Neuroprotection by NGF and BDNF Against Neurotoxin-Exerted Apoptotic Death in Neural Stem Cells Are Mediated Through Trk Receptors, Activating PI3-Kinase and MAPK Pathways
Neuroprotection by NGF and BDNF Against Neurotoxin-Exerted Apoptotic Death in Neural Stem Cells Are Mediated Through Trk Receptors, Activating PI3-Kinase and MAPK Pathways
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DOI：
10.1007/s11064-008-9848-9
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发表时间：
2009-05-01
影响因子：
4.4
通讯作者：
Ahn, Jee-Yin
中科院分区：
文献类型：
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作者：
Nguyen, Nga;Lee, Sang Bae;Ahn, Jee-Yin
神经干细胞（Neural Stem Cells，NSC）在神经系统发育过程中和成年后经历凋亡性细胞死亡.然而，鲜为人知的是，在这些细胞中的神经营养因子的神经保护的生化调节。在这份报告中，我们证明了星形孢菌素（STS）和依托泊苷（ETS）诱导神经干细胞凋亡的机制，需要半胱天冬酶3激活，聚（ADP-核糖）聚合酶和核纤层蛋白A/C切割。尽管C17.2细胞中p75神经营养因子受体（p75（NTR））的mRNA水平高于TrkA或TrkB受体，但神经生长因子（NGF）和脑源性生长因子（BDNF）的神经保护作用均通过激活原肌球蛋白受体激酶（Trk）受体来介导。此外，NGF和BDNF均诱导磷脂酰肌醇3激酶（PI 3 K）/Akt和丝裂原活化蛋白激酶（MAPK）通路的激活。通过K252 a抑制Trk受体降低PARP裂解以及细胞活力，而抑制p75（NTR）不影响神经营养因子对神经毒性损伤的作用。因此，我们的研究表明，NGF和BDNF对神经干细胞抗凋亡刺激的保护作用是通过Trk受体介导的PI 3 K/Akt和MAPK信号通路实现的。
Neural stem cells (NSC) undergo apoptotic cell death during development of nervous system and in adult. However, little is known about the biochemical regulation of neuroprotection by neurotrophin in these cells. In this report, we demonstrate that Staurosporine (STS) and Etoposide (ETS) induced apoptotic cell death of NSC by a mechanism requiring Caspase 3 activation, poly (ADP-ribose) polymerase and Lamin A/C cleavage. Although C17.2 cells revealed higher mRNA level of p75 neurotrophin receptor (p75(NTR)) compared with TrkA or TrkB receptor, neuroprotective effect of both nerve growth factor (NGF) and brain-derived growth factor (BDNF) mediated through the activation of tropomyosin receptor kinase (Trk) receptors. Moreover, both NGF and BDNF induced the activation of the phosphatidylinositide 3 kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) pathway. Inhibition of Trk receptor by K252a reduced PARP cleavage as well as cell viability, whereas inhibition of p75(NTR) did not affect the effect of neurotrophin on neurotoxic insults. Thus our studies indicate that the protective effect of NGF and BDNF in NSC against apoptotic stimuli is mediated by the PI3K/Akt and MAPK signaling pathway via Trk receptors.