Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, 45 Cheng Hsin Street, Taipei, Taiwan, Republic of China.
J Biomed Sci. 2019 Jul 15;26(1):53. doi: 10.1186/s12929-019-0543-8.
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.
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.
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.
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.
脑出血（ICH）诱导一系列细胞凋亡级联反应，导致继发性神经元损伤。原肌球蛋白相关激酶受体 B（TrkB）信号在脑损伤后促进神经元存活中发挥关键作用。
本研究通过胶原酶诱导的 ICH 模型和神经元培养物，探讨了特异性 TrkB 激动剂 7,8-二羟基黄酮（7,8-DHF）激活 TrkB 的保护作用及其潜在机制。在 ICH 后 10 分钟，用 7,8-DHF 或载体对胶原酶诱导的 ICH 小鼠进行腹腔注射，随后连续 3 天每天注射一次。进行行为学研究、脑水测量和组织学分析。通过 Western blot 分析 TrkB 信号相关分子和凋亡相关蛋白的水平。
20mg/kg 7,8-DHF 治疗可显著改善功能恢复，减少 ICH 后 28 天的脑损伤。ICH 后 3 天，7,8-DHF 治疗也观察到神经元死亡、凋亡和脑水肿减少。这些变化伴随着 1 和 3 天 TrkB 和 Akt（Ser473/Thr308）磷酸化的显著增加，但对 Erk 44/42 磷酸化没有影响。7,8-DHF 还增强了 Akt 的下游靶标 Ask-1 Ser967 和 FOXO-1 的磷酸化，时间为 1 和 3 天。此外，7,8-DHF 在 1 天增加了脑源性神经营养因子的水平。在血红素刺激的原代培养神经元中，7,8-DHF 促进了神经元的存活并减少了凋亡。此外，将 7,8-DHF 的给药时间延迟至 ICH 后 3 小时，可减少脑组织损伤和神经元死亡。
我们的研究结果表明，7,8-DHF 通过 Akt 而不是 Erk 途径激活 TrkB 信号，从而对 ICH 起到保护作用。这些数据为 TrkB 信号缺失在 ICH 病理生理学中的作用提供了新的见解，并强调了 TrkB/Akt 作为该疾病的潜在治疗靶点。
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