Plasminogen Activators in Neurovascular and Neurodegenerative Disorders

Yepes, Manuel; Woo, Yena; Martin-Jimenez, Cynthia

doi:10.3390/ijms22094380

Cited by 15 publications

(9 citation statements)

References 184 publications

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“…In run, these ECs produce pro-MMPs (MMP-2, MMP-3, and MMP-9) (Wang et al, 2003 ; Cheng et al, 2006 ; Suzuki et al, 2009 ). Subsequently, tPA converts the surface-bound inactive plasminogen (Plg) into active plasmin (Plm) (Doeuvre et al, 2010 ; Yepes et al, 2021 ). Plasmin, in turn, activates the MMPs, leading to the degradation of TJs and basal lamina (Mazzieri et al, 1997 ; Ramos-DeSimone et al, 1999 ; Monea et al, 2002 ; Rosenberg and Yang, 2007 ; Yang Y. et al, 2011 ).…”

Section: Bbb Breakdown In Normal Agingmentioning

confidence: 99%

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

2021

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The blood–brain barrier (BBB) plays a vital role in maintaining the specialized microenvironment of the neural tissue. It separates the peripheral circulatory system from the brain parenchyma while facilitating communication. Alterations in the distinct physiological properties of the BBB lead to BBB breakdown associated with normal aging and various neurodegenerative diseases. In this review, we first briefly discuss the aging process, then review the phenotypes and mechanisms of BBB breakdown associated with normal aging that further cause neurodegeneration and cognitive impairments. We also summarize dementia such as Alzheimer's disease (AD) and vascular dementia (VaD) and subsequently discuss the phenotypes and mechanisms of BBB disruption in dementia correlated with cognition decline. Overlaps between AD and VaD are also discussed. Techniques that could identify biomarkers associated with BBB breakdown are briefly summarized. Finally, we concluded that BBB breakdown could be used as an emerging biomarker to assist to diagnose cognitive impairment associated with normal aging and dementia.

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Section: Bbb Breakdown In Normal Agingmentioning

confidence: 99%

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

2021

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“…Urokinase (uPA) binding to uPAR activates the uPA/uPAR complex at the leading edge of migrating cell promoting their migration via extracellular matrix remodeling. These changes contribute to various physiological processes—morphogenesis, tissue regeneration and nerve fiber growth ( Parfenova et al, 2009 ; Tkachuk et al, 2009 ; Semina et al, 2016 ; Klimovich et al, 2020 ; Yepes et al, 2021 ), as well as to pathophysiological processes—fibrosis, tumor growth and metastasis ( Mahmood et al, 2018 ; Tkachuk et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Small RNA Encoded in the Mouse Urokinase Receptor uPAR Gene (Plaur) and Its Molecular Target Mef2d

Rysenkova

Troyanovskiy

Klimovich

et al. 2022

Front. Mol. Neurosci.

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Urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored receptor of urokinase (uPA), which is involved in brain development, nerve regeneration, wound healing and tissue remodeling. We have recently shown that Plaur, which encodes uPAR, is an early response gene in murine brain. Assumingly, diverse functions of Plaur might be attributed to hypothetical, unidentified microRNAs encoded within introns of the Plaur gene. Using a bioinformatic approach we identified novel small RNAs within the Plaur gene and named them Plaur-miR1-3p and Plaur-miR1-5p. We confirmed Plaur-dependent expression of Plaur-miR1-3p and Plaur-miR1-5p in the mouse brain and mouse neuroblastoma Neuro2a cells. Utilizing an in silico MR-microT algorithm in DianaTools we selected two target genes – Mef2d and Emx2 with the highest binding scores to small RNAs selected from identified Plaur-Pre-miR1. Furthermore, sequencing of mouse brain samples for Plaur-miR1-5p target genes revealed two more genes—Nrip3 and Snrnp200. The expression of Emx2, Mef2d, and Snrnp200 in the mouse brain and Mef2d and Snrnp200 in Neuro2a cells correlated with expression of Plaur and small RNAs—Plaur-miR1-3p and Plaur-miR1-5p. Finally, we demonstrated elevated MEF2D protein expression in the mouse brain after Plaur induction and displayed activating effects of Plaur-miR1-5p on Mef2d expression in Neuro2a cells using Luciferase reporter assay. In conclusion, we have identified Plaur-miR1-3p and Plaur-miR1-5p as novel small RNAs encoded in the Plaur gene. This finding expands the current understanding of Plaur function in brain development and functioning.

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“…This therapy is usually administered within 4.5 h of stroke onset (Gravanis and Tsirka, 2008;Campbell et al, 2019) but can be extended to at least 9 h when imaging has confirmed the presence of salvageable tissue (Ma et al, 2019). Although tPA can promote cerebral reperfusion it also increases the risk of intracerebral hemorrhage (Gravanis and Tsirka, 2008;Vivien, 2017;Boese et al, 2020) and may negatively affect neuronal viability (Wang et al, 1998) and exert direct neurotoxic effects (Vivien, 2017;Zhu et al, 2019;Yepes et al, 2021). Overall, thrombolytic therapy benefits only ~20-25% of stroke patients (Vanacker et al, 2016;Stroke Foundation, 2017).…”

Section: Discussionmentioning

confidence: 99%

Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator

Barreto-Arce,

Kim,

Chan

et al. 2023

Front. Neurosci.

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BackgroundThrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intravenous administration of human amnion epithelial cells (hAECs) can limit brain inflammation and infarct growth in experimental stroke. Here, we have tested whether hAECs exert cerebroprotective effects in combination with tPA in mice.MethodsMale C57Bl/6 mice were subjected to middle cerebral artery occlusion for 60 min followed by reperfusion. Immediately following reperfusion, vehicle (saline, n = 31) or tPA (10 mg/kg; n = 73) was administered intravenously. After 30 min of reperfusion, tPA-treated mice were injected intravenously with either hAECs (1×106; n = 32) or vehicle (2% human serum albumin; n = 41). A further 15 sham-operated mice were treated with vehicle (n = 7) or tPA + vehicle (n = 8). Mice were designated to be euthanised at 3, 6 or 24 h post-stroke (n = 21, 31, and 52, respectively), and brains were collected to assess infarct volume, blood–brain barrier (BBB) disruption, intracerebral bleeding and inflammatory cell content.ResultsThere was no mortality within 6 h of stroke onset, but a high mortality occurred in tPA + saline-treated mice between 6 h and 24 h post-stroke in comparison to mice treated with tPA + hAECs (61% vs. 27%, p = 0.04). No mortality occurred within 24 h of sham surgery in mice treated with tPA + vehicle. We focused on early infarct expansion within 6 h of stroke and found that infarction was ~50% larger in tPA + saline- than in vehicle-treated mice (23 ± 3 mm3 vs. 15 ± 2 mm3, p = 0.02) but not in mice receiving tPA + hAECs (13 ± 2 mm3, p < 0.01 vs. tPA + saline) in which intracerebral hAECs were detected. Similar to the profiles of infarct expansion, BBB disruption and intracerebral bleeding in tPA + saline-treated mice at 6 h was 50–60% greater than in vehicle-treated controls (2.6 ± 0.5 vs. 1.6 ± 0.2, p = 0.05) but not after tPA + hAECs treatment (1.7 ± 0.2, p = 0.10 vs. tPA + saline). No differences in inflammatory cell content were detected between treatment groups.ConclusionWhen administered following tPA in acute stroke, hAECs improve safety and attenuate infarct growth in association with less BBB disruption and lower 24 h mortality.

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Plasminogen Activators in Neurovascular and Neurodegenerative Disorders

Cited by 15 publications

References 184 publications

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

Identification of a Novel Small RNA Encoded in the Mouse Urokinase Receptor uPAR Gene (Plaur) and Its Molecular Target Mef2d

Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator

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