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25 pages, 3383 KiB

Open AccessArticle

Interplay between Systemic Glycemia and Neuroprotective Activity of Resveratrol in Modulating Astrocyte SIRT1 Response to Neuroinflammation

by Anna D. Grabowska, Mateusz Wątroba, Joanna Witkowska, Agnieszka Mikulska, Nuno Sepúlveda and Dariusz Szukiewicz

Int. J. Mol. Sci. 2023, 24(14), 11640; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411640 - 19 Jul 2023

Cited by 5 | Viewed by 1231

Abstract

The flow of substances between the blood and the central nervous system is precisely regulated by the blood–brain barrier (BBB). Its disruption due to unbalanced blood glucose levels (hyper- and hypoglycemia) occurring in metabolic disorders, such as type 2 diabetes, can lead to [...] Read more.

The flow of substances between the blood and the central nervous system is precisely regulated by the blood–brain barrier (BBB). Its disruption due to unbalanced blood glucose levels (hyper- and hypoglycemia) occurring in metabolic disorders, such as type 2 diabetes, can lead to neuroinflammation, and increase the risk of developing neurodegenerative diseases. One of the most studied natural anti-diabetic, anti-inflammatory, and neuroprotective compounds is resveratrol (RSV). It activates sirtuin 1 (SIRT1), a key metabolism regulator dependent on cell energy status. The aim of this study was to assess the astrocyte SIRT1 response to neuroinflammation and subsequent RSV treatment, depending on systemic glycemia. For this purpose, we used an optimized in vitro model of the BBB consisting of endothelial cells and astrocytes, representing microvascular and brain compartments (MC and BC), in different glycemic backgrounds. Astrocyte-secreted SIRT1 reached the highest concentration in hypo-, the lowest in normo-, and the lowest in hyperglycemic backgrounds. Lipopolysaccharide (LPS)-induced neuroinflammation caused a substantial decrease in SIRT1 in all glycemic backgrounds, as observed earliest in hyperglycemia. RSV partially counterbalanced the effect of LPS on SIRT1 secretion, most remarkably in normoglycemia. Our results suggest that abnormal glycemic states have a worse prognosis for RSV-therapy effectiveness compared to normoglycemia. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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14 pages, 5155 KiB

Open AccessArticle

C-X-C Motif Chemokine 3 Promotes the Inflammatory Response of Microglia after Escherichia coli-Induced Meningitis

by Xinyi Qu, Beibei Dou, Ruicheng Yang, Chen Tan, Huanchun Chen and Xiangru Wang

Int. J. Mol. Sci. 2023, 24(13), 10432; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310432 - 21 Jun 2023

Cited by 1 | Viewed by 1051

Abstract

Meningitis is a major clinical manifestation of Escherichia coli (E. coli) infection characterized by inflammation of the meninges and subarachnoid space. Many chemokines are secreted during meningitic E. coli infection, of which C-X-C motif chemokine 3 (CXCL3) is the most highly [...] Read more.

Meningitis is a major clinical manifestation of Escherichia coli (E. coli) infection characterized by inflammation of the meninges and subarachnoid space. Many chemokines are secreted during meningitic E. coli infection, of which C-X-C motif chemokine 3 (CXCL3) is the most highly expressed. However, it is unclear how CXCL3 plays a role in meningitic E. coli infection. Therefore, this study used in vitro and in vivo assays to clarify these contributions and to identify novel therapeutic targets for central nervous system inflammation. We found a significantly upregulated expression of CXCL3 in human brain microvascular endothelial cells and U251 cells after meningitic E. coli infection, and the CXCL3 receptor, C-X-C motif chemokine receptor 2 (CXCR2), was expressed in microglia. Furthermore, CXCL3 induced M1 microglia by selectively activating mitogen-activated protein kinases signaling and significantly upregulating tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, nitric oxide synthase 2 (NOS2), and cluster of differentiation 86 (CD86) expression levels, promoting an inflammatory response. Our findings clarify the role of CXCL3 in meningitic E. coli-induced neuroinflammation and demonstrate that CXCL3 may be a potential therapeutic target for future investigation and prevention of E. coli-induced neuroinflammation. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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12 pages, 2323 KiB

Open AccessArticle

Microvascular Environment Influences Brain Microvascular Heterogeneity: Relative Roles of Astrocytes and Oligodendrocytes for the EPCR Expression in the Brain Endothelium

by Manjusha Thakar, Midrelle E. Noumbissi and Monique F. Stins

Int. J. Mol. Sci. 2023, 24(8), 6908; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24086908 - 07 Apr 2023

Viewed by 1177

Abstract

Postmortem neuropathology shows clear regional differences in many brain diseases. For example, brains from cerebral malaria (CM) patients show more hemorrhagic punctae in the brain’s white matter (WM) than grey matter (GM). The underlying reason for these differential pathologies is unknown. Here, we [...] Read more.

Postmortem neuropathology shows clear regional differences in many brain diseases. For example, brains from cerebral malaria (CM) patients show more hemorrhagic punctae in the brain’s white matter (WM) than grey matter (GM). The underlying reason for these differential pathologies is unknown. Here, we assessed the effect of the vascular microenvironment on brain endothelial phenotype, focusing endothelial protein C receptor (EPCR). We demonstrate that the basal level of EPCR expression in cerebral microvessels is heterogeneous in the WM compared to the GM. We used in vitro brain endothelial cell cultures and showed that the upregulation of EPCR expression was associated with exposure to oligodendrocyte conditioned media (OCM) compared to astrocyte conditioned media (ACM). Our findings shed light on the origin of the heterogeneity of molecular phenotypes at the microvascular level and might help better understand the variation in pathology seen in CM and other neuropathologies associated with vasculature in various brain regions. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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Review

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13 pages, 579 KiB

Open AccessReview

The Cellular Dysfunction of the Brain–Blood Barrier from Endothelial Cells to Astrocytes: The Pathway towards Neurotransmitter Impairment in Schizophrenia

by Stefano Stanca, Martina Rossetti, Leona Bokulic Panichi and Paolo Bongioanni

Int. J. Mol. Sci. 2024, 25(2), 1250; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25021250 - 19 Jan 2024

Cited by 1 | Viewed by 961

Abstract

Schizophrenia (SCZ) is an articulated psychiatric syndrome characterized by a combination of genetic, epigenetic, and environmental factors. Our intention is to present a pathogenetic model combining SCZ alterations and the main cellular actors of the blood–brain barrier (BBB): endothelial cells (ECs), pericytes, and [...] Read more.

Schizophrenia (SCZ) is an articulated psychiatric syndrome characterized by a combination of genetic, epigenetic, and environmental factors. Our intention is to present a pathogenetic model combining SCZ alterations and the main cellular actors of the blood–brain barrier (BBB): endothelial cells (ECs), pericytes, and astrocytes. The homeostasis of the BBB is preserved by the neurovascular unit which is constituted by ECs, astrocytes and microglia, neurons, and the extracellular matrix. The role of the BBB is strictly linked to its ability to preserve the biochemical integrity of brain parenchyma integrity. In SCZ, there is an increased BBB permeability, demonstrated by elevated levels of albumin and immunoglobulins in the cerebrospinal fluid, and this is the result of an intrinsic endothelial impairment. Increased BBB permeability would lead to enhanced concentrations of neurotoxic and neuroactive molecules in the brain. The pathogenetic involvement of astrocytes in SCZ reverberates its consequences on BBB, together with the impact on its permeability and selectivity represented by the EC and pericyte damage occurring in the psychotic picture. Understanding the strict interaction between ECs and astrocytes, and its consequent impact on cognition, is diriment not only for comprehension of neurotransmitter dyshomeostasis in SCZ, but also for focusing on other potential therapeutic targets. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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24 pages, 2045 KiB

Open AccessReview

Astrocyte Involvement in Blood–Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions

by Doina Ramona Manu, Mark Slevin, Laura Barcutean, Timea Forro, Tudor Boghitoiu and Rodica Balasa

Int. J. Mol. Sci. 2023, 24(24), 17146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242417146 - 05 Dec 2023

Cited by 4 | Viewed by 1571

Abstract

Neurological disorders have been linked to a defective blood–brain barrier (BBB), with dysfunctions triggered by stage-specific disease mechanisms, some of these being generated through interactions in the neurovascular unit (NVU). Advanced knowledge of molecular and signaling mechanisms in the NVU and the emergence [...] Read more.

Neurological disorders have been linked to a defective blood–brain barrier (BBB), with dysfunctions triggered by stage-specific disease mechanisms, some of these being generated through interactions in the neurovascular unit (NVU). Advanced knowledge of molecular and signaling mechanisms in the NVU and the emergence of improved experimental models allow BBB permeability prediction and the development of new brain-targeted therapies. As NVU constituents, astrocytes are the most numerous glial cells, characterized by a heterogeneity that occurs as a result of developmental and context-based gene expression profiles and the differential expression of non-coding ribonucleic acids (RNAs). Due to their heterogeneity and dynamic responses to different signals, astrocytes may have a beneficial or detrimental role in the BBB’s barrier function, with deep effects on the pathophysiology of (and on the progression of) central nervous system diseases. The implication of astrocytic-derived extracellular vesicles in pathological mechanisms, due to their ability to pass the BBB, must also be considered. The molecular mechanisms of astrocytes’ interaction with endothelial cells at the BBB level are considered promising therapeutic targets in different neurological conditions. Nevertheless, a personalized and well-founded approach must be addressed, due to the temporal and spatial heterogeneity of reactive astrogliosis states during disease. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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17 pages, 992 KiB

Open AccessReview

Post-Ischemic Permeability of the Blood–Brain Barrier to Amyloid and Platelets as a Factor in the Maturation of Alzheimer’s Disease-Type Brain Neurodegeneration

by Ryszard Pluta, Barbara Miziak and Stanisław J. Czuczwar

Int. J. Mol. Sci. 2023, 24(13), 10739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310739 - 27 Jun 2023

Cited by 5 | Viewed by 1467

Abstract

The aim of this review is to present evidence of the impact of ischemic changes in the blood–brain barrier on the maturation of post-ischemic brain neurodegeneration with features of Alzheimer’s disease. Understanding the processes involved in the permeability of the post-ischemic blood–brain barrier [...] Read more.

The aim of this review is to present evidence of the impact of ischemic changes in the blood–brain barrier on the maturation of post-ischemic brain neurodegeneration with features of Alzheimer’s disease. Understanding the processes involved in the permeability of the post-ischemic blood–brain barrier during recirculation will provide clinically relevant knowledge regarding the neuropathological changes that ultimately lead to dementia of the Alzheimer’s disease type. In this review, we try to distinguish between primary and secondary neuropathological processes during and after ischemia. Therefore, we can observe two hit stages that contribute to Alzheimer’s disease development. The onset of ischemic brain pathology includes primary ischemic neuronal damage and death followed by the ischemic injury of the blood–brain barrier with serum leakage of amyloid into the brain tissue, leading to increased ischemic neuronal susceptibility to amyloid neurotoxicity, culminating in the formation of amyloid plaques and ending in full-blown dementia of the Alzheimer’s disease type. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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20 pages, 2739 KiB

Open AccessReview

Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood–Brain Barrier and the Risk of Dementia

by Mateusz Wątroba, Anna D. Grabowska and Dariusz Szukiewicz

Int. J. Mol. Sci. 2023, 24(12), 10069; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210069 - 13 Jun 2023

Cited by 9 | Viewed by 2318

Abstract

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood–brain barrier [...] Read more.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood–brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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16 pages, 1974 KiB

Open AccessReview

How Organ-on-a-Chip Technology Can Assist in Studying the Role of the Glymphatic System in Neurodegenerative Diseases

by Sarah Spitz, Eunkyung Ko, Peter Ertl and Roger D. Kamm

Int. J. Mol. Sci. 2023, 24(3), 2171; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032171 - 21 Jan 2023

Cited by 8 | Viewed by 3458

Abstract

The lack of a conventional lymphatic system that permeates throughout the entire human brain has encouraged the identification and study of alternative clearance routes within the cerebrum. In 2012, the concept of the glymphatic system, a perivascular network that fluidically connects the cerebrospinal [...] Read more.

The lack of a conventional lymphatic system that permeates throughout the entire human brain has encouraged the identification and study of alternative clearance routes within the cerebrum. In 2012, the concept of the glymphatic system, a perivascular network that fluidically connects the cerebrospinal fluid to the lymphatic vessels within the meninges via the interstitium, emerged. Although its exact mode of action has not yet been fully characterized, the key underlying processes that govern solute transport and waste clearance have been identified. This review briefly describes the perivascular glial-dependent clearance system and elucidates its fundamental role in neurodegenerative diseases. The current knowledge of the glymphatic system is based almost exclusively on animal-based measurements, but these face certain limitations inherent to in vivo experiments. Recent advances in organ-on-a-chip technology are discussed to demonstrate the technology’s ability to provide alternative human-based in vitro research models. Herein, the specific focus is on how current microfluidic-based in vitro models of the neurovascular system and neurodegenerative diseases might be employed to (i) gain a deeper understanding of the role and function of the glymphatic system and (ii) to identify new opportunities for pharmacological intervention. Full article

(This article belongs to the Special Issue Astrocyte-Endothelial Interactions at the Blood-Brain Barrier)

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