title: Valproic acid induces astrocyte-dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI-1 activity.
abstract: 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.
authors: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors: Kyu Suk
authors: KS
authors: Cho
authors: Kyoung Ja
authors: KJ
authors: Kwon
authors: Chang Soon
authors: CS
authors: Choi
authors: Se Jin
authors: SJ
authors: Jeon
authors: Ki Chan
authors: KC
authors: Kim
authors: Jin Hee
authors: JH
authors: Park
authors: Hyun Myung
authors: HM
authors: Ko
authors: Sung Hoon
authors: SH
authors: Lee
authors: Jae Hoon
authors: JH
authors: Cheong
authors: Jong Hoon
authors: JH
authors: Ryu
authors: Seol Heui
authors: SH
authors: Han
authors: Chan Young
authors: CY
authors: Shin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D018920:Coculture Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016501:Neurites / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D014635:Valproic Acid; D010959:Tissue Plasminogen Activator