Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview

Pharmaceutics, Journal Year: 2021, Volume and Issue: 13(11), P. 1779 - 1779

Published: Oct. 26, 2021

The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity vital to maintain homeostasis brain microenvironment by controlling passage substances regulating trafficking immune cells between blood brain. BBB primarily composed highly specialized microvascular endothelial cells. These cells' special features physiological properties are acquired maintained through concerted effort hemodynamic cellular cues from surrounding environment. This complex multicellular system, comprising cells, astrocytes, pericytes, neurons, known as neurovascular unit (NVU). strictly controls transport nutrients metabolites into parenchyma tightly regulated while limiting access potentially harmful via efflux transcytosis metabolic mechanisms. Not surprisingly, disruption has been associated with onset and/or progression major neurological disorders. Although association disease clear, its nature not always evident, specifically regard whether an impaired function results pathological condition or damage primary pathogenic factor prodromal disease. In either case, repairing could be viable option for treating reducing effects CNS this review, we describe structure in both healthy altered/diseased conditions. Additionally, provide overview potential therapeutic targets that leveraged restore concomitant treatment these

Language: Английский

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Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 26, 2022

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection central nervous system or structural brain damage. Microglia are thought to be macrophages system, devouring bits neuronal cells and dead brain. They activated various ways, microglia-mediated neuroinflammation characteristic diseases, including SAE. Here, we systematically described pathogenesis SAE demonstrated microglia closely related occurrence development Furthermore, comprehensively discussed function phenotype summarized their activation mechanism role pathogenesis. Finally, this review summarizes recent studies on treating by blocking microglial toxic factors produced after activation. We suggest targeting may putative treatment for

Language: Английский

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Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs)

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(16), P. 9274 - 9274

Published: Aug. 17, 2022

The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity mortality. Despite an improvement in understanding physiological pathological mechanisms underlying its genesis growing number studies exploring even higher range targeted therapies, no significant clinical progress has emerged past decade. In this context, mesenchymal stem cells (MSCs) appear more as attractive approach for cell therapy both experimental models. Pre-clinical data suggest cornerstone role these their secretome control host immune response. Host-derived factors released from infected (i.e., alarmins, HMGB1, ATP, DNA) well pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located parenchyma around vessels upregulate expression cytokines/chemokines growth that influence, respectively, recruitment mobilization. However, way which exert beneficial effects terms survival inflammation states unclear. This review presents interactions identified between mediators immunity tissue repair sepsis. We also propose paradigms related plausible roles process shock. Finally, we offer presentation open innovative avenues research involving prognostic, diagnostic, therapeutic point view

Language: Английский

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Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-α/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 9, 2023

This study aimed to explore the protective roles of malvidin in life-threatened sepsis-associated encephalopathy (SAE) and illustrate underlying mechanism. SAE mice models were developed treated with for subsequently effects evaluation. Malvidin restored neurobehavioral retardation, declined serum S100β NSE levels, sustained cerebrum morphological structure, improved blood-brain barrier integrity elevated tight junction proteins, decreased evans blue leakage, finally protect from brain injury. Mechanistically, prevented mitochondrial dysfunction enhanced JC-1 aggregates ATP ROS accumulation lipid peroxidation increased antioxidant enzymes. UCP2 protein levels found be after LPS stimulation BV-2 cells, recovered its a dependent manner. In vivo inhibition genipin or vitro interference siRNA both disrupted membrane potential, intensified DCF signals, being key target malvidin. Moreover, dorsomorphin block assays verified that upregulated expression through phosphorylating AMPK models. Also, alleviated progression ROS-dependent NLRP3 inflammasome activation mediated pro-inflammatory cytokines secretion pathway apoptosis weakened body formation tunel positive Bax, cytochrome C, caspase-3 Bcl-2 levels. Overall, this illustrated targeted AMPK-α/UCP2 axis restore LPS-induced alleviate accumulation, which further inhibits way, ultimately protected mice, providing reference development prophylactic approach.

Language: Английский

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Puerarin protects against sepsis-associated encephalopathy by inhibiting NLRP3/Caspase-1/GSDMD pyroptosis pathway and reducing blood-brain barrier damage

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 945, P. 175616 - 175616

Published: Feb. 28, 2023

Puerarin (Pue), an isoflavone compound extracted from Pueraria, has been shown to inhibit inflammation and reduce cerebral edema. The neuroprotective effect of puerarin attracted much attention in recent years. Sepsis-associated encephalopathy (SAE) is a serious complication sepsis that causes damage the nervous system. This study aimed investigate on SAE elucidate potential underlying mechanisms. A rat model was established by cecal ligation puncture, injected intraperitoneally immediately after operation. found improve survival rate neurobehavioral score rats, alleviate symptoms, level brain injury markers NSE S100β, pathological changes tissue. also factors related classical pathway pyroptosis, such as NLRP3, Caspase-1, GSDMD, ASC, IL-1β, IL-18. reduced water content penetration Evan's Blue dye expression MMP-9. In vitro experiments, we further confirmed inhibitory neuronal pyroptosis establishing HT22 cells. Our findings suggest may inhibiting NLRP3/Caspase-1/GSDMD-mediated reducing blood-brain barrier damage, thus playing role protection. provide novel therapeutic strategy for SAE.

Language: Английский

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Molecular mechanism of METTL3 regulating hippocampal neuronal injury induced by sepsis-associated encephalopathy

Archives of Physiology and Biochemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 11

Published: March 2, 2025

Objective: This study explores the mechanism of methyltransferase like 3 (METTL3) on sepsis-associated encephalopathy (SAE)-induced hippocampal neuronal injury.

Language: Английский

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Mast cell activation mediates blood–brain barrier impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 1, 2023

Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction resulting from systemic inflammatory response to infection; however, its pathophysiology remains unclear. Sepsis-induced neuroinflammation and blood-brain barrier (BBB) disruption are crucial factors in brain function disturbance SAE. Mast cells (MCs) activation plays an important role several models; SAE has not been comprehensively investigated.We first established model by cecal ligation puncture (CLP) surgery checked the of MCs. MCs was using immumohistochemical staining Toluidine Blue staining. We administrated cromolyn (10mg/ml), MC stabilizer, rescue septic mice. Brain cytokines levels were measured biochemical assays. BBB assessed measuring key tight-junction (TJ) proteins. Cognitive mice analyzed Y maze open field test. Transwell cultures microvascular endothelial (BMVECs) co-cultured with used assess interaction BMVECs MCs.Results showed that overactivated hippocampus CLP-induced Cromolyn intracerebroventricular (i.c.v) injection substantially inhibited responses, ameliorated impairment, improved survival rate alleviated cognitive In vitro experiments, we revealed increased sensitivity against lipopolysaccharide (LPS) challenge. Furthermore, found histamine/histamine 1 receptor (H1R) mediated between BMVECs, amplifies LPS-induced responses modulating TLR2/4-MAPK signaling pathway.MCs could mediate impairment histamine-dependent pathway.

Language: Английский

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TRIM45 aggravates microglia pyroptosis via Atg5/NLRP3 axis in septic encephalopathy

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Nov. 30, 2023

Neuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 associated with tumours and inflammatory diseases. However, the role in SAE relationship between are unknown. In this study, we found played regulating molecular mechanism.SAE was induced intraperitoneal injection LPS WT AAV-shTRIM45 mice. BV2 cells were treated LPS/ATP vitro. Cognitive function assessed Morris water maze. Nissl staining used to evaluate histological structural lesions. ELISA dectect neuroinflammation. qPCR detect mRNA levels cytokines, NLRP3, autophagy genes. Western blotting immunofluorescence analysis analyse expression proteins. Changes reactive oxygen species (ROS) observed flow cytometry. mitochondrial membrane potential detected JC-1 staining. Peripheral blood mononuclear extracted from density gradient centrifugation then for qPCR, western detection. To further explore mechanism, overexpression plasmids Atg5 as well siRNA-TRIM45 siRNA-Atg5 downstream pathway NLRP3. The protein peripheral sepsis patients examined.Knocking down protected against neuronal damage cognitive impairment knockdown inhibited secretion cytokines vivo vitro, which NLRP3/Gsdmd-N activation. Overexpression could activate NLRP3 Further examination showed regulated activation altering autophagic flux. also affected changes ROS potential. Thus, knocking reduce pyroptosis, proinflammatory improve function. addition, level increased. There a positive linear correlation APACHE II score TRIM45, SOFA TRIM45. Compared group GCS > 9, increased ≤ 8.TRIM45 plays key neuroinflammation caused LPS, may involve TRIM45-mediated exacerbation via Atg5/NLRP3 axis.

Language: Английский

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Integrating single-nucleus RNA sequencing and spatial transcriptomics to elucidate a specialized subpopulation of astrocytes, microglia and vascular cells in brains of mouse model of lipopolysaccharide-induced sepsis-associated encephalopathy

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: July 3, 2024

Abstract Background Understanding the mechanism behind sepsis-associated encephalopathy (SAE) remains a formidable task. This study endeavors to shed light on complex cellular and molecular alterations that occur in brains of mouse model with SAE, ultimately unraveling underlying mechanisms this condition. Methods We established murine using intraperitoneal injection lipopolysaccharide (LPS) wild type Anxa1 −/− mice collected brain tissues for analysis at 0-hour, 12-hour, 24-hour, 72-hour post-injection. Utilizing advanced techniques such as single-nucleus RNA sequencing (snRNA-seq) Stereo-seq, we conducted comprehensive characterization responses patterns within brain. Results Our uncovered notable temporal differences response LPS challenge between (annexin A1 knockout) mice, specifically 12-hour 24-hour time points following injection. observed significant increase proportion Astro-2 Micro-2 cells these mice. These exhibited colocalization pattern vascular subtype Vas-1, forming distinct region known V1A2M2, where surrounded Vas-1. Moreover, through further analysis, discovered upregulation ligands receptors Timp1-Cd63 , Timp1-Itgb1 Timp1-Lrp1 well Ccl2-Ackr1 Cxcl2-Ackr1 region. In addition, expression Cd14-Itgb1 Cd14-Tlr2 Cd14-C3ar1 regions enriched cells. Additionally, Cxcl10-Sdc4 showed broad containing both Notably, upon challenge, there was an Furthermore, our revealed noteworthy mortality rates knockdown. However, did not observe substantial types, numbers, or distribution other wildtype over time. Nevertheless, when comparing post point, decrease vicinity blood vessels noted reduced levels several ligand-receptor pairs including . Conclusions By combining snRNA-seq Stereo-seq techniques, successfully identified distinctive colocalization, referred special pathological niche, comprising Astro-2, Micro-2, Vas-1 niche. findings suggest potential association arrangement contributing SAE increased knockdown

Language: Английский

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Enhanced meningeal lymphatic drainage ameliorates lipopolysaccharide-induced brain injury in aged mice

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Jan. 30, 2024

Abstract Background Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction caused by sepsis. Neuroinflammation induced sepsis considered a potential mechanism of SAE; however, very little known about the role meningeal lymphatic system in SAE. Methods Sepsis was established male C57BL/6J mice intraperitoneal injection 5 mg/kg lipopolysaccharide, and function drainage assessed. Adeno-associated virus 1-vascular endothelial growth factor C (AAV1-VEGF-C) injected into cisterna magna to induce lymphangiogenesis. Ligation deep cervical lymph nodes (dCLNs) performed pre-existing dysfunction. Cognitive evaluated fear conditioning test, inflammatory factors were detected enzyme-linked immunosorbent assay. Results The aged with SAE showed significant decrease OVA-647 dCLNs coverage Lyve-1 lymphatic, indicating that impaired morphology. more vulnerable comparison young mice. also decreased protein levels caspase-3 PSD95, which accompanied reductions activity hippocampal neurons. Microglia significantly activated hippocampus mice, increase neuroinflammation, as indicated increases interleukin-1 beta, interleukin-6 Iba1 expression. However, AAV1-VEGF-C increased tracer dye uptake dCLNs, suggesting promotes lymphangiogenesis drainage. Furthermore, reduced microglial activation neuroinflammation improved cognitive Improvement lymphatics sepsis-induced expression disease-associated genes Pre-existing ligating bilateral aggravated impairment. Conclusion damaged sepsis, defects this exacerbate SAE-induced Promoting improves Manipulation could be new strategy for treatment

Language: Английский

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