- 作者: Chun-Hu Wu, Chien-Cheng Chen, Tai-Ho Hung, Yen-Chieh Chuang, Min Chao, Song-Kun Shyue and Szu-Fu Chen
- 作者服務機構: 1.Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 2.Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, 45 Cheng Hsin Street, Taipei, Taiwan, Republic of China 3.Graduate Institute of Gerontology and Health Care Management, Chang Gung University of Science and Technology, Taoyuan, Taiwan 4.Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Taipei and College of Medicine, Chang Gung University, Taoyuan, Taiwan 5.Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan 6.School of Medicine, National Defense Medical Center, Taipei, Taiwan 7.Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 8.Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, Taiwan, Republic of China 9.Song-Kun Shyue and Szu-Fu Chen contributed equally to this work.
- 中文摘要:
- 英文摘要:
Background
Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades that contribute to secondary neuronal damage. Tropomyosin-related kinase receptor B (TrkB) signaling plays a crucial role in promoting neuronal survival following brain damage.
Methods
The present study investigated the protective effects and underlying mechanisms of TrkB activation by the specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), in a model of collagenase-induced ICH and in neuronal cultures. Mice subjected to collagenase-induced ICH were intraperitoneally injected with either 7,8-DHF or vehicle 10 min after ICH and, subsequently, daily for 3 days. Behavioral studies, brain edema measurement, and histological analysis were conducted. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed by western blots.
Results
Treatment with 20 mg/kg 7,8-DHF significantly improved functional recovery and reduced brain damage up to 28 days post-ICH. Reduction in neuronal death, apoptosis, and brain edema were also observed in response to 7,8-DHF treatment at 3 days post-ICH. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt (Ser473/Thr308) at 1 and 3 days, but had no effect on Erk 44/42 phosphorylation. 7,8-DHF also enhanced the phosphorylation of Ask-1 Ser967 and FOXO-1, downstream targets of Akt at 1 and 3 days. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels at 1 day. In primary cultured neurons stimulated with hemin, 7,8-DHF promoted survival and reduced apoptosis. Furthermore, delaying the administration of 7,8-DHF to 3 h post-ICH reduced brain tissue damage and neuronal death.
Conclusions
Our findings demonstrate that the activation of TrkB signaling by 7,8-DHF protects against ICH via the Akt, but not the Erk, pathway. These data provide new insights into the role of TrkB signaling deficit in the pathophysiology of ICH and highlight TrkB/Akt as possible therapeutic targets in this disease. - 中文關鍵字:
- 英文關鍵字: 7,8-dihydroxyflavone, Apoptosis, Akt, Intracerebral hemorrhage, TrkB