Tissue plasminogen activator and glial function

Gravanis, Iordanis; Tsirka, Stella E.

doi:10.1002/glia.20115

Cited by 52 publications

(40 citation statements)

References 75 publications

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“…Failure of nonmetalloproteinase inhibitors to inhibit astrocyte migration further stressed the involvement of metalloproteinases. This is in keeping with the finding that serine proteinases like uPA, thought to be involved in migration (Alfano et al, 2005;Montuori et al, 2005), are poorly expressed in astrocytes (Gravanis and Tsirka, 2005;Le et al, 2003). The poor inhibitory capacity of BB-3103 for ADAMS in general and for TACE (ADAM17) in particular (Whittaker et al, 1999) highlights the importance of MMPs among metalloproteinases in astrocyte migration, although we cannot exclude the participation of ADAM10 for which BB-3103 is a good inhibitor.…”

Section: Mmp-2 But Not Mmp-9 Is Important For Astrocyte Motilitysupporting

confidence: 79%

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Ogier

Bernard

Chollet

et al. 2006

Glia

109

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Matrix Metalloproteinases (MMPs) play a role in migration of many cell types outside the central nervous system (CNS). Among neural cells, astrocytes are one of the main sources of MMPs in physiological and postlesional conditions. However, no data are available on the possible role of MMPs in astrocyte motility. Using an in vitro model of 2D migration and broad spectrum and selective MMP inhibitors, the authors demonstrated that MMP-2, but not MMP-9, is a key enzyme for astrocyte migration. In support of these data, the authors found constitutive expression of MMP-2 in astrocytes, while MMP-9 was nearly undetectable by gel zymography and immunocytochemical methods. The inhibition of migration by MMP inhibitors correlated with changes in cell morphology and in the organization of the actin cytoskeleton. In parallel, the characteristic focalized distribution of MMP-2 at the migration front observed in control cells became more diffuse and internalized by treatments that inhibited migration. The disruption of actin by cytochalasin D caused the partial recruitment of MMP-2 and gelatinolytic activity into actin aggregates, indicating a connection between the proteinase and the actin cytoskeleton. Finally, the authors found a co-localization of beta1-integrin with MMP-2 at the leading edge of migrating astrocytes. Altogether, these data provide the first evidence for the implication of MMP-2 in astrocyte motility, probably through the interaction of the proteinase with beta1-integrin that could act as a linker between pericellular proteolysis and the actin cytoskeleton.

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Section: Mmp-2 But Not Mmp-9 Is Important For Astrocyte Motilitysupporting

confidence: 79%

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Ogier

Bernard

Chollet

et al. 2006

Glia

109

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“…While using conditioned media to stimulate microglia prevents ''overactivation,'' because of the presence of inhibitory molecules such as g-amino-butyric acid (GABA) and noradrenaline (Dello et al, 2004;Kuhn et al, 2004), it does present difficulties in isolating the specific signaling messengers involved in the differential activation of microglia. The list of known microglial activators present in neurons continues to expand: In addition to a wide range of neurotransmitters, there are the chemokines, such as MCP-1 and fractalkine, and proteinases, such as tissue plasminogen activator (Gravanis and Tsirka, 2005;Lai and Todd, 2006b). Other than glutamate and ATP, we have also detected changes in GABA, aspartate, and taurine in the conditioned media (unpublished data).…”

Section: Discussionmentioning

confidence: 98%

Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury

Lai

Todd

2007

Glia

129

116

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Microglial activation has been reported to promote neurotoxicity and also neuroprotective effects. A possible contributor to this dichotomy of responses may be the degree to which proximal neurons are injured. The aim of this study was to determine whether varying the severity of neuronal injury influenced whether microglia were neuroprotective or neurotoxic. We exposed cortical neuronal cultures to varying degrees of hypoxia thereby generating mild (<20% death, 30 min hypoxia), moderate (40-60% death, 2 h hypoxia), or severe (>70% death, 6 h hypoxia) injuries. Twenty-four hours after hypoxia, the media from the neuronal cultures was collected and incubated with primary microglial cultures for 24 h. Results showed that the classic microglial proinflammatory mediators including inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin-1-beta were upregulated only in response to mild neuronal injuries, while the trophic microglial effectors brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor were upregulated in response to all degrees of neuronal injury. Microglia stimulated with media from damaged neurons were co-cultured with hypoxic neurons. Microglia stimulated by moderate, but not mild or severe damage were neuroprotective in these co-cultures. We also showed that the severity-dependent phenomenon was not related to autocrine microglial signaling and was dependent on the neurotransmitters released by neurons after injury, namely glutamate and adenosine 5'-triphosphate. Together our results show that severity of neuronal injury is an important factor in determining microglial release of "toxic" versus "protective" effectors and the resulting neurotoxicity versus neuroprotection.

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“…Recently, tPA/PAI-1 system in CNS has been implicated in CNS pathophysiology of several CNS diseases and conditions including, cerebral ischemia, addiction, fetal alcohol syndrome, multiple sclerosis, spinal cord injury and Alzheimer's disease (Benarroch 2007;Gravanis and Tsirka 2005;Melchor and Strickland 2005;Samson and Medcalf 2006). At present, there is no report whether propofol may affect tPA/PAI-1 system in CNS.…”

Section: Introductionmentioning

confidence: 96%

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

Joo

Lee

et al. 2014

Arch. Pharm. Res.

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Propofol, a widely used anesthetic, regulates neurological processes including neurotoxicity, neuroprotection, glial activation, synaptic plasticity and neuronal maturation. Tissue plasminogen activator/tissue plasminogen activator inhibitor-1 (tPA/PAI-1) in CNS acts as a neuromodulator regulating synaptic plasticity, neurite outgrowth, seizure spreading and cell survival. Here, we investigated the effects of propofol on tPA/PAI-1 system using cultured neurons and astrocytes and their role in the regulation of neurite extension. Cultured rat primary astrocytes were treated with propofol (1-10 µM) and LPS (10 ng/ml). The expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and RT-PCR. Alternatively, culture supernatants were added to cultured rat primary neuron to investigate the effects on neurite extension. Propofol alone did not affect tPA activity in rat primary cortical neuron. Similarly, propofol alone changed neither tPA nor PAI-1 activity in rat primary astrocytes. In immunologically challenged situation using LPS, propofol synergistically increased expression of PAI-1 in rat primary astrocytes without affecting tPA expression in a manner dependent on MAPKs activation. 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 immunologically-challenged situation, dysregulates tPA/PAI-1 system in brain. Whether the dysregulated tPA/PAI-1 activity adversely affects neural differentiation as well as regeneration of neuron in vivo should be empirically determined in the future.

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Tissue plasminogen activator and glial function

Cited by 52 publications

References 75 publications

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury

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

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