Klöcker N, Kermer P, Weishaupt J H, Labes M, Ankerhold R, Bähr M
Department of Neurology, University of Tübingen, 72076 Tübingen, Germany.
J Neurosci. 2000 Sep 15;20(18):6962-7. doi: 10.1523/JNEUROSCI.20-18-06962.2000.
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.
神经营养因子脑源性神经营养因子（BDNF）在中枢神经系统（CNS）和外周神经系统（PNS）的发育及成年期均作为一种存活、促有丝分裂和分化因子发挥作用。为了确定BDNF神经保护作用的分子机制，我们在中枢神经系统创伤模型中研究了BDNF对两条潜在神经保护信号转导通路的激活情况。成年大鼠视神经横断会导致视网膜神经节细胞（RGCs）继发性死亡。反复眼内注射BDNF可在视神经损伤后14天预防RGCs的退变，这很可能是通过抑制细胞凋亡实现的。在此，我们报告BDNF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）以及丝裂原活化蛋白激酶细胞外信号调节激酶1（ERK1）和ERK2。此外，我们提供证据表明BDNF可抑制神经元细胞死亡效应因子半胱天冬酶-3的切割及酶活性。与我们最近的研究不同，在最近的研究中抑制PI-3-K/PKB通路会减弱胰岛素样生长因子-I对轴突切断的RGCs的促存活作用（Kermer等人，2000年），但在BDNF的情况下并非如此。因此，我们认为BDNF并不依赖单一信号转导通路对受损的中枢神经系统神经元发挥神经保护作用。
