Bone marrow-derived cells are the major source of MMP-9 contributing to blood–brain barrier dysfunction and infarct formation after ischemic stroke in mice

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

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Blood-brain barrier dysfunction and recovery after ischemic stroke

Progress in Neurobiology ◽

10.1016/j.pneurobio.2017.10.001 ◽

2018 ◽

Vol 163-164 ◽

pp. 144-171 ◽

Cited By ~ 137

Author(s):

Xiaoyan Jiang ◽

Anuska V. Andjelkovic ◽

Ling Zhu ◽

Tuo Yang ◽

Michael V.L. Bennett ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain

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Attenuated Blood-Brain Barrier Dysfunction by XQ-1H Following Ischemic Stroke in Hyperlipidemic Rats

Molecular Neurobiology ◽

10.1007/s12035-014-8851-1 ◽

2014 ◽

Vol 52 (1) ◽

pp. 162-175 ◽

Cited By ~ 23

Author(s):

Weirong Fang ◽

Lan Sha ◽

Nandani Darshika Kodithuwakku ◽

Jie Wei ◽

Rui Zhang ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain

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Vitamin D deficiency increases blood-brain barrier dysfunction after ischemic stroke in male rats

Experimental Neurology ◽

10.1016/j.expneurol.2018.11.005 ◽

2019 ◽

Vol 312 ◽

pp. 63-71 ◽

Cited By ~ 14

Author(s):

Iqbal Sayeed ◽

Nefize Turan ◽

Donald G. Stein ◽

Bushra Wali

Keyword(s):

Vitamin D ◽

Ischemic Stroke ◽

Vitamin D Deficiency ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Male Rats ◽

Barrier Dysfunction ◽

Blood Brain

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Blood-brain barrier dysfunction in ischemic stroke and diabetes: the underlying link, mechanisms and future possible therapeutic targets

Anatomy & Cell Biology ◽

10.5115/acb.20.290 ◽

2021 ◽

Author(s):

Piyawadee Wicha ◽

Srijit Das ◽

Pasuk Mahakkanukrauh

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Therapeutic Targets ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain

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Blood-brain barrier dysfunction in hemorrhagic transformation: a therapeutic opportunity for nanoparticles and melatonin.

Journal of Neurophysiology ◽

10.1152/jn.00638.2020 ◽

2021 ◽

Author(s):

Esteban Figueroa ◽

Alejandro González-Candia ◽

Aitor Caballero-Román ◽

Cristina Fornaguera ◽

Elvira Escribano-Ferrer ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Blood Brain Barrier ◽

Medical Condition ◽

Brain Area ◽

Hemorrhagic Transformation ◽

Brain Barrier ◽

World Population ◽

Barrier Dysfunction ◽

Blood Brain

Stroke is the second leading cause of death worldwide, estimated that 1/6 of the world population will suffer it once in their life. The most common type of this medical condition is the ischemic stroke (IS), produced by a thrombotic or embolic occlusion of a major cerebral artery or its branches, leading to the formation of a complex infarct region caused by oxidative stress, excitotoxicity and endothelial dysfunction. Nowadays, the immediate treatment for IS involves thrombolytic agents or mechanical thrombectomy, depending on the integrity of the blood-brain barrier (BBB). A common stroke complication is the hemorrhagic transformation (HT), which consists of bleeding into the ischemic brain area. Currently, better treatments for IS are urgently needed. As such, the neurohormone melatonin has been proposed as a good candidate due to its antioxidant, anti-inflammatory and neuroprotective effects, particularly against lipid peroxidation and oxidative stress during brain ischemia. Here, we proposed to develop intravenous or intranasal melatonin nanoformulation to specifically target the brain in stroke patients. Nowadays, the challenge is to find a formulation able to cross the barriers and reach the target organ in an effective dose to generate the pharmacological effect. In this review, we discuss the current literature about stroke pathophysiology, melatonin properties and its potential use in nanoformulations as a novel therapeutic approach for ischemic stroke.

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Abstract 2792: Bone Marrow Mononuclear Cells Improve Blood-Brain Barrier Permeability And Decrease Hemorrhagic Transformation After Treatment With Tissue Plasminogen Activator In An Embolic Stroke Model

Stroke ◽

10.1161/str.43.suppl_1.a2792 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Bing Yang ◽

Xiaopei Xi ◽

Sean.I Savitz

Keyword(s):

Bone Marrow ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Blood Brain Barrier ◽

Hemorrhagic Transformation ◽

Brain Barrier ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability

Background: Tissue plasminogen activator (t-PA) is the only treatment approved in the US for acute ischemic stroke. Cell-based therapies are being studied as a new investigational treatment approach for stroke but few studies have assessed the interaction of cell therapies with IV t-PA in an embolic model. Our laboratory has been investigating the therapeutic potential of bone marrow mononuclear cells (MNCs), which have been shown to enhance recovery after acute ischemic stroke and are currently being studied in safety clinical trials. Methods: An embolic ischemic stroke model was established by deposition of an autologous blood clot into the internal carotid artery in adult Long Evans rats. IV t-PA (10 mg/kg) was administered at 1 hour after occlusion. Two hours later, 10 million allogeneic MNCs per kilogram or saline were given intravenously (N=12 per group). Hemorrhagic transformation (HT) and blood-brain barrier permeability using Evans Blue were quantified at 3 days after stroke. In an in vitro study, astrocytes were isolated from postnatal P1 rats, pre-conditioned by oxygen-glucose deprivation (OGD) for 45 min, and then cultured with MNCs derived from the mother’s bone marrow. MMP-3 was assayed in the media. Results: Over 40% (42%) of animals treated with t-PA had HT at 3 days after stroke. The incidence of HT did not differ in the MNC and saline treated groups. However, the ICH scores were significantly reduced in the MNC group (2±1.2) compared to saline controls (3.8±0.8) ( Fig A, p =0.027). BBB permeability was also reduced in the MNC group (0.28±0.07) compared to saline controls (0.6±0.12) ( Fig B, p =0.033). In the in vitro study, MMP-3 levels in the medium of cultured pre-conditioned astrocytes (30.6±3.7 ng/ml) were reduced when co-cultured directly with MNCs (23.1±2.0 ng/ml, p =0.047) but MMP-3 levels were unchanged when astrocytes and MNCs were co-cultured in transwell (32.8±3.2 ng/ml) ( Fig C&D). Conclusion: We have found for the first time that bone marrow derived MNCs reduce hemorrhagic transformation and blood brain barrier permeability after treatment with IV t-PA for acute ischemic stroke. Our results suggest a novel mechanism in which MNCs may attenuate hemorrhagic risk from t-PA by reducing the release of MMP-3 from astrocytes.

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