scholarly journals Oxidative Stress and Blood–Brain Barrier Dysfunction Under Particular Consideration of Matrix Metalloproteinases

2011 ◽  
Vol 15 (5) ◽  
pp. 1305-1323 ◽  
Author(s):  
Christine Lehner ◽  
Renate Gehwolf ◽  
Herbert Tempfer ◽  
Istvan Krizbai ◽  
Bernhard Hennig ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Matrix Metalloproteinases ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Blood Brain

The Blood-Brain Barrier Interface in Diabetes Mellitus: Dysfunctions, Mechanisms and Approaches to Treatment

2020 ◽  
Vol 26 (13) ◽  
pp. 1438-1447 ◽  
Author(s):  
William A. Banks
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Growth Factor ◽  
Matrix Metalloproteinases ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Type I ◽  
Type Ii ◽  
P Glycoprotein ◽  
Blood Brain

Diabetes mellitus (DM) is one of the most common diseases in the world. Among its effects are an increase in the risk of cognitive impairment, including Alzheimer’s disease, and blood-brain barrier (BBB) dysfunction. DM is characterized by high blood glucose levels that are caused by either lack of insulin (Type I) or resistance to the actions of insulin (Type II). The phenotypes of these two types are dramatically different, with Type I animals being thin, with low levels of leptin as well as insulin, whereas Type II animals are often obese with high levels of both leptin and insulin. The best characterized change in BBB dysfunction is that of disruption. The brain regions that are disrupted, however, vary between Type I vs Type II DM, suggesting that factors other than hyperglycemia, perhaps hormonal factors such as leptin and insulin, play a regionally diverse role in BBB vulnerability or protection. Some BBB transporters are also altered in DM, including P-glycoprotein, lowdensity lipoprotein receptor-related protein 1, and the insulin transporter as other functions of the BBB, such as brain endothelial cell (BEC) expression of matrix metalloproteinases (MMPs) and immune cell trafficking. Pericyte loss secondary to the increased oxidative stress of processing excess glucose through the Krebs cycle is one mechanism that has shown to result in BBB disruption. Vascular endothelial growth factor (VEGF) induced by advanced glycation endproducts can increase the production of matrix metalloproteinases, which in turn affects tight junction proteins, providing another mechanism for BBB disruption as well as effects on P-glycoprotein. Through the enhanced expression of the redox-related mitochondrial transporter ABCB10, redox-sensitive transcription factor NF-E2 related factor-2 (Nrf2) inhibits BEC-monocyte adhesion. Several potential therapies, in addition to those of restoring euglycemia, can prevent some aspects of BBB dysfunction. Carbonic anhydrase inhibition decreases glucose metabolism and so reduces oxidative stress, preserving pericytes and blocking or reversing BBB disruption. Statins or N-acetylcysteine can reverse the BBB opening in some models of DM, fibroblast growth factor-21 improves BBB permeability through an Nrf2-dependent pathway, and nifedipine or VEGF improves memory in DM models. In summary, DM alters various aspects of BBB function through a number of mechanisms. A variety of treatments based on those mechanisms, as well as restoration of euglycemia, may be able to restore BBB functions., including reversal of BBB disruption.

scholarly journals Hemoglobin-Induced Oxidative Stress Contributes to Matrix Metalloproteinase Activation and Blood–Brain Barrier Dysfunction in vivo

2010 ◽  
Vol 30 (12) ◽  
pp. 1939-1950 ◽  
Author(s):  
Masataka Katsu ◽  
Kuniyasu Niizuma ◽  
Hideyuki Yoshioka ◽  
Nobuya Okami ◽  
Hiroyuki Sakata ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Apoptotic Cell ◽  
Brain Barrier ◽  
Intracerebral Injection ◽  
Barrier Dysfunction ◽  
Mmp Inhibitor ◽  
Blood Brain ◽  
Albumin Leakage

Hemoglobin (Hb) released from extravasated erythrocytes is implicated in brain edema after intracerebral hemorrhage (ICH). Hemoglobin is a major component of blood and a potent mediator of oxidative stress after ICH. Oxidative stress and matrix metalloproteinases (MMPs) are associated with blood–brain barrier (BBB) dysfunction. This study was designed to elucidate whether Hb-induced oxidative stress contributes to MMP-9 activation and BBB dysfunction in vivo. An intracerebral injection of Hb into rat striata induced increased hydroethidine (HEt) signals in parallel with MMP-9 levels. In situ gelatinolytic activity colocalized with oxidized HEt signals in vessel walls, accompanied by immunoglobulin G leakage and a decrease in immunoactivity of endothelial barrier antigen, a marker of endothelial integrity. Administration of a nonselective MMP inhibitor prevented MMP-9 levels and albumin leakage in injured striata. Moreover, reduction in oxidative stress by copper/zinc-superoxide dismutase (SOD1) overexpression reduced oxidative stress, MMP-9 levels, albumin leakage, and subsequent apoptosis compared with wild-type littermates. We speculate that Hb-induced oxidative stress may contribute to early BBB dysfunction and subsequent apoptosis, partly through MMP activation, and that SOD1 overexpression may reduce Hb-induced oxidative stress, BBB dysfunction, and apoptotic cell death.

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

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.

scholarly journals CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis

2013 ◽  
Vol 304 (11) ◽  
pp. C1105-C1115 ◽  
Author(s):  
Shyamali Basuroy ◽  
Charles W. Leffler ◽  
Helena Parfenova
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Antioxidant Properties ◽  
Brain Barrier ◽  
Glutamate Excitotoxicity ◽  
Ros Production ◽  
Barrier Dysfunction ◽  
Semipermeable Membranes ◽  
Endothelial Apoptosis ◽  
Blood Brain

In cerebral microvascular endothelial cells (CMVEC) of newborn pigs, glutamate at excitotoxic concentrations (mM) causes apoptosis mediated by reactive oxygen species (ROS). Carbon monoxide (CO) produced by CMVEC or delivered by a CO-releasing molecule, CORM-A1, has antioxidant properties. We tested the hypothesis that CORM-A1 prevents cerebrovascular endothelial barrier dysfunction caused by glutamate excitotoxicity. First, we identified the glutamate receptors (GluRs) and enzymatic sources of ROS involved in the mechanism of endothelial apoptosis. In glutamate-exposed CMVEC, ROS formation and apoptosis were blocked by rotenone, 2-thenoyltrifluoroacetone (TTFA), and antimycin, indicating that mitochondrial complexes I, II, and III are the major sources of oxidative stress. Agonists of ionotropic GluRs (iGluRs) N-methyl-D-aspartate (NMDA), cis-ACPD, AMPA, and kainate increased ROS production and apoptosis, whereas iGluR antagonists exhibited antiapoptotic properties, suggesting that iGluRs mediate glutamate-induced endothelial apoptosis. The functional consequences of endothelial injury were tested in the model of blood-brain barrier (BBB) composed of CMVEC monolayer on semipermeable membranes. Glutamate and iGluR agonists reduced transendothelial electrical resistance and increased endothelial paracellular permeability to 3-kDa dextran. CORM-A1 exhibited potent antioxidant and antiapoptotic properties in CMVEC and completely prevented BBB dysfunction caused by glutamate and iGluR agonists. Overall, the endothelial component of the BBB is a cellular target for excitotoxic glutamate that, via a mechanism involving a iGluR-mediated activation of mitochondrial ROS production and apoptosis, leads to BBB opening that may be prevented by the antioxidant and antiapoptotic actions of CORMs. Antioxidant CORMs therapy may help preserve BBB functional integrity in neonatal cerebrovascular disease.

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