
Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Jiayi
J
Chen
Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Yujing
Y
Zhang
Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: yuan_shiying@163.com.
Shiying
S
Yuan
Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Anesthesia, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: franklinyun@hust.edu.cn.
Yun
Y
Lin
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage*; D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010696:Phloroglucinol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000150:complications / Q000378:metabolism*; D013729:Terpenes / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D020381:Interleukin-17; D013729:Terpenes; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D010696:Phloroglucinol; C001654:hyperforin
Angiogenesis; Hyperforin; Il-17a; Ischemic stroke; Vegf