Brain-derived neurotrophic factor-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on phosphatidyl-inositol-3′-kinase/protein kinase B signaling
Brain-derived neurotrophic factor-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on phosphatidyl-inositol-3′-kinase/protein kinase B signaling
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DOI：
10.1523/jneurosci.20-18-06962.2000
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发表时间：
2000-09-15
影响因子：
5.3
通讯作者：
Bähr, M
中科院分区：
文献类型：
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作者：
Klöcker, N;Kermer, P;Bähr, M
神经营养因子脑源性神经营养因子（BDNF）在发育和成人CNS和PNS中作为存活、促有丝分裂和分化因子。在试图确定BDNF神经保护的分子机制，我们研究了激活两个潜在的神经保护信号转导通路的BDNF在中枢神经系统创伤模型。成年大鼠视神经切断后视网膜神经节细胞继发性死亡。反复眼内注射BDNF可防止视网膜节细胞在ON损伤后14 d的变性，这很可能是通过抑制细胞凋亡实现的。在这里，我们报告了脑源性神经营养因子通过磷脂酰肌醇-3 '-激酶（PI-3-K）依赖性机制激活蛋白激酶B（PKB）和促分裂原激活蛋白激酶细胞外信号调节激酶1（ERK 1）和ERK 2。此外，我们提供的证据表明，BDNF抑制神经元细胞死亡效应caspase-3的裂解和酶活性。不同于我们最近的研究，其中PI-3-K/PKB途径的抑制减弱了胰岛素样生长因子-I对轴突切断的RGC的存活促进作用（Kermer等人，2000），它不在BDNF的情况下。因此，我们假设BDNF不依赖于一个单一的信号转导通路发挥其对受损的中枢神经系统神经元的神经保护作用。
The neurotrophin brain-derived neurotrophic factor (BDNF) serves as a survival, mitogenic, and differentiation factor in both the developing and adult CNS and PNS. In an attempt to identify the molecular mechanisms underlying BDNF neuroprotection, we studied activation of two potentially neuroprotective signal transduction pathways by BDNF in a CNS trauma model. Transection of the optic nerve (ON) in the adult rat induces secondary death of retinal ganglion cells (RGCs). Repeated intraocular injections of BDNF prevent the degeneration of RGCs 14 d after ON lesion most likely by inhibition of apoptosis. Here, we report that BDNF activates both protein kinase B (PKB) via a phosphatidyl-inositol-3'-kinase (PI-3-K)-dependent mechanism and the mitogen-activated protein kinases extracellular signal-regulated kinase 1 (ERK1) and ERK2. Furthermore, we provide evidence that BDNF suppresses cleavage and enzymatic activity of the neuronal cell death effector caspase-3. Distinct from our recent study in which inhibition of the PI-3-K/PKB pathway attenuated the survival-promoting action of insulin-like growth factor-I on axotomized RGCs (Kermer et al., 2000), it does not in the case of BDNF. Thus, we assume that BDNF does not depend on a single signal transduction pathway exerting its neuroprotective effects on lesioned CNS neurons.