Tissue-Type Plasminogen Activator: A Multifaceted Modulator of Neurotransmission and Synaptic Plasticity

Samson, André L.; Medcalf, Robert L.

doi:10.1016/j.neuron.2006.04.013

Cited by 184 publications

(172 citation statements)

References 31 publications

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“…Lithium also increases the protein level of tPA (data not shown), a direct target of PAI-1 (Wind et al, 2002). Multiple roles of the tPA-plasmin system in the central nervous system have been suggested, ranging from neural organization to brain disorders (reviewed in Samson and Medcalf, 2006;Vivien and Ali, 2006). Our study shows that lithium regulates the PAI-1-tPA-plasmin system through cross-talk among TGF-β/Smad and lithium-targeted signaling pathways, and thus provides critical information regarding lithium's novel molecular and cellular actions.…”

Section: Discussionmentioning

confidence: 93%

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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Smad proteins are intracellular transducers for transforming growth factor-β (TGF-β signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-β and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3β protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3β (GSK-3β), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB Ser133 protein levels, an enhanced interaction between pCREB Ser133 and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.

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Section: Discussionmentioning

confidence: 93%

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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“…The tPA has pleiotropic actions in the brain besides its well-established fibrinolytic action. It induces neural injury in the setting of acute stroke (Benchenane et al, 2004), but is also involved in synaptic plasticity (Samson and Medcalf, 2006), dendritic remodeling (Mataga et al, 2004), and axonal outgrowth (Minor et al, 2009). Thus, we hypothesized that administration of tPA during the recovery phase may provide beneficial effects on stroke recovery by promoting axonal remodeling.…”

Section: Discussionmentioning

confidence: 99%

Multipotent Mesenchymal Stromal Cells Increase tPA Expression and Concomitantly Decrease PAI-1 Expression in Astrocytes through the Sonic Hedgehog Signaling Pathway after Stroke (in vitro Study)

Xin

Shen

et al. 2011

J Cereb Blood Flow Metab

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Multipotent mesenchymal stromal cells (MSCs) increase tissue plasminogen activator (tPA) activity in astrocytes of the ischemic boundary zone, leading to increased neurite outgrowth in the brain. To probe the mechanisms that underlie MSC-mediated activation of tPA, we investigated the morphogenetic gene, sonic hedgehog (Shh) pathway. In vitro oxygen and glucose deprivation and coculture of astrocytes and MSCs were used to mimic an in vivo ischemic condition. Both real-time-PCR and western blot showed that MSC coculture significantly increased the Shh level and concomitantly increased tPA and decreased plasminogen activator inhibitor 1 (PAI-1) levels in astrocytes. Inhibiting the Shh signaling pathway with cyclopamine blocked the increase of tPA and the decrease of PAI-1 expression in astrocytes subjected to MSC coculture or recombinant mouse Shh (rm-Shh) treatment. Both MSCs and rm-Shh decreased the transforming growth factor-b1 level in astrocytes, and the Shh pathway inhibitor cyclopamine reversed these decreases. Both Shh-small-interfering RNA (siRNA) and Glil-siRNA downregulated Shh and Gli1 (a key mediator of the Shh transduction pathway) expression in cultured astrocytes and concomitantly decreased tPA expression and increased PAI-1 expression in these astrocytes after MSC or rm-Shh treatment. Our data indicate that MSCs increase astrocytic Shh, which subsequently increases tPA expression and decreases PAI-1 expression after ischemia.

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“…tPA, although best known as an initiator of intravascular fibrinolysis, is also widely expressed in the central nervous system (CNS) in which it mediates numerous physiological (eg memory, reward and anxiety) and pathological (eg seizure and blood-brain barrier breakdown) processes. [1][2][3] Given these recognised neural roles for tPA, there is need for an efficient and sensitive assay to measure tPA activity in brain tissues. There are several existing methods for the detection of tPA activity, including zymographic, amidolytic, immunocapture/ELISA-based and clot lysis assays.…”

mentioning

confidence: 99%

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Sashindranath

Samson

Downes

et al. 2011

Laboratory Investigation

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Tissue-type plasminogen activator (tPA) is a major protease of the central nervous system. Most studies to date have used in situ-or gel-based zymographic assays to monitor in vivo changes in neural tPA activity. In this study, we demonstrate that the amidolytic assay can be adapted to accurately detect changes in net tPA activity in mouse brain tissues. Using the amidolytic assay, we examined differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wildtype (WT) and tPA À/À mice, and in transgenic mice selectively overexpressing tPA in neurons. In addition, we assessed changes in endogenous net tPA activity in WT mice following morphine administration, epileptic seizures, traumatic brain injury and ischaemic stroke-neurological settings in which tPA has a known functional role. Under these conditions, acute and compartment-specific regulation of tPA activity was observed. tPA also participates in various forms of chronic neurodegeneration. Accordingly, we assessed tPA activity levels in mouse models of Alzheimer's disease (AD) and spinocerebellar ataxia type-1 (SCA1). Decreased tPA activity was detected in the cortex and subcortex of AD mice, whereas increased tPA activity was found in the cerebellum of SCA1 mice. These findings extend the existing hypotheses that low tPA activity promotes AD, whereas increased tPA activity contributes to cerebellar degeneration. Collectively, our results exemplify the utility of the amidolytic assay and emphasise tPA as a complex mediator of brain function and dysfunction. On the basis of this evidence, we propose that alterations in tPA activity levels could be used as a biomarker for perturbations in brain homeostasis.

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Tissue-Type Plasminogen Activator: A Multifaceted Modulator of Neurotransmission and Synaptic Plasticity

Cited by 184 publications

References 31 publications

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Multipotent Mesenchymal Stromal Cells Increase tPA Expression and Concomitantly Decrease PAI-1 Expression in Astrocytes through the Sonic Hedgehog Signaling Pathway after Stroke (in vitro Study)

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

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