Department of Pathology, Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2687-92. doi: 10.1073/pnas.0913572107. Epub 2010 Jan 25.
Brain-derived neurotrophic factor (BDNF), a cognate ligand for the tyrosine kinase receptor B (TrkB) receptor, mediates neuronal survival, differentiation, synaptic plasticity, and neurogenesis. However, BDNF has a poor pharmacokinetic profile that limits its therapeutic potential. Here we report the identification of 7,8-dihydroxyflavone as a bioactive high-affinity TrkB agonist that provokes receptor dimerization and autophosphorylation and activation of downstream signaling. 7,8-Dihydroxyflavone protected wild-type, but not TrkB-deficient, neurons from apoptosis. Administration of 7,8-dihydroxyflavone to mice activated TrkB in the brain, inhibited kainic acid-induced toxicity, decreased infarct volumes in stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson disease. Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, providing a powerful therapeutic tool for the treatment of various neurological diseases.
脑源性神经营养因子（BDNF）是酪氨酸激酶受体 B（TrkB）受体的同源配体，介导神经元存活、分化、突触可塑性和神经发生。然而，BDNF 的药代动力学特性较差，限制了其治疗潜力。在这里，我们报告了 7,8-二羟基黄酮的鉴定，它是一种具有生物活性的高亲和力 TrkB 激动剂，可引发受体二聚化和自身磷酸化，并激活下游信号转导。7,8-二羟基黄酮可保护野生型神经元，但不能保护 TrkB 缺陷型神经元免于凋亡。7,8-二羟基黄酮在小鼠体内给药可激活脑中的 TrkB，抑制红藻氨酸诱导的毒性，以 TrkB 依赖的方式减少中风中的梗死体积，并在帕金森病动物模型中具有神经保护作用。因此，7,8-二羟基黄酮模拟 BDNF 并作为一种有效的 TrkB 激动剂，为治疗各种神经疾病提供了强大的治疗工具。
