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Valproic acid induces astrocyte‐dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI‐1 activity
Author(s) -
Cho Kyu Suk,
Kwon Kyoung Ja,
Choi Chang Soon,
Jeon Se Jin,
Kim Ki Chan,
Park Jin Hee,
Ko Hyun Myung,
Lee Sung Hoon,
Cheong Jae Hoon,
Ryu Jong Hoon,
Han Seol Heui,
Shin Chan Young
Publication year - 2013
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22463
Subject(s) - neurite , astrocyte , biology , tissue plasminogen activator , neuroprotection , plasminogen activator inhibitor 1 , neuron , plasminogen activator , pharmacology , microbiology and biotechnology , neuroscience , biochemistry , endocrinology , central nervous system , in vitro
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