Blood–brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model

Özkan, Esra; Çetin-Taş, Yağmur; Şekerdağ, Emine; Kızılırmak, Ali B; Taş, Ali; Yıldız, Erdost; Yapici-Eser, Hale; Karahüseyinoğlu, Serçin; Zeybel, Müjdat; Gürsoy‐Özdemir, Yasemin

doi:10.1007/s11011-021-00767-8

Cited by 14 publications

(9 citation statements)

References 50 publications

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“…An association has also been shown between seizures and deposition of collagen in porcine brain with taenia-solium neurocysticercosis [54]. ColIV was increased in other models of pathology, but around rather than in the microvasculature in rat chronic hypertension [56] and ColIV expression has been shown in brains of TLE patients, albeit outside the vasculature and in meninges [57]. We thus find some discrepancies on vascular vs perivascular ColIV distribution in our aforementioned results, considering that at the time points we studied, ColIV labeling was predominantly vascular in rat TLE.…”

Section: Discussionmentioning

confidence: 87%

Pilocarpine-Induced Status Epilepticus in the Rat Hippocampus is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ and Collagen IV in Endothelial Cells and Pericytes of the Blood Brain Barrier

Kyriatzis,

Bernard,

Bôle

et al. 2023

Preprint

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Temporal lobe epilepsy (TLE) is associated with reorganization of neuronal networks, gliosis, neuroinflammation, loss of integrity of the blood brain barrier (BBB) in the hippocampus in humans and animal models. More than 30% of epilepsies remain intractable and characterization of the molecular mechanisms involved in BBB dysfunction is essential to the identification of new therapeutic strategies. In this work, we induced status epilepticus in rats by injection of the proconvulsant drug pilocarpine that leads to TLE. Using RT-qPCR, double immunohistochemistry and confocal imaging, we studied at different time points of epileptogenesis (latent phase, 3, 7, 14 days; chronic phase, 1 and 3 months) the regulation of reactive glia and vascular markers. In the hippocampus, increased expression of mRNA encoding the glial proteins GFAP and Iba1 confirmed neuroinflammatory status. We report for the first time the concomitant induction in endothelial cells, pericytes and basal membrane of the BBB of specific proteins CD31, PDGFR and ColIV, that peaks at the same time points as inflammation. The altered expression of these proteins occurs early in TLE, during the latent phase, suggesting that they could be associated with early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy.

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Section: Discussionmentioning

confidence: 87%

Pilocarpine-Induced Status Epilepticus in the Rat Hippocampus is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ and Collagen IV in Endothelial Cells and Pericytes of the Blood Brain Barrier

Kyriatzis,

Bernard,

Bôle

et al. 2023

Preprint

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“…The increased BBB permeability could be related to the breakdown of tight junctions, but circulating factors may also be involved. Although the effect of chronic hypertension on the condition of the BBB is currently unknown, accumulating evidence from animal models suggests that chronic hypertension is accompanied by BBB dysfunction 45 , 46 , 47 . Even though the correction for hypertension status at MRI in our statistical analysis did not significantly alter the results, because of the small number of women with hypertension at the time of MRI ( n = 6), we cannot exclude the possibility that long‐term hypertension may contribute to BBB impairment.…”

Section: Discussionmentioning

confidence: 99%

Blood–brain barrier leakage years after pre‐eclampsia: dynamic contrast‐enhanced 7‐Tesla MRI study

Canjels

Jansen

Alers

et al. 2022

Ultrasound in Obstet & Gyne

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Objective Pre‐eclampsia is a hypertensive complication of pregnancy that is associated with an increased risk of long‐term cardiovascular and cerebrovascular disorders. Although the underlying mechanism of persistent susceptibility to cerebral complications after pre‐eclampsia remains largely unclear, impaired blood–brain barrier (BBB) integrity has been suggested to precede several cerebrovascular diseases. In this study, we aimed to investigate the integrity of the BBB years after pre‐eclampsia. Methods This was an observational study of premenopausal formerly pre‐eclamptic women and controls with a history of normotensive pregnancy who underwent cerebral magnetic resonance imaging (MRI) at ultra‐high field (7 Tesla) to assess the integrity of the BBB. Permeability of the BBB was determined by assessing leakage rate and fractional leakage volume of the contrast agent gadobutrol using dynamic contrast‐enhanced MRI. BBB leakage measures were determined for the whole brain and lobar white and gray matter. Multivariable analyses were performed, and odds ratios were calculated to compare women with and those without a history of pre‐eclampsia, adjusting for potential confounding effects of age, hypertension status at MRI and Fazekas score. Results Twenty‐two formerly pre‐eclamptic women (mean age, 37.8 ± 5.4 years) and 13 control women with a history of normotensive pregnancy (mean age, 40.8 ± 5.5 years) were included in the study. The time since the index pregnancy was 6.6 ± 3.2 years in the pre‐eclamptic group and 9.0 ± 3.7 years in controls. The leakage rate and fractional leakage volume were significantly higher in formerly pre‐eclamptic women than in controls in the global white (P = 0.001) and gray (P = 0.02) matter. Regionally, the frontal (P = 0.04) and parietal (P = 0.009) cortical gray matter, and the frontal (P = 0.001), temporal (P < 0.05) and occipital (P = 0.007) white matter showed higher leakage rates in formerly pre‐eclamptic women. The odds of a high leakage rate after pre‐eclampsia were generally higher in white‐matter regions than in gray‐matter regions. Conclusion This observational study demonstrates global impairment of the BBB years after a pre‐eclamptic pregnancy, which could be an early marker of long‐term cerebrovascular disorders. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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“…Serum-derived inflammatory mediators, such as TGF-beta, can interact with BBB cells, activating the inflammasome complex and pericytes. This activation leads to enhanced immune responses and disruption of the BBB [200], resulting in an increased number of immunological cells, such as T and B cells, in the brain parenchyma [94].…”

Section: Bbb Alterations In Pd and The Immune Responsementioning

confidence: 99%

Experimental Models to Study Immune Dysfunction in the Pathogenesis of Parkinson’s Disease

Saponjic,

Mejías,

Nikolovski

et al. 2024

IJMS

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Parkinson’s disease (PD) is a chronic, age-related, progressive multisystem disease associated with neuroinflammation and immune dysfunction. This review discusses the methodological approaches used to study the changes in central and peripheral immunity in PD, the advantages and limitations of the techniques, and their applicability to humans. Although a single animal model cannot replicate all pathological features of the human disease, neuroinflammation is present in most animal models of PD and plays a critical role in understanding the involvement of the immune system (IS) in the pathogenesis of PD. The IS and its interactions with different cell types in the central nervous system (CNS) play an important role in the pathogenesis of PD. Even though culture models do not fully reflect the complexity of disease progression, they are limited in their ability to mimic long-term effects and need validation through in vivo studies. They are an indispensable tool for understanding the interplay between the IS and the pathogenesis of this disease. Understanding the immune-mediated mechanisms may lead to potential therapeutic targets for the treatment of PD. We believe that the development of methodological guidelines for experiments with animal models and PD patients is crucial to ensure the validity and consistency of the results.

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Blood–brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model

Cited by 14 publications

References 50 publications

Pilocarpine-Induced Status Epilepticus in the Rat Hippocampus is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ and Collagen IV in Endothelial Cells and Pericytes of the Blood Brain Barrier

Pilocarpine-Induced Status Epilepticus in the Rat Hippocampus is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ and Collagen IV in Endothelial Cells and Pericytes of the Blood Brain Barrier

Blood–brain barrier leakage years after pre‐eclampsia: dynamic contrast‐enhanced 7‐Tesla MRI study

Experimental Models to Study Immune Dysfunction in the Pathogenesis of Parkinson’s Disease

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