Han B H, Holtzman D M
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Neurosci. 2000 Aug 1;20(15):5775-81. doi: 10.1523/JNEUROSCI.20-15-05775.2000.
Neurotrophins activate several different intracellular signaling pathways that in some way exert neuroprotective effects. In vitro studies of sympathetic and cerebellar granule neurons have demonstrated that the survival effects of neurotrophins can be mediated via activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway. Neurotrophin-mediated protection of other neuronal types in vitro can be mediated via the extracellular signal-related protein kinase (ERK) pathway. Whether either of these pathways contributes to the neuroprotective effects of neurotrophins in the brain in vivo has not been determined. Brain-derived neurotrophic factor (BDNF) is markedly neuroprotective against neonatal hypoxic-ischemic (H-I) brain injury in vivo. We assessed the role of the ERK and PI3-kinase pathways in neonatal H-I brain injury in the presence and absence of BDNF. Intracerebroventricular administration of BDNF to postnatal day 7 rats resulted in phosphorylation of ERK1/2 and the PI3-kinase substrate AKT within minutes. Effects were greater on ERK activation and occurred in neurons. Pharmacological inhibition of ERK, but not the PI3-kinase pathway, inhibited the ability of BDNF to block H-I-induced caspase-3 activation and tissue loss. These findings suggest that neuronal ERK activation in the neonatal brain mediates neuroprotection against H-I brain injury, a model of cerebral palsy.
神经营养因子可激活多种不同的细胞内信号通路，这些通路以某种方式发挥神经保护作用。对交感神经元和小脑颗粒神经元的体外研究表明，神经营养因子的存活效应可通过磷脂酰肌醇3激酶（PI3激酶）通路的激活来介导。神经营养因子在体外对其他神经元类型的保护作用可通过细胞外信号相关蛋白激酶（ERK）通路来介导。这些通路是否对神经营养因子在体内脑内的神经保护作用有贡献尚未确定。脑源性神经营养因子（BDNF）在体内对新生儿缺氧缺血性（H-I）脑损伤具有显著的神经保护作用。我们评估了ERK和PI3激酶通路在有或没有BDNF存在的情况下对新生儿H-I脑损伤的作用。对出生后第7天的大鼠脑室内注射BDNF，数分钟内即可导致ERK1/2和PI3激酶底物AKT磷酸化。对ERK激活的作用更大，且发生在神经元中。对ERK的药理抑制而非PI3激酶通路的抑制，抑制了BDNF阻断H-I诱导的半胱天冬酶-3激活和组织损失的能力。这些发现表明，新生脑内神经元ERK激活介导了对H-I脑损伤（一种脑瘫模型）的神经保护作用。
