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.

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

“…The VPA treatment in our current findings led to significantly reduced PAI-1 expression. This effect of VPA has been noted previously on in vitro expression of PAI-1, and recently in a human model by others in our group [ 19 , 28 ]. This may be clinically relevant since fibrinolytic status in man is determined by t-PA/PAI-1 ratios.…”

Propofol treatment modulates neurite extension regulated by immunologically challenged rat primary astrocytes: a possible role of PAI-1

“…Increased expression of PAI-1 reduced tPA activity in LPS plus propofol-treated rat primary astrocytes. Consistent with the critical role of tPA activity in the regulation of neurite extension (Cho et al 2013), the diminished tPA activity in astrocyte culture supernatants resulted in decreased neurite extension when administered to cultured rat primary cortical neuron. The results from the present study suggest that propofol, especially in immunologicallychallenged situation, dysregulates tPA/PAI-1 system in brain.…”

“…The neurite extension was induced by the addition of astrocytes culture supernatants, which showed dependence on the overall level of tPA activity (Cho et al 2013). As expected from the increased PAI-1 activity and reduced tPA activity, addition of astrocytes culture supernatant treated with LPS to rat Fig.…”

Role of plasminogen activator inhibitor‑1 in the diagnosis and prognosis of patients with Parkinson's disease

“…PAI-1 is abundantly expressed in infarcted myocardium, but the pathogenic role of plasma PAI-1 plasma remains unknown in patients with Parkinson's disease (30). Cho et al (31) have previously demonstrated that valproic acid may induce astrocyte-dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tissue plasmogen activator PAI-1 activity. Previous studies have reported changes in the plasminogen activator system and the inhibitors PAI-1 and PAI-2 in posttraumatic lesions in the central nervous system and brain injuries (32,33).…”