ACTIVATION OF p38 MITOGEN-ACTIVATED PROTEIN KINASE IS REQUIRED FOR IN VIVO BRAIN-DERIVED NEUROTROPHIC FACTOR PRODUCTION IN THE RAT HIPPOCAMPUS
ACTIVATION OF p38 MITOGEN-ACTIVATED PROTEIN KINASE IS REQUIRED FOR IN VIVO BRAIN-DERIVED NEUROTROPHIC FACTOR PRODUCTION IN THE RAT HIPPOCAMPUS
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DOI：
10.1016/j.neuroscience.2009.06.011
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发表时间：
2009-09-29
期刊：
影响因子：
3.3
通讯作者：
Kato, K.
中科院分区：
文献类型：
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作者：
Katoh-Semba, R.;Kaneko, R.;Kato, K.
大量证据表明，脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）与海马内记忆的形成、储存和回忆有关，维持一定水平的BDNF对维持正常功能十分重要。BDNF可以以活性依赖性方式合成。事实上，红藻氨酸或AMPA增强海马颗粒神经元中的BDNF水平。然而，BDNF产生的机制在很大程度上尚不清楚。最近，我们发现，利鲁唑，阻断电压门控钠通道，从而减少谷氨酸的释放，实际上加强了大鼠海马颗粒神经元BDNF的免疫反应性。因此，我们研究了利鲁唑激活的BDNF产生的信号通路。阿曲唑增加磷酸化p38丝裂原活化蛋白激酶（p38 MAPK）水平以及BDNF水平。SB 203580抑制p38 MAPK降低利鲁唑的作用，而茴香霉素激活p38 MAPK增加BDNF的水平，表明p38 MAPK可以介导BDNF的产生。还观察到阿曲唑诱导的磷酸活化转录因子-2（p38 MAPK下游的转录因子）升高。N型电压门控钙通道阻滞剂可降低利鲁唑对BDNF产生和p38 MAPK激活的影响。我们还研究了腺苷A1受体可能参与脑源性神经营养因子的产生，因为利鲁唑可以影响外核苷酸水平。A1受体激动剂抑制利鲁唑诱导的BDNF水平升高，而拮抗剂不仅增加了BDNF和活性p38 MAPK的水平，而且增强了利鲁唑的作用。这些结果表明，在大鼠海马中，有一个在体内的信号转导通路p38 MAPK介导的BDNF合成，和N型电压门控钙通道和/或腺苷A1受体有助于p38 MAPK激活。(C)2009年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Several lines of evidence strongly suggest that brain-derived neurotrophic factor (BDNF) is associated with the formation, storage and recall of memory in the hippocampus and that it is important to maintain a considerable level of hippocampal BDNF in order to keep normal functions. BDNF can be synthesized in an activity-dependent manner. In fact, kainic acid or AMPA enhances BDNF levels in hippocampal granule neurons. However, the mechanisms of BDNF production are largely unclear. Recently, we have found that riluzole, which blocks voltage-gated sodium channels and thereby reduces glutamate release, actually strengthens immunoreactivity of BDNF in hippocampal granule neurons of rats. Therefore, we examined the riluzole-activated signaling pathways for BDNF production. Riluzole increased levels of phospho-p38 mitogen-activated protein kinase (p38 MAPK), as well as BDNF levels. Inhibition of p38 MAPK by SB203580 reduced riluzole effects, while activation of p38 MAPK by anisomycin increased levels of BDNF, suggesting that p38 MAPK can mediate BDNF production. Riluzole-induced elevation of phospho-activating transcription factor-2, a transcription factor downstream of p38 MAPK, was also observed. A blocker of N-type voltage-gated calcium channels reduced the effects of riluzole on BDNF production and p38 MAPK activation. We also examined a possible involvement of the adenosine A1 receptor in BDNF production because riluzole can influence ecto-nucleotide levels. An A1 receptor agonist inhibited riluzole-induced elevation of BDNF levels, whereas an antagonist not only increased levels of BDNF and active p38 MAPK but also augmented riluzole effects. These results indicate that, in the rat hippocampus, there is an in vivo signaling pathway for BDNF synthesis mediated by p38 MAPK, and that N-type voltage-gated calcium channels and/or adenosine A1 receptors contribute to p38 MAPK activation. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.