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The activity of tPA is regulated by an endogenous inhibitor plasminogen activator inhibitor\u20101 (PAI\u20101), 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\u20101 system. VPA dose\u2010dependently increased tPA activity and decreased PAI\u20101 activity in rat primary astrocytes but not in neurons. PAI\u20101 protein level secreted into the culture medium but not tPA <jats:italic>per se<\/jats:italic> was decreased by VPA. In co\u2010culture 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\u20101 activity in astrocytes. The decrease in PAI\u20101 activity and increased neurite extension was regulated via JNK mediated post\u2010transcriptional pathway. The essential role of tPA\/PAI\u20101 system in the regulation of VPA\u2010mediated neurite extension was further demonstrated by experiments using astrocyte conditioned media obtained from tPA or PAI\u20101 knockout mice. Regulation of PAI\u20101 activity in astrocyte by VPA may affect both physiological and pathological processes in brain by upregulating tPA activity. 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