Activity-dependent neurotrophic factor-14 requires protein kinase C and mitogen-associated protein kinase kinase activation to protect the developing mouse brain against excitotoxicity
Activity-dependent neurotrophic factor-14 requires protein kinase C and mitogen-associated protein kinase kinase activation to protect the developing mouse brain against excitotoxicity
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DOI：
10.1385/jmn:13:1-2:199
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发表时间：
1999-08-01
影响因子：
3.1
通讯作者：
Evrard, P
中科院分区：
文献类型：
--
作者：
Gressens, P;Marret, S;Evrard, P
活性依赖性神经营养因子（ADNF）是一种新发现的化合物，当以fentomolar浓度存在时，可防止体外神经元死亡。ADNF-14是由ADNF衍生的14个氨基酸的肽，具有与亲本分子相同的生长作用。然而，这些高效营养因子的转导途径和靶细胞仍然是未知的。我们先前描述了一个小鼠模型的兴奋性毒性病变的发展中的新皮质模仿几个缺氧或缺氧样脑病变中观察到的人类胎儿和新生儿。在这个模型中，cotentiation与兴奋性毒素鹅膏蕈氨酸和ADNF-14防止神经元死亡的幼崽在出生当天注射和白色囊性病变的幼崽出生后5天。在本研究中，鹅膏蕈氨酸，ADNF-14和选择性转导通路抑制剂的共同管理表明，蛋白激酶C（PKC）和丝裂原相关蛋白激酶的激活是神经保护的关键。免疫细胞化学显示，ADNF-14激活PKC和丝裂原相关蛋白激酶在出生当天的皮质神经元和出生后第五天的白色星形胶质细胞。总之，这些数据确定PKC和丝裂原相关蛋白激酶途径对ADNF-14诱导的发育中大脑神经保护作用至关重要。
Activity-dependent neurotrophic factor (ADNF) is a newly identified compound that prevents in vitro neuronal death when present in fentomolar concentrations. ADNF-14, a 14 amino acid peptide derived from ADNF, has the same effects on growth as the parent molecule. However, the transduction pathways and target cells for these highly potent trophic factors are still unknown. We previously described a mouse model of excitotoxic lesions of the developing neocortex mimicking several hypoxic or hypoxic-like brain lesions observed in human fetuses and neonates. In this model, cotreatment with the excitotoxin ibotenate and ADNF-14 prevented both neuronal death in pups injected on the day of birth and white matter cystic lesions in pups treated 5 d after birth. In the present study, coadministration of ibotenate, ADNF-14, and selective transduction pathway inhibitors showed that activation of protein kinase C (PKC) and mitogen-associated protein kinase kinase was critical for neuroprotection. Immunocytochemistry revealed that ADNF-14 activated PKC and mitogen-associated protein kinase in cortical neurons on the day of birth and in white matter astrocytes on the fifth postnatal day. Taken in concert, these data identify PKC and mitogen-associated protein kinase pathways as critical to ADNF-14-induced neuroprotection of the developing brain against excitotoxic damage.