Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
J Neurochem. 2012 Nov;123 Suppl 2(Suppl 2):58-64. doi: 10.1111/j.1471-4159.2012.07944.x.
The cerebral endothelium can be a vital source of signaling factors such as brain-derived neurotrophic factor that defends the neuronal parenchyma against stress and injury. But the underlying mechanisms remain to be fully defined. Here, we use cell models to ask how vascular neuroprotection is sustained. Human brain endothelial cells were grown in culture, and conditioned media were transferred to primary rat cortical neurons. Brain endothelial cell-conditioned media activated neuronal Akt signaling and protected neurons against hypoxia and oxygen-glucose deprivation. Blockade of Akt phosphorylation with the PI3-kinase inhibitor LY294002 negated this vascular neuroprotective effect. Upstream of Akt signaling, the brain-derived neurotrophic factor receptor TrkB (neurotrophic tyrosine kinase receptor, type 2) was involved because depletion with TrkB/Fc eliminated the ability of endothelial-conditioned media to protect neurons against hypoxia. Downstream of Akt signaling, activation of GSK-3β (glycogen synthase kinase 3 beta), caspase 9, caspase 3 and Bad pathways were detected. Taken together, these findings suggest that the molecular basis for vascular neuroprotection involves TrkB-Akt signaling that ameliorates neuronal apoptosis. Further investigation of these mechanisms may reveal new approaches for augmenting endogenous vascular neuroprotection in stroke, brain injury, and neurodegeneration.
脑内皮细胞可以成为信号因子的重要来源，如脑源性神经营养因子，它可以保护神经元实质免受应激和损伤。但是，其潜在的机制仍有待完全确定。在这里，我们使用细胞模型来研究血管神经保护是如何维持的。将人脑内皮细胞在培养中生长，并将条件培养基转移到原代大鼠皮质神经元中。脑内皮细胞条件培养基激活神经元 Akt 信号通路，并保护神经元免受缺氧和氧葡萄糖剥夺。用 PI3-激酶抑制剂 LY294002 阻断 Akt 磷酸化会消除这种血管神经保护作用。Akt 信号通路的上游涉及脑源性神经营养因子受体 TrkB（神经营养酪氨酸激酶受体，类型 2），因为 TrkB/Fc 的耗竭消除了内皮条件培养基保护神经元免受缺氧的能力。Akt 信号通路的下游，检测到 GSK-3β（糖原合成酶激酶 3β）、caspase 9、caspase 3 和 Bad 途径的激活。总之，这些发现表明，血管神经保护的分子基础涉及 TrkB-Akt 信号通路，该通路改善神经元凋亡。对这些机制的进一步研究可能会揭示增强中风、脑损伤和神经退行性变中内源性血管神经保护的新方法。
