International Journal of Molecular Sciences

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13 pages, 4207 KiB

Open AccessArticle

Modulation of the Blood–Brain Barrier by Sigma-1R Activation

by Eugen Brailoiu, Jeffrey L. Barr, Hailey N. Wittorf, Saadet Inan, Ellen M. Unterwald and Gabriela Cristina Brailoiu

Int. J. Mol. Sci. 2024, 25(10), 5147; https://doi.org/10.3390/ijms25105147 - 9 May 2024

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Abstract

Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein residing on the endoplasmic reticulum at the mitochondrial-associated membrane (MAM) region. Sigma-1R is abundant in the brain and is involved in several physiological processes as well as in various disease states. The [...] Read more.

Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein residing on the endoplasmic reticulum at the mitochondrial-associated membrane (MAM) region. Sigma-1R is abundant in the brain and is involved in several physiological processes as well as in various disease states. The role of Sigma-1R at the blood–brain barrier (BBB) is incompletely characterized. In this study, the effect of Sigma-1R activation was investigated in vitro on rat brain microvascular endothelial cells (RBMVEC), an important component of the blood–brain barrier (BBB), and in vivo on BBB permeability in rats. The Sigma-1R agonist PRE-084 produced a dose-dependent increase in mitochondrial calcium, and mitochondrial and cytosolic reactive oxygen species (ROS) in RBMVEC. PRE-084 decreased the electrical resistance of the RBMVEC monolayer, measured with the electric cell-substrate impedance sensing (ECIS) method, indicating barrier disruption. These effects were reduced by pretreatment with Sigma-1R antagonists, BD 1047 and NE 100. In vivo assessment of BBB permeability in rats indicates that PRE-084 produced a dose-dependent increase in brain extravasation of Evans Blue and sodium fluorescein brain; the effect was reduced by the Sigma-1R antagonists. Immunocytochemistry studies indicate that PRE-084 produced a disruption of tight and adherens junctions and actin cytoskeleton. The brain microcirculation was directly visualized in vivo in the prefrontal cortex of awake rats with a miniature integrated fluorescence microscope (aka, miniscope; Doric Lenses Inc.). Miniscope studies indicate that PRE-084 increased sodium fluorescein extravasation in vivo. Taken together, these results indicate that Sigma-1R activation promoted oxidative stress and increased BBB permeability. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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11 pages, 2349 KiB

Open AccessCommunication

The Microglial Transcriptome of Age-Associated Deep Subcortical White Matter Lesions Suggests a Neuroprotective Response to Blood–Brain Barrier Dysfunction

by Taghreed Almansouri, Rachel Waller, Stephen B. Wharton, Paul R. Heath, Fiona E. Matthews, Carol Brayne, Fredericus van Eeden and Julie E. Simpson

Int. J. Mol. Sci. 2024, 25(8), 4445; https://doi.org/10.3390/ijms25084445 - 18 Apr 2024

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Abstract

Age-associated deep-subcortical white matter lesions (DSCLs) are an independent risk factor for dementia, displaying high levels of CD68⁺ microglia. This study aimed to characterize the transcriptomic profile of microglia in DSCLs and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control [...] Read more.

Age-associated deep-subcortical white matter lesions (DSCLs) are an independent risk factor for dementia, displaying high levels of CD68⁺ microglia. This study aimed to characterize the transcriptomic profile of microglia in DSCLs and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68⁺ microglia were isolated from white matter groups (n = 4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort using immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material in the CFAS cohort and identified significantly differentially expressed genes (DEGs). Functional grouping and pathway analysis were assessed using the Database for Annotation Visualization and Integrated Discovery (DAVID) software, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCLs compared to non-lesional control white matter identified 181 significant DEGs (93 upregulated and 88 downregulated). Functional clustering analysis in DAVID revealed dysregulation of haptoglobin–haemoglobin binding (Enrichment score 2.5, p = 0.017), confirmed using CD163 immunostaining, suggesting a neuroprotective microglial response to blood–brain barrier dysfunction in DSCLs. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p < 0.001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in ageing white matter pathology, highlighting a neuroprotective adaptation in DSCLs microglia and a potentially lesion-promoting phenotype in NAWM microglia. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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16 pages, 5355 KiB

Open AccessArticle

In the Rat Hippocampus, Pilocarpine-Induced Status Epilepticus 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

by Grigorios Kyriatzis, Anne Bernard, Angélique Bôle, Michel Khrestchatisky and Lotfi Ferhat

Int. J. Mol. Sci. 2024, 25(3), 1693; https://doi.org/10.3390/ijms25031693 - 30 Jan 2024

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Abstract

In humans and animal models, temporal lobe epilepsy (TLE) is associated with reorganization of hippocampal neuronal networks, gliosis, neuroinflammation, and loss of integrity of the blood–brain barrier (BBB). More than 30% of epilepsies remain intractable, and characterization of the molecular mechanisms involved in [...] Read more.

In humans and animal models, temporal lobe epilepsy (TLE) is associated with reorganization of hippocampal neuronal networks, gliosis, neuroinflammation, and loss of integrity of the blood–brain barrier (BBB). 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 through injection of the proconvulsant drug pilocarpine, which leads to TLE. Using RT-qPCR, double immunohistochemistry, and confocal imaging, we studied the regulation of reactive glia and vascular markers at different time points of epileptogenesis (latent phase—3, 7, and 14 days; chronic phase—1 and 3 months). 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 of the specific proteins CD31, PDGFRβ, and ColIV—which peak at the same time points as inflammation—in the endothelial cells, pericytes, and basement membrane of the BBB. The altered expression of these proteins occurs early in TLE, during the latent phase, suggesting that they could be associated with the early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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13 pages, 3563 KiB

Open AccessArticle

Prednisolone Targets Claudins in Mouse Brain Blood Vessels

by Alexander G. Markov, Anastasia E. Bikmurzina, Arina A. Fedorova, Ekaterina P. Vinogradova, Natalia M. Kruglova, Igor I. Krivoi and Salah Amasheh

Int. J. Mol. Sci. 2024, 25(1), 276; https://doi.org/10.3390/ijms25010276 - 24 Dec 2023

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Abstract

Endothelial cells in brain capillaries are crucial for the function of the blood–brain barrier (BBB), and members of the tight junction protein family of claudins are regarded to be primarily responsible for barrier properties. Thus, the analysis of bioactive substances that can affect [...] Read more.

Endothelial cells in brain capillaries are crucial for the function of the blood–brain barrier (BBB), and members of the tight junction protein family of claudins are regarded to be primarily responsible for barrier properties. Thus, the analysis of bioactive substances that can affect the BBB’s permeability is of great importance and may be useful for the development of new therapeutic strategies for brain pathologies. In our study, we tested the hypothesis that the application of the glucocorticoid prednisolone affects the murine blood–brain barrier in vivo. Isolated brain tissue of control and prednisolone-injected mice was examined by employing immunoblotting and confocal laser scanning immunofluorescence microscopy, and the physiological and behavioral effects were analyzed. The control tissue samples revealed the expression of barrier-forming tight junction proteins claudin-1, -3, and -5 and of the paracellular cation and water-channel-forming protein claudin-2. Prednisolone administration for 7 days at doses of 70 mg/kg caused physiological and behavioral effects and downregulated claudin-1 and -3 and the channel-forming claudin-2 without altering their localization in cerebral blood vessels. Changes in the expression of these claudins might have effects on the ionic and acid–base balance in brain tissue, suggesting the relevance of our findings for therapeutic options in disorders such as cerebral edema and psychiatric failure. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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12 pages, 2393 KiB

Open AccessArticle

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients

by Hugo Alarcan, Patrick Vourc’h, Lise Berton, Isabelle Benz-De Bretagne, Eric Piver, Christian R. Andres, Philippe Corcia, Charlotte Veyrat-Durebex and Hélène Blasco

Int. J. Mol. Sci. 2023, 24(13), 11196; https://doi.org/10.3390/ijms241311196 - 7 Jul 2023

Viewed by 904

Abstract

Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time [...] Read more.

Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2–4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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18 pages, 3807 KiB

Open AccessArticle

Involvement of the Restoration of Cerebral Blood Flow and Maintenance of eNOS Expression in the Prophylactic Protective Effect of the Novel Ferulic Acid Derivative FAD012 against Ischemia/Reperfusion Injuries in Rats

by Takashi Asano, Meiyan Xuan, Naohiro Iwata, Jun Takayama, Kousuke Hayashi, Yosuke Kato, Toshiya Aoyama, Hiroshi Sugo, Hirokazu Matsuzaki, Bo Yuan, Shinya Kamiuchi, Yasuhide Hibino, Takeshi Sakamoto and Mari Okazaki

Int. J. Mol. Sci. 2023, 24(11), 9663; https://doi.org/10.3390/ijms24119663 - 2 Jun 2023

Viewed by 1408

Abstract

Tissue plasminogen activator, aiming to restore cerebral blood flow (CBF), has been used for acute ischemic strokes in clinics; however, its narrow therapeutic time window remains a serious concern. To develop novel prophylactic drugs to alleviate cerebral ischemia/reperfusion injuries, ferulic acid derivative 012 [...] Read more.

Tissue plasminogen activator, aiming to restore cerebral blood flow (CBF), has been used for acute ischemic strokes in clinics; however, its narrow therapeutic time window remains a serious concern. To develop novel prophylactic drugs to alleviate cerebral ischemia/reperfusion injuries, ferulic acid derivative 012 (FAD012) was synthesized and showed comparable antioxidant properties to ferulic acid (FA) and probably possesses the potent ability to cross the blood–brain barrier. A more potent cytoprotective effect of FAD012 against H₂O₂-induced cytotoxicity in PC12 cells was also observed. In vivo toxicity was not observed in rats given a long-term oral administration of FAD012, indicating its good tolerability. A one-week-course oral administration of FAD012 significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral ischemia/reperfusion injuries in rats, accompanied by the restoration of CBF and endothelial nitrogen oxide synthetase (eNOS) expression. Treatment with FAD012 significantly restored the cell viability and eNOS expression damaged by H₂O₂, used to mimic MCAO-triggered oxidative stress, in rat brain microvascular endothelial cells. Our findings suggested that FAD012 protected the viability of vascular endothelium and maintained eNOS expression, ultimately contributing to the restoration of CBF, and may provide a rationale for the development of FAD012 into an effective prophylactic drug for patients at high risk of stroke. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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16 pages, 2523 KiB

Open AccessArticle

Blood–Brain Barrier Biomarkers before and after Kidney Transplantation

by Leah Hernandez, Liam J. Ward, Samsul Arefin, Peter Barany, Lars Wennberg, Magnus Söderberg, Stefania Bruno, Vincenzo Cantaluppi, Peter Stenvinkel and Karolina Kublickiene

Int. J. Mol. Sci. 2023, 24(7), 6628; https://doi.org/10.3390/ijms24076628 - 1 Apr 2023

Cited by 3 | Viewed by 2125

Abstract

Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific biomarkers. This study compares the levels of neuron specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), and circulating [...] Read more.

Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific biomarkers. This study compares the levels of neuron specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), and circulating plasma extracellular vesicles (EVs) in kidney-failure patients before KT and at a two-year follow up. Using ELISA, NSE, BDNF, and NfL levels were measured in the plasma of 74 living-donor KT patients. Plasma EVs were isolated with ultracentrifugation, and characterized for concentration/size and surface protein expression using flow cytometry from a subset of 25 patients. Lower NSE levels, and higher BDNF and NfL were observed at the two-year follow-up compared to the baseline (p < 0.05). Male patients had significantly higher BDNF levels compared to those of females. BBB biomarkers correlated with the baseline lipid profile and with glucose, vitamin D, and inflammation markers after KT. BBB surrogate marker changes in the microcirculation of early vascular aging phenotype patients with calcification and/or fibrosis were observed only in NSE and BDNF. CD31+ microparticles from endothelial cells expressing inflammatory markers such as CD40 and integrins were significantly reduced after KT. KT may, thus, improve the neurological status of CKD patients, as reflected by changes in BBB-specific biomarkers. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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Review

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45 pages, 668 KiB

Open AccessReview

Vulnerability of the Hippocampus to Insults: Links to Blood–Brain Barrier Dysfunction

by Terry L. Davidson and Richard J. Stevenson

Int. J. Mol. Sci. 2024, 25(4), 1991; https://doi.org/10.3390/ijms25041991 - 6 Feb 2024

Viewed by 1406

Abstract

The hippocampus is a critical brain substrate for learning and memory; events that harm the hippocampus can seriously impair mental and behavioral functioning. Hippocampal pathophysiologies have been identified as potential causes and effects of a remarkably diverse array of medical diseases, psychological disorders, [...] Read more.

The hippocampus is a critical brain substrate for learning and memory; events that harm the hippocampus can seriously impair mental and behavioral functioning. Hippocampal pathophysiologies have been identified as potential causes and effects of a remarkably diverse array of medical diseases, psychological disorders, and environmental sources of damage. It may be that the hippocampus is more vulnerable than other brain areas to insults that are related to these conditions. One purpose of this review is to assess the vulnerability of the hippocampus to the most prevalent types of insults in multiple biomedical domains (i.e., neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative disease, acquired brain injury, mental health conditions, endocrine disorders, developmental disabilities, nutrition) and to evaluate whether these insults affect the hippocampus first and more prominently compared to other brain loci. A second purpose is to consider the role of hippocampal blood–brain barrier (BBB) breakdown in either causing or worsening the harmful effects of each insult. Recent research suggests that the hippocampal BBB is more fragile compared to other brain areas and may also be more prone to the disruption of the transport mechanisms that act to maintain the internal milieu. Moreover, a compromised BBB could be a factor that is common to many different types of insults. Our analysis indicates that the hippocampus is more vulnerable to insults compared to other parts of the brain, and that developing interventions that protect the hippocampal BBB may help to prevent or ameliorate the harmful effects of many insults on memory and cognition. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Blood–Brain Barrier Dysfunction 3.0)

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