Is tissue-type plasminogen activator a neuromodulator?

Fernández‐Monreal, Mónica; López‐Atalaya, José P.; Benchenane, Karim; Léveillé, Frédéric; Cacquevel, Mathias; Laurent, Pascale; MacKenzie, Eric T.; Bu, Guojun; Buisson, Alain; Vivien, Denis

doi:10.1016/j.mcn.2003.11.002

Cited by 58 publications

(60 citation statements)

References 34 publications

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“…Nevertheless, it has been reported that tissue plasminogen activator, a ligand for LRP1, potentiates the NMDA-stimulated Ca 2ϩ influx in primary cultured cortical neurons (39). In addition, ␣2-macroglobulin itself induced Ca 2ϩ influx through the NMDA receptor in cortical neurons (18).…”

Section: Discussionmentioning

confidence: 99%

A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma

Hayashi

Eguchi

Fukuchi-Nakaishi

et al. 2012

Journal of Biological Chemistry

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Background:No effective treatment exists for normal tension glaucoma (NTG), which induces a significant loss of retinal ganglion cells (RGCs). Results: Apolipoprotein E-containing lipoproteins (E-LPs) blocked Ca 2ϩ -dependent apoptosis induced by glutamate in RGCs. Conclusion: Administration of E-LPs protects RGCs from glutamate-induced degeneration in vitro and in vivo.Significance: Protection from neuron death by E-LPs provides a novel strategy of treatment for NTG.

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Section: Discussionmentioning

confidence: 99%

A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma

Hayashi

Eguchi

Fukuchi-Nakaishi

et al. 2012

Journal of Biological Chemistry

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“…Various inhibitors of tPA such as type 1 plasminogen activator inhibitor (PAI-1) or neuroserpin can block the protease activity of tPA (Gautier et al, 2003). Recently, Fernandez-Monreal et al (2004) demonstrated that astrocytes can scavenge extracellular tPA by a receptor dependent mechanism. Therefore, an understanding of the physiological regulation of tPA within the CNS will be crucial in developing newer strategies of stroke therapy.…”

Section: Figmentioning

confidence: 99%

The Neurotoxicity of Tissue Plasminogen Activator?

Kaur

Zhao

Klein

et al. 2004

J Cereb Blood Flow Metab

240

185

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Abstract:Tissue plasminogen activator (tPA), a fibrin specific activator for the conversion of plasminogen to plasmin, stimulates thrombolysis and rescues ischemic brain by restoring blood flow. However, emerging data suggests that under some conditions, both tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. Animal models suggest that in severe ischemia with injury to the blood brain barrier (BBB) there is injury attributed to the protease effects of this exogenous tPA. Besides clot lysis per se, tPA may have pleiotropic actions in the brain, including direct vasoactivity, cleaveage of the N-methyl-Daspartate (NMDA) NR1 subunit, amplification of intracellular Ca ++ conductance, and activation of other extracellular proteases from the matrix metalloproteinase (MMP) family, e.g. MMP-9. These effects may increase excitotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage. If tPA is effective and reverses ischemia promptly, the BBB remains intact and exogenous tPA remains within the vascular space. If tPA is ineffective and ischemia is prolonged, there is the risk that exogenous tPA will injure both the neurovascular unit and the brain. Methods of neuroprotection, which prevent tPA toxicity or additional mechanical means to open cerebral vessels, are now needed.

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“…A number of previous studies have demonstrated the presence of tPA and uPA in various eye tissues including, retinal neovascular membranes (41,42), and in normal (43)(44)(45)(46) and diabetic retinas (47). In a clinical setting, tPA has been used to treat stroke patients (48,49), as well as patients with submacular hemorrhage (50)(51)(52)(53)(54). Although the functional roles of these proteases in the retina are unclear, mounting evidence indicates that tPA and uPA might play a degenerative role in the CNS (30)(31)(32)(55)(56)(57)(58)(59)(60) and retina (42,(61)(62)(63)(64).…”

Section: Introductionmentioning

confidence: 99%

Plasminogen activators promote excitotoxicity‐induced retinal damage

2005

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Increased levels of extracellular L-glutamate have been suggested to play a role in retinal damage in a number of blinding diseases such as glaucoma and diabetic retinopathy. Although glutamate can cause retinal damage, in part, by hyper-stimulating its receptors ("excitotoxicity"), the down-stream events that lead to retinal damage are poorly understood. In this study, we injected kainic acid (KA), a glutamate receptor agonist that specifically hyper-stimulates non-NMDA-type receptors, into the vitreous humor of CD-1 mice and have investigated the role of plasminogen activators (PAs) [tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA)] in excitotoxicity-induced retinal damage. Injection of KA into the vitreous humor led to an up-regulation in tPA and an induction in uPA activity in the retina and this was associated with activation of zymogen plasminogen to active plasmin. Immunocytochemical analysis indicated that retinal ganglion cells (RGCs), constitutively, express tPA and release it into the extracellular space upon KA injection. Immunocytochemical analysis also indicated an increase in uPA in the nerve fiber layer after KA injection which was absent in the control retinas. These events were associated with apoptotic death of cells initially in the ganglion cell layer and subsequently in the inner and outer nuclear layer, associated with loss of both RGCs and amacrine cells. These phenomena were inhibited when recombinant plasminogen activator inhibitor (rPAI-1) or tPA-STOP were injected into the vitreous humor with KA, whereas a plasmin inhibitor, alpha-2-antiplasmin, failed to attenuate KA-induced retinal damage. Taken together, these results suggest that inhibition of plasminogen activators might attenuate retinal damage in blinding retinal diseases in which hyper-stimulation of glutamate receptors is implicated as a causative factor to retinal damage.

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Is tissue-type plasminogen activator a neuromodulator?

Cited by 58 publications

References 34 publications

A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma

A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma

The Neurotoxicity of Tissue Plasminogen Activator?

Plasminogen activators promote excitotoxicity‐induced retinal damage

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