Expression of VEGF- and tight junction-related proteins in the neocortical microvasculature of patients with drug-resistant temporal lobe epilepsy

Castañeda‐Cabral, José Luis; Colunga-Durán, Adacrid; Ureña‐Guerrero, Mónica E.; Beas‐Zárate, Carlos; Nuñez-Lumbreras, Maria de Los Angeles; Orozco‐Suárez, Sandra; Alonso-Vanegas, Mario; Guevara‐Guzmán, Rosalinda; Deli, Mária A.; Valle-Dorado, María Guadalupe; Sánchez-Valle, Vicente; Rocha, Luísa

doi:10.1016/j.mvr.2020.104059

Cited by 25 publications

(23 citation statements)

References 51 publications

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“… 59 Surgically resected brain tissue of epilepsy patients has been reported to contain both increased and decreased levels of the main structural components of tight junctions such as claudins (especially claudin-5) and occludin. 60 Adherence junctions and their associated proteins have furthermore been implied in the onset and progression of epilepsy in animal studies. 61 In addition, matrix metalloproteinases (MMPs) are an important player in extracellular matrix remodeling, and contribute to a large variety of brain disorders by their involvement in inflammatory responses and BBB disruption by mediating the loss of basal lamina proteins.…”

Section: Angiogenesis and Epilepsymentioning

confidence: 99%

“…Previously, we discussed the possible relationship between seizure frequency, vascular density 16 and increased levels of VEGF and its receptor, 60 contributing to typical vascular injuries seen in epileptic foci, such as edema, inflammation and increased vessel permeability, contributing to BBB dysfunction. As angiogenesis affects the local vascular network, it subsequently triggers release of neuroinflammatory factors, leading to neuronal scarring, promoting atrophy and seizure progression.…”

Section: Angiogenesis and Epilepsymentioning

confidence: 99%

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Microvascular changes associated with epilepsy: A narrative review

Lanen

Melchers

Hoogland

et al. 2021

J Cereb Blood Flow Metab

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The blood-brain barrier (BBB) is dysfunctional in temporal lobe epilepsy (TLE). In this regard, microvascular changes are likely present. The aim of this review is to provide an overview of the current knowledge on microvascular changes in epilepsy, and includes clinical and preclinical evidence of seizure induced angiogenesis, barriergenesis and microcirculatory alterations. Anatomical studies show increased microvascular density in the hippocampus, amygdala, and neocortex accompanied by BBB leakage in various rodent epilepsy models. In human TLE, a decrease in afferent vessels, morphologically abnormal vessels, and an increase in endothelial basement membranes have been observed. Both clinical and experimental evidence suggests that basement membrane changes, such as string vessels and protrusions, indicate and visualize a misbalance between endothelial cell proliferation and barriergenesis. Vascular endothelial growth factor (VEGF) appears to play a crucial role. Following an altered vascular anatomy, its physiological functioning is affected as expressed by neurovascular decoupling that subsequently leads to hypoperfusion, disrupted parenchymal homeostasis and potentially to seizures”. Thus, epilepsy might be a condition characterized by disturbed cerebral microvasculature in which VEGF plays a pivotal role. Additional physiological data from patients is however required to validate findings from models and histological studies on patient biopsies.

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Section: Angiogenesis and Epilepsymentioning

confidence: 99%

Section: Angiogenesis and Epilepsymentioning

confidence: 99%

Microvascular changes associated with epilepsy: A narrative review

Lanen

Melchers

Hoogland

et al. 2021

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…The preservation of BBB integrity may be the main reason for its neuroprotective effect. Tight junction proteins bind endothelial cells to each other, resulting in a barrier that prevents most molecules from penetrating through the cross-cellular pathway [ 41 ]. Perampanel, an AED similar to RUF, acts as a non-competitive AMPA receptor antagonist and provides a protective effect against ischemic stroke through claudin 5-mediated permeability regulation of BBB [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage

Han

et al. 2021

Open Life Sciences

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Rufinamide (RUF) is a structurally unique anti-epileptic drug, but its protective mechanism against brain injury remains unclear. In the present study, we validated how the RUF protected mice with kainic acid (KA)-induced neuronal damage. To achieve that, a mouse epilepsy model was established by KA intraperitoneal injection. After Nissl staining, although there was a significant reduction in Nissl bodies in mice treated with KA, 40, 80, and 120 mg/kg, RUF significantly reduced KA-induced neuronal damage, in a dose-dependent manner. Among them, 120 mg/kg RUF was most pronounced. Immunohistochemistry (IHC) and western blot analysis showed that RUF inhibited the IBA-1 overexpression caused by KA to block microglia cell overactivation. Further, RUF treatment partially reversed neuroinflammatory cytokine (IL-1β, TNFα, HMGB1, and NLRP3) overexpression in mRNA and protein levels in KA mice. Moreover, although KA stimulation inhibited the expression of tight junctions, RUF treatment significantly upregulated expression of tight junction proteins (occludin and claudin 5) in both mRNA and protein levels in the brain tissues of KA mice. RUF inhibited the overactivation of microglia, suppressed the neuroinflammatory response, and reduced the destruction of blood–brain barrier, thereby alleviating the excitatory nerve damage of the KA-mice.

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“…Besides, reactive glial cells, members of the NVU, are likely to contribute to the permeability of the BBB observed in cerebral hypoxia through downregulation of paracellular proteins such as Claudin-5 (CLDN5), occludin, and ZO-1 (Obermeier et al, 2013 ). On the other hand, hypoxia-induced vascular endothelial growth factor (VEGF) type 2 receptor (VEGFR-2) pathway activation, increasing permeability in the brain microvascular endothelium by decreasing junctional proteins claudin-5, occludin, and ZO-1 (Castañeda-Cabral et al, 2020 ). Besides, in postnatal cerebral ischemia, VEGF may affect BBB damage by inducing metalloproteinases (MMP)-2 expression, increasing the BBB permeability by brain endothelial dysfunction (Shen et al, 2018 ).…”

Section: Neurovascular Unit In Intrauterine Growth Restrictionmentioning

confidence: 99%

Gestational Hypoxia and Blood-Brain Barrier Permeability: Early Origins of Cerebrovascular Dysfunction Induced by Epigenetic Mechanisms

Herrera

Gonzaléz‐Candia

2021

Front. Physiol.

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Fetal chronic hypoxia leads to intrauterine growth restriction (IUGR), which is likely to reduce oxygen delivery to the brain and induce long-term neurological impairments. These indicate a modulatory role for oxygen in cerebrovascular development. During intrauterine hypoxia, the fetal circulation suffers marked adaptations in the fetal cardiac output to maintain oxygen and nutrient delivery to vital organs, known as the “brain-sparing phenotype.” This is a well-characterized response; however, little is known about the postnatal course and outcomes of this fetal cerebrovascular adaptation. In addition, several neurodevelopmental disorders have their origins during gestation. Still, few studies have focused on how intrauterine fetal hypoxia modulates the normal brain development of the blood-brain barrier (BBB) in the IUGR neonate. The BBB is a cellular structure formed by the neurovascular unit (NVU) and is organized by a monolayer of endothelial and mural cells. The BBB regulates the entry of plasma cells and molecules from the systemic circulation to the brain. A highly selective permeability system achieves this through integral membrane proteins in brain endothelial cells. BBB breakdown and dysfunction in cerebrovascular diseases lead to leakage of blood components into the brain parenchyma, contributing to neurological deficits. The fetal brain circulation is particularly susceptible in IUGR and is proposed to be one of the main pathological processes deriving BBB disruption. In the last decade, several epigenetic mechanisms activated by IU hypoxia have been proposed to regulate the postnatal BBB permeability. However, few mechanistic studies about this topic are available, and little evidence shows controversy. Therefore, in this mini-review, we analyze the BBB permeability-associated epigenetic mechanisms in the brain exposed to chronic intrauterine hypoxia.

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Expression of VEGF- and tight junction-related proteins in the neocortical microvasculature of patients with drug-resistant temporal lobe epilepsy

Cited by 25 publications

References 51 publications

Microvascular changes associated with epilepsy: A narrative review

Microvascular changes associated with epilepsy: A narrative review

Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage

Gestational Hypoxia and Blood-Brain Barrier Permeability: Early Origins of Cerebrovascular Dysfunction Induced by Epigenetic Mechanisms

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