Valproic acid induces astrocyte-dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI-1 activity

被引：37

作者：

Cho, Kyu Suk ^{[1
,2
]}

Kwon, Kyoung Ja ^{[2
]}

Choi, Chang Soon ^{[1
,2
]}

Jeon, Se Jin ^{[1
,2
]}

Kim, Ki Chan ^{[1
,2
]}

Park, Jin Hee ^{[1
,2
]}

Ko, Hyun Myung ^{[1
,2
]}

Lee, Sung Hoon ^{[1
,2
]}

Cheong, Jae Hoon ^{[3
]}

Ryu, Jong Hoon ^{[4
]}

Han, Seol Heui ^{[2
,5
]}

Shin, Chan Young ^{[1
,2
,6
]}

机构：

[1] Konkuk Univ, Sch Med, Dept Neurosci, Seoul 143701, South Korea

[2] Konkuk Univ, Dept Neurol, SMART Inst Adv Biomed Sci, Seoul 143701, South Korea

[3] Sahmyook Univ, Dept Pharm, Seoul, South Korea

[4] Kyung Hee Univ, Dept Oriental Pharmaceut Sci, Seoul, South Korea

[5] Konkuk Univ, Sch Med, Dept Neurol, Seoul 143701, South Korea

[6] Konkuk Univ, Sch Med, Dept Pharmacol, Seoul 143701, South Korea

来源：

GLIA | 2013年 / 61卷 / 05期

基金：

新加坡国家研究基金会;

关键词：

valproic acid; tPA; PAI-1; neurite outgrowth; TISSUE-PLASMINOGEN ACTIVATOR; SCIATIC-NERVE CRUSH; NEUROBLASTOMA-CELLS; MICE LACKING; DOPAMINERGIC-NEURONS; ALZHEIMERS-DISEASE; SIGNALING PATHWAY; GENE-EXPRESSION; PROTEIN-KINASE; UP-REGULATION;

D O I：

10.1002/glia.22463

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Tissue plasminogen activator (tPA) is expressed in several regions of brain and plays regulatory roles such as neurite outgrowth, synaptic plasticity and long term potentiation. The activity of tPA is regulated by an endogenous inhibitor plasminogen activator inhibitor-1 (PAI-1), which is expressed mainly in astrocytes. Valproic acid (VPA), a histone deacetylase inhibitor that is used for the treatment of epilepsy and bipolar disorders, promotes neurite extension, neuronal growth and has neuroprotective effect in neurodegenerative diseases. In this study, we examined whether the neurite extension effects of VPA is mediated by modulating tPA/PAI-1 system. VPA dose-dependently increased tPA activity and decreased PAI-1 activity in rat primary astrocytes but not in neurons. PAI-1 protein level secreted into the culture medium but not tPA per se was decreased by VPA. In co-culture system or in neuronal culture stimulated with astrocyte conditioned media but not in pure neuronal cell culture, VPA induced neurite outgrowth via increased tPA activity due to the decreased PAI-1 activity in astrocytes. The decrease in PAI-1 activity and increased neurite extension was regulated via JNK mediated post-transcriptional pathway. The essential role of tPA/PAI-1 system in the regulation of VPA-mediated neurite extension was further demonstrated by experiments using astrocyte conditioned media obtained from tPA or PAI-1 knockout mice. Regulation of PAI-1 activity in astrocyte by VPA may affect both physiological and pathological processes in brain by upregulating tPA activity. GLIA 2013

引用

页码：694 / 709

页数：16

共 77 条

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