Blood-brain Barrier Integrity Research Articles

Regional dynamic cerebral autoregulation across anterior and posterior circulatory territories: A detailed exploration and its clinical implications.

Cerebral autoregulation (CA) is the mechanism that maintains stable cerebral blood flow (CBF) despite fluctuations in systemic blood pressure, crucial for brain homeostasis. Recent evidence highlights distinct regional variations in CA between the anterior (carotid) and posterior (vertebrobasilar) circulations. Non-invasive neuromonitoring techniques, such as transcranial Doppler, transfer function analysis, and near-infrared spectroscopy, facilitate the dynamic assessment of CBF and autoregulation. Studies indicate a robust autoregulatory capacity in the anterior circulation, characterized by rapid adjustments in vascular resistance. On the contrary, the posterior circulation, mainly supplied by the vertebral arteries, may have a lower autoregulatory capacity. in acute brain injuries such as intracerebral and subarachnoid hemorrhage, and traumatic brain injuries, dynamic CA can be significantly altered in the posterior circulation. Proposed physiological mechanisms of impaired CA in the posterior circulation include: (1) Decreased sympathetic innervation of the vasculature impairing compensatory vasoreactivity; (2) Endothelial dysfunction; (3) Increased cerebral metabolic rate of oxygen consumption within the visual cortex causing CBF-metabolism (i.e., neurovascular) uncoupling; and (4) Impaired blood-brain barrier integrity leading to impaired astrocytic mediated release of vasoactive substances (e.g. nitric oxide, potassium, and calcium ions). Furthermore, more research is needed on the effects of collateral circulation, as well as the circle of Willis variants, such as the fetal-type posterior cerebral artery, on dynamic CA. Improving our understanding of these mechanisms is crucial to improving the diagnosis, prognosis, and management of various cerebrovascular disorders.

Th22 cells promote the transition from homeostatic to reactive microglia in diabetic encephalopathy.

Diabetic encephalopathy (DE) is one of the most serious complications of diabetes mellitus (DM), and its pathogenesis has not yet been clarified. Th22 cells are a newly discovered class of CD4+ T cells that play important roles in inflammatory, autoimmune and infectious diseases. However, it is unclear whether Th22 cells are involved in the pathogenesis of DE. We established a T2DM mouse model in vivo and cocultured Th22 cells with microglia under high glucose (HG) conditions in vitro. Cognitive dysfunction was evaluated using the Morris water maze (MWM) test; blood‒brain barrier (BBB) integrity was evaluated using the Evans blue (EB) extravasation assay; Th22 cells and IL-22 receptors were detected by immunofluorescence; and IL-1β, TNF-α, iNOS, CD86, Arg-1, and CD206 protein expression was measured by Western Blot (WB) analysis. Th22 cells passed through the BBB into the hippocampus and secreted interleukin-22 (IL-22), and the mice subsequently exhibited decreased learning and memory abilities. In the DE model, IL-22 promoted the transformation of homeostatic microglia into reactive microglia as well as the inflammatory response. Additionally, coculture of Th22 cells with BV2 microglia cultured under HG conditions increased the production of proinflammatory cytokines, and the microglia showed reactive changes. Mechanistically, IL-22Rα1 acted as a ligand, and IL-22 bound to IL-22Rα1 on microglia to drive primary microglia-induced inflammatory responses. Interestingly, interleukin-22 binding protein (IL-22BP) directly binds to IL-22Rα1 on microglia to inhibit the proinflammatory effects of IL-22. Th22 cells secrete IL-22 after passing through the BBB into the hippocampus and promote the transformation of homeostatic microglia into reactive microglia, which induces an inflammatory response, exacerbates learning and memory impairment and cognitive deficits, and contributes to and accelerates the development of DE.

Genetic Mutations in Cell Junction Proteins Associated with Brain Calcification

AbstractIntracerebral calcium deposition, classified into primary familial brain calcification (PFBC) and secondary brain calcification, occurs within the brain parenchyma and vasculature. PFBC manifests with progressive motor decline, dysarthria, and cognitive impairment, with limited treatment options available. Recent research has suggested a link between dysfunction of the blood–brain barrier (BBB) and PFBC, with certain genetic variants potentially affecting neurovascular unit (NVU) function, thereby contributing to BBB integrity disruption and brain calcification. Cell junctions play an indispensable role in maintaining the function of NVUs. The pathogenic mechanisms of PFBC‐causative genes, such as PDGFRB, PDGFB, MYORG, and JAM2, involve NVU disruption. Cell junctions, such as tight junctions, gap junctions, adherens junctions, desmosomes, hemidesmosomes, and focal adhesions, are vital for cell–cell and cell–extracellular matrix connections, maintaining barrier function, cell adhesion, and facilitating ion and metabolite exchange. Several recent studies have highlighted the role of mutations in genes encoding cell junction proteins in the onset and progression of brain calcification and its related phenotypes. This emerging body of research offers a unique perspective for investigating the underlying mechanisms driving brain calcification. In this review, we conducted an examination of the literature reporting on genetic variants in cell junction proteins associated with brain calcification to delineate potential molecular pathways and investigate genotype–phenotype correlations. This approach not only reinforces the rationale for molecular subtyping of brain calcification but also lays the groundwork for the discovery of novel causative genes involved in pathogenesis. © 2024 International Parkinson and Movement Disorder Society.

The Role of Chitinase 3-Like-1 (YKL-40) and Proinflammatory Biomarkers in the Pathogenesis of Pediatric Tick-Borne Encephalitis in a Polish Cohort.

Chitinase 3-like-1 (CHI3L1), also known as YKL-40, is a potential biomarker for neuroinflammatory conditions. It is upregulated in Alzheimer's disease, multiple sclerosis, and traumatic brain injury. However, its involvement in pediatric tick-borne encephalitis (TBE) has not been addressed yet. This study aimed to evaluate CHI3L1 and its relationship with other inflammatory cytokines, blood-brain barrier (BBB) integrity, immune response, and disease severity in pediatric patients with TBE. A total of 22 pediatric TBE patients hospitalized in Bialystok, Poland were included in this study. Participants were categorized as having meningoencephalitis (n=6) or meningitis (n=16). The integrity of the brain-blood barrier (BBB) was assessed using the albumin quotient (albQ). Biomarker indices were calculated to account for variations in BBB permeability. The concentrations of CHI3L1, CCL2, chemerin, CXCL2, IFN-γ, IL-1-β, IL-4, IL-6, IL-13, and TNF-α in both serum and CSF, were measured using the Luminex Multiplex Assay od admission and two weeks later when symptoms resolved. CSF and serum concentrations of CHI3L1 did not differ between the encephalitis and meningitis cases. After adjusting for BBB permeability, the CHI3L1 index was 2.4-fold lower in patients with encephalitis than in those with meningitis (P=0.008). There was a post-treatment reduction of CHI3L1, IL-6, and TNF-α CSF concentrations. We also found and improvement in BBB permeability in younger children but in older albQ remained abnormal. Correlation analysis revealed associations between CHI3L1 levels and pro-inflammatory markers, notably chemerin, IL-6, and TNF-α, across both clinical groups. Our findings suggest that CHI3L1 CSF levels reflect the inflammatory activity in pediatric TBE and may help to differentiate between meningoencephalitis and meningitis. The observed interactions between CHI3L1 and other cytokines underscore its potential involvement in inflammatory response to the virus. The prolonged disruption in BBB integrity in older children might reflect age-dependent differences in the severity of TBE. These insights advance our understanding of TBE pathogenesis in children and support further investigation of CHI3L1 as a biomarker for TBE diagnosis and management.

Snake venom weakens neurovascular integrity and promotes vulnerability to neuroinflammation

Snake envenomation poses significant medical challenges, particularly in subtropical and tropical regions, with long-term impacts on neurovascular integrity and neuroinflammation remaining underexplored. This study investigates the effects of venom from four species of venomous snakes in southern China—Zhoushan Cobra (Naja atra, NA), Many-banded Krait (Bungarus multicinctus, BM), Five-paced Pit Viper (Deinagkistrodon acutus, DA), and Chinese Moccasin (Protobothrops mucrosquamatus, PM) — on the blood–brain barrier (BBB) and chronic neuroinflammation. Using mass spectrometry, we analyzed venom protein compositions, while cytotoxic effects on mouse brain endothelial cells (bEND.3) were evaluated to determine IC50 values. In vitro BBB models and in vivo experiments in C57BL/6J mice revealed that NA venom, in particular, significantly compromised BBB integrity without inducing large-scale apoptosis, leading to persistent BBB disruption characterized by increased permeability and selective degradation of extracellular matrix and tight junction proteins. Moreover, to simulate secondary infections that often occur following snakebites, we combined venom exposure with lipopolysaccharide (LPS) treatment, which exacerbated neuroinflammatory responses by intensifying microglial activation and promoting a pro-inflammatory phenotype. These findings highlight the role of snake venom in compromising neurovascular integrity and promoting vulnerability to chronic neuroinflammation, emphasizing the need for further research into venom-induced neuroinflammatory pathways and their potential as therapeutic targets.

RVG29-modified oncolytic herpes simplex virus for intracranial tumor treatment

Oncolytic virus therapy for brain tumors has achieved breakthrough progress in clinical applications, yet its potential is severely constrained by the mode of administration-direct intratumoral injection into the cranial cavity. Other administration routes face rapid clearance by neutralizing antibodies and obstacles posed by the blood-brain barrier. Herein, we engineered the oncolytic herpes simplex virus type 2 (OH2) with surface modifications of polyethylene glycol (PEG) and rabies virus glycoprotein 29 (RVG29, a BBB-penetrating peptide from the rabies virus), to form OH2-PEG-RVG. OH2-PEG-RVG could efficiently traversed the blood-brain barrier even in BALB/c mice with pre-existing anti-OH2 antibodies, leading to the accumulation of OH2 in the brain. More importantly, OH2-PEG-RVG maintained blood-brain barrier integrity without causing pathological changes or behavioral abnormalities in mice. Furthermore, OH2-PEG-RVG effectively inhibited brain tumor growth, transforming immunologically "cold" tumors into "hot" tumors, inducing a robust anti-tumor immune response, and prolonging the survival of the mice. These findings underscore the potential of OH2-PEG-RVG as a multifaceted therapeutic strategy for effective brain tumor treatment, offering insights into addressing blood-brain barrier limitations.

Exploring molecular mechanisms of postoperative delirium through multi-omics strategies in plasma exosomes

Currently, the diagnosis of delirium is solely based on clinical observation, lacking objective diagnostic tools, and the regulatory networks and pathological mechanisms behind it are not yet fully understood. Exosomes have garnered considerable interest as potential biomarkers for a variety of illnesses. This research aimed to delineate both the proteomic and metabolomic landscapes inherent to exosomes, assessing their diagnostic utility in postoperative delirium (POD) and understanding the underlying pathophysiological frameworks. Integrated analyses of proteomics and metabolomics were conducted on exosomes derived from plasma of individuals from both the non-postoperative delirium (NPOD) control group and the POD group. Subsequently, the study utilized the Connectivity Map (CMap) methodology for the identification of promising small-molecule drugs and carried out molecular docking assessments to explore the binding affinities with the enzyme MMP9 of these identified molecules. We identified significant differences in exosomal metabolites and proteins between the POD and control groups, highlighting pathways related to neuroinflammation and blood-brain barrier (BBB) integrity. Our CMap analysis identified potential small-molecule therapeutics, and molecular docking studies revealed two compounds with high affinity to MMP9, suggesting a new therapeutic avenue for POD. This study highlights MMP9, TLR2, ICAM1, S100B, and glutamate as key biomarkers in the pathophysiology of POD, emphasizing the roles of neuroinflammation and BBB integrity. Notably, molecular docking suggests mirin and orantinib as potential inhibitors targeting MMP9, providing new therapeutic avenues. The findings broaden our understanding of POD mechanisms and suggest targeted strategies for its management, reinforcing the importance of multidimensional biomarker analysis and molecular targeting in POD intervention.

Is there a link between peripheral inflammation and blood brain barrier integrity in children with attention-deficit/hyperactivity disorder? A case-control study.

Claudin-5 is a vital constituent of tight junctions, which are critical elements of the blood-brain barrier. In people with neuropsychiatric disorders, peripheral inflammation is often found, although it is less common in healthy populations. The objective of this study was to examine the relationship between Claudin-5, peripheral immune cells, and the severity of symptoms in children with attention deficit hyperactivity disorder (ADHD). The study included a cohort of 33 children diagnosed with ADHD and 29 control subjects, all aged between 5 and 12 years. The intensity of ADHD symptoms was evaluated using Conner's questionnaire, which the parents completed. Each kid had serum level measurements of Claudin-5 and a complete blood count in order to establish a correlation with symptoms of ADHD. Serum Claudin-5 levels are lower in the ADHD group compared to the control group; median (IQR) = 30.94 (4-137) and 44.12 (4-223.3) respectively (p = 0.69). The levels of neutrophils and neutrophil/lymphocyte ratio are significantly higher in ADHD than in controls (p = 0.011 and 0.015, respectively). Lymphocytes have a significant positive correlation with ADHD symptoms severity, namely, total Conner's scale and inattention (p = 0.021 and 0.004 respectively), while NLR has a significant negative correlation with total Conner's score and impulsivity (p = 0.046, p = 0.038), also a negative correlation yet not significant between serum Claudin-5 level and total Conner's score, hyperactivity, impulsivity, and inattention. Neutrophils were found to have a significant positive linear regression with Claudin-5 (p = 0.023). These results revealed that BBB integrity is affected in ADHD children, as claudin-5 levels were found to be lower in children with ADHD, lymphocytes were found to be associated with increased ADHD symptoms severity, and NLR was associated with decreased symptoms severity, which may be via the positive effects of increased neutrophils on Claudin-5 levels.

Pediatric Traumatic Brain Injury and Microvascular Blood-Brain Barrier Pathology

Pediatric traumatic brain injury (TBI) is a major cause of morbidity and mortality, with an increased risk of catastrophic outcome compared with adult TBI, including diffuse brain swelling and so-called second impact syndrome. Nevertheless, the biological substrates driving adverse outcomes in pediatric TBI remain poorly described. To compare neuropathological evidence of brain swelling and blood-brain barrier (BBB) disruption after moderate or severe acute TBI in adult vs pediatric case material. In this retrospective case series, cases of pediatric (aged 3-18 years) and adult (aged ≥19 years) TBI were accrued from January 1, 1979, to December 31, 2005, and underwent laboratory-based assessment of autopsy material from the Glasgow TBI Archive. Data analysis was performed from January 2019 to January 2024. Single moderate or severe TBI. Evaluation of representative brain tissue sections stained for markers of endothelia (CD34) and BBB integrity (fibrinogen and immunoglobin G). Eighty-one pediatric patients (mean [SD] age, 12.1 [4.6] years; 50 [62%] male) and 62 adult patients (mean [SD] age, 38.7 [12.9] years; 35 [56%] male) were studied. At autopsy, when present, brain swelling was more often diffuse and bilateral among pediatric patients (64 of 81 cases [83%]) when compared with adult patients (21 of 62 [34%]) (P < .001). Histologic evidence of BBB disruption was common in material from both adult (57 of 62 [91%]) and pediatric (65 of 81 [80%]) (P = .06) patients. In pediatric patients, however, this was a predominantly microvascular, capillary-level pathology, which was a less common finding in adult case material (mean [SD], 84.7% [8.6%] vs 31.2% [7.7%]; P < .001). This autopsy case series of patients dying in the acute phase after single moderate or severe TBI provides neuropathological evidence of age-dependent differences in vascular pathology. Specifically, although BBB disruption in pediatric material was typically confined to microvascular, capillary-level vessels, in adult case material, BBB disruption more typically involved larger-diameter vessels. This observation of distinct microvascular pathology in pediatric acute TBI requires further investigation. In the meantime, this study presents an intriguing potential candidate pathology contributing to diffuse brain swelling in this age group.

Retraction: Hyperglycemia via activation of thromboxane A2 receptor impairs the integrity and function of blood-brain barrier in microvascular endothelial cells.

Retraction: Hyperglycemia via activation of thromboxane A2 receptor impairs the integrity and function of blood-brain barrier in microvascular endothelial cells.

Angiotensin-II drives changes in microglia–vascular interactions in rats with heart failure

Activation of microglia, the resident immune cells of the central nervous system, leading to the subsequent release of pro-inflammatory cytokines, has been linked to cardiac remodeling, autonomic disbalance, and cognitive deficits in heart failure (HF). While previous studies emphasized the role of hippocampal Angiotensin II (AngII) signaling in HF-induced microglial activation, unanswered mechanistic questions persist. Evidence suggests significant interactions between microglia and local microvasculature, potentially affecting blood–brain barrier integrity and cerebral blood flow regulation. Still, whether the microglial-vascular interface is affected in the brain during HF remains unknown. Using a well-established ischemic HF rat model, we demonstrate the increased abundance of vessel-associated microglia (VAM) in HF rat hippocampi, along with an increased expression of AngII AT1a receptors. Acute AngII administration to sham rats induced microglia recruitment to brain capillaries, along with increased expression of TNFα. Conversely, administering an AT1aR blocker to HF rats prevented the recruitment of microglia to blood vessels, normalizing their levels to those in healthy rats. These results highlight the critical importance of a rather understudied phenomenon (i.e., microglia-vascular interactions in the brain) in the context of the pathophysiology of a highly prevalent cardiovascular disease, and unveil novel potential therapeutic avenues aimed at mitigating neuroinflammation in cardiovascular diseases.

A review on gut microbiota and miRNA crosstalk: implications for Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and progressive neuronal damage. Recent research has highlighted the significant roles of the gut microbiota and microRNAs (miRNAs) in the pathogenesis of AD. This review explores the intricate interaction between gut microbiota and miRNAs, emphasizing their combined impact on Alzheimer's progression. First, we discuss the bidirectional communication within the gut-brain axis and how gut dysbiosis contributes to neuroinflammation and neurodegeneration in AD. Changes in gut microbiota composition in Alzheimer's patients have been linked to inflammation, which exacerbates disease progression. Next, we delve into the biology of miRNAs, focusing on their roles in gene regulation, neurodevelopment, and neurodegeneration. Dysregulated miRNAs are implicated in AD pathogenesis, influencing key processes like inflammation, tau pathology, and amyloid deposition. We then examine how the gut microbiota modulates miRNA expression, particularly in the brain, potentially altering neuroinflammatory responses and synaptic plasticity. The interplay between gut microbiota and miRNAs also affects blood-brain barrier integrity, further contributing to Alzheimer's pathology. Lastly, we explore therapeutic strategies targeting this gut microbiota-miRNA axis, including probiotics, prebiotics, and dietary interventions, aiming to modulate miRNA expression and improve AD outcomes. While promising, challenges remain in fully elucidating these interactions and translating them into effective therapies. This review highlights the importance of understanding the gut microbiota-miRNA relationship in AD, offering potential pathways for novel therapeutic approaches aimed at mitigating the disease's progression.

Diacerein ameliorates thioacetamide-induced hepatic encephalopathy in rats via modulation of TLR4/AQP4/MMP-9 axis

Astrocyte swelling, blood brain barrier (BBB) dissipation and the subsequent brain edema are serious consequences of persistent hyperammonemia in hepatic encephalopathy (HE) in which if inadequately controlled it will lead to brain death. The current study highlights the potential neuroprotective effect of diacerein against thioacetamide (TAA)-induced HE in acute liver failure rat model. HE was induced in male Sprague–Dawley rats via I.P. injection of TAA (200 mg/kg) for three alternative times/week at 3rd week of the experiment. Diacerein (50 mg/kg) was gavaged for 14 days prior to induction of HE and for further 7 days together with TAA injection for an overall period of 21 days. Diacerein attenuated TAA-induced HE in acute liver failure rat model; as proofed by significant lowering of serum and brain ammonia concentrations, serum AST and ALT activities and significant attenuation of both brain and hepatic MDA contents and IL-1β with marked increases in GSH contents (P < 0.0001). The neuroprotective effect of diacerein was demonstrated by marked improvement of motor and cognitive deficits, brain histopathological changes; hallmarks of HE. As shown by immunohistochemical results, diacerein markedly downregulated brain TLR4 expression which in turn significantly increased the GFAP expression, and significantly decreased AQP4 expression; the astrocytes swelling biomarkers (P < 0.0001). Moreover, diacerein preserved BBB integrity via downregulation of MMP-9 mediated digestion of tight junction proteins such as occludin (P < 0.0001). Collectively, diacerein ameliorated cerebral edema and maintained BBB integrity via modulation of TLR4/AQP4/MMP-9 axis thus may decrease the progression of HE induced in acute liver failure.

Effects of 1800MHz and 2100MHz mobile phone radiation on the blood-brain barrier of New Zealand rabbits.

In this study, the impact of mobile phone radiation on blood-brain barrier (BBB) permeability was investigated. A total of 21 New Zealand rabbits were used for the experiments, divided into three groups, each consisting of 7 rabbits. One group served as the control, while the other two were exposed to electromagnetic radiation at frequencies of 1800MHz with a distance of 14.5cm and 2100MHz with a distance of 17cm, maintaining a constant power intensity of 15 dBm, for a duration equivalent to the current average daily conversation time of 38min. The exposure was conducted under non-thermal conditions, with RF radiation levels approximately ten times lower than normal values. Evans blue (EB) dye was used as a marker to assess BBB permeability. EB binds to plasma proteins, and its presence in brain tissue indicates a disruption in BBB integrity, allowing for a quantitative evaluation of radiation-induced permeability changes. Left and right brain tissue samples were analyzed using trichloroacetic acid (TCA) and phosphate-buffered solution (PBS) solutions to measure EB amounts at 620nm via spectrophotometry. After the experiments, BBB tissue samples were collected from the right and left brains of all rabbits in the three groups and subjected to a series of medical procedures. Samples from Group 1 were compared with those from Group 2 and Group 3 using statistical methods to determine if there were any significant differences. As a result, it was found that there was no statistically significant difference in the BBB of rabbits exposed to 1800MHz radiation, whereas there was a statistically significant difference at a 95% confidence level in the BBB of rabbits exposed to 2100MHz radiation. A decrease in EB values was observed upon the arithmetic examination of the BBB.

Inhibition of PCSK9 Protects against Cerebral Ischemia‒Reperfusion Injury via Attenuating Microcirculatory Dysfunction.

Proprotein convertase substilin/kexin type 9 (PCSK9), a pivotal protein regulating lipid metabolism, has been implicated in promoting microthrombotic formation and inflammatory cascades, thereby contributing to cardiovascular ischemia/reperfusion (I/R) injury. However, its involvement in cerebral I/R injury and its potential role in microcirculation protection remain unexplored. In this investigation, we utilized a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate ischemic stroke. Different concentrations of evolocumab (1, 5, 10mg/kg, i.v.), a PCSK9 inhibitor, were administered to assess its impact. Immunofluorescence staining was employed to analyze changes in the expression of occludin, claudin-5, thrombocyte, ICAM-1, VCAM-1, and CD45, providing insights into blood-brain barrier integrity, platelet adhesion, and immune cell infiltration. Moreover, the Morris water maze and elevated plus maze were utilized to evaluate neurological and behavioral functions in MCAO/R mice, shedding light on the effects of PCSK9 inhibition. Our findings revealed a surge in plasma PCSK9 levels post-MCAO/R, peaking at 24h post-reperfusion. Evolocumab (10mg/kg) treatment significantly mitigated brain infarction and neurological deficits, evidenced by enhanced locomotor function and reduced post-stroke anxiety. However, it did not ameliorate cognitive impairment following MCAO/R. Additionally, evolocumab administration led to diminished leakage of evans blue solution and upregulated expression of occludin and claudin-5. Thrombocyte, ICAM-1, VCAM-1, and CD45 levels were notably reduced in the penumbral area post-evolocumab treatment. These protective effects are speculated to be mediated through the inhibition of the ERK/NF-κB pathway. The PCSK9 inhibitor evolocumab holds promise as a therapeutic agent during the acute phase of stroke, exerting its beneficial effects by modulating the ERK/NF-κB signaling pathway.

The Role of Microglia and Astrocytes in the Pathomechanism of Neuroinflammation in Parkinson's Disease-Focus on Alpha-Synuclein.

Glial cells, including astrocytes and microglia, are pivotal in maintaining central nervous system (CNS) homeostasis and responding to pathological insults. This review elucidates the complex immunomodulatory functions of glial cells, with a particular focus on their involvement in inflammation cascades initiated by the accumulation of alpha-synuclein (α-syn), a hallmark of Parkinson's disease (PD). Deriving insights from studies on both sporadic and familial forms of PD, as well as animal models of PD, we explore how glial cells contribute to the progression of inflammation triggered by α-syn aggregation. Additionally, we analyze the interplay between glial cells and the blood-brain barrier (BBB), highlighting the role of these cells in maintaining BBB integrity and permeability in the context of PD pathology. Furthermore, we delve into the potential activation of repair and neuroprotective mechanisms mediated by glial cells amidst α-syn-induced neuroinflammation. By integrating information on sporadic and familial PD, as well as BBB dynamics, this review aims to deepen our understanding of the multifaceted interactions between glial cells, α-syn pathology, and CNS inflammation, thereby offering valuable insights into therapeutic strategies for PD and related neurodegenerative disorders.

Optimization of Transcardiac Perfusion for More Accurately Evaluating Biodistribution of Large Molecules.

The accurate assessment of drug concentrations in biodistribution studies is crucial for evaluating the efficacy and toxicity of compounds in drug development. As the concentration of biologics in plasma can be higher than in tissue due to their potentially low volume of distribution, transcardiac perfusion is commonly employed to reduce the influence of excess drugs in residual blood. However, there is a lack of consistency in the literature on the conditions and methods of perfusion. To enhance blood removal during transcardiac perfusion, sodium nitrite (NaNO2), a vasodilator, has been widely used with concentrations up to 5% in publications. However, we found that such high NaNO2 could disrupt the BBB during perfusion, which should be avoided in experiments. In this study, we examined the impact of various vasodilators on blood-brain barrier integrity and vascular permeability using the ratio of FITC-Dextran to Texas Red-Dextran (FITC/Texas Red). Additionally, we optimized perfusion conditions-including euthanasia method and perfusion flow rate-based on hemoglobin levels and the FITC/Texas Red ratio in tissues. Despite the superiority of NaNO2 in terms of solubility and cost over other vasodilators, we found that 2% NaNO2 disrupted blood-brain barrier integrity, significantly altering the FITC/Texas Red ratio. In contrast, 100 mM NaNO2 did not significantly affect this ratio. Moreover, under Ketamine/Xylazine (Ket/Xyl) anesthesia, which reduced blood clot formation compared to CO2 euthanasia, 100 mM NaNO2 achieved the lowest hemoglobin levels in the brain. Compared to other vasodilators and the PBS control group, 100 mM NaNO2 decreased the tissue/plasma ratio (Kp,t) but not brain/plasma ratio (Kp,b) of hIgG1 and human transferrin. We have developed a method to efficiently evaluate blood-brain barrier integrity during transcardiac perfusion. The combination of Ket/Xyl anesthesia and 100 mM NaNO2 effectively removes residual blood from tissues without significantly affecting blood vessel permeability.

Exercise rescues cognitive impairment through inhibiting the fibrinogen neuroinflammative pathway in diabetes.

Fibrinogen is a pivotal factor in the activation of neuroinflammation and cognitive impairment. While exercise, especifically swimming, has demonstrated cognitive benefits, the molecular protective mechanisms orchestrated by exercise in response to blood-brain barrier (BBB) leakage in diabetes remain elusive. This study systematically investigates the impact of fibrinogen on neuroinflammation and the role of exercise in diabetic rats. Diabetic rats underwent an 8-week swimming exercise regimen, and subsequent assessments included changes in interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), astroglia activation, BBB permeability, and key epithelial tight junction proteins such as zona occludins (ZO)-1, Claudin-5, and matrix metalloproteinase-9 (MMP-9). Spatial learning and memory were evaluated using the Morris water maze test and the novel object recognition test. The study revealed that exercise significantly improved cognitive function, potentially by suppressing fibrinogen levels and astroglia activation. Intriguingly, heightened fibrinogen expression markedly attenuated the protective effects of exercise on BBB integrity. Fibrinogen emerged as a potential compromise to exercise protective effect by increasing expression levels of inflammatory factors IL-1β and TNF-α. In summary, our findings elucidate that fibrinogen may contribute to the deterioration of cognition and diminish the protective effects of exercise by amplifying the neuroinflammatory process through damaged BBB in diabetes.

Intergenerational crosstalk of brain-gut axis in parental Nd2O3 exposure-induced offspring neurotoxicity and cognitive dysfunction: a mechanistic study.

Rare earth elements (REEs) are widely used in plenty of fields. REEs have significant neurotoxicity and it may adversely affect the development of cognitive. For example, neodymium will causing neurological damage through penetrate the blood-brain barrier (BBB). However, whether it disrupts the balance of brain-gut axis (BGA) crosstalk and affects the intestinal microecology disorder of host is still unclear. This study investigated the neural damage on children caused by maternal exposure to Neodymium oxide (Nd2O3) during pregnancy, and its involved mechanism of BGA injury. We used rat model to investigated the mechanisms of the offspring's neural damage that Nd2O3 exposure in pregnancy. To verify the neural damage of offspring rats, we examed BBB-related factors, such like glutamate and ROS levels in brain tissue, behavioral tests, hippocampal and cortical damage, as well as changes in gut microbiota, intestinal mucosal barrier, and SCFAs in the intestine. Also, we observed some specific indicators of intestinal immune barrier function and gut nerve-related indicators. Maternal Nd2O3 exposure reduced the content of offspring tight junction proteins, increased BBB permeability, leading to Nd accumulation and brain tissue inflammation, affecting offspring's neural development and weakening their spatial learning ability. Nd2O3 also disrupted BBB integrity by regulating SCFAs and BGA. Probiotic intervention in the offspring rats exposed to 2% Nd2O3 showed significant recovery of inflammation in both brain and colon tissues, and reduced BBB permeability. Maternal exposure to Nd2O3 affects the offspring's BGA, targeting brain and colon tissues, increasing BBB permeability, affecting neural development, causing damage to the intestinal mucosa, and impacting children's gut development. Probiotics can alleviate these effects. These findings provide valuable insights into understanding the neurodevelopmental and intestinal developmental toxicity of Nd2O3 and its prevention and treatment. It also calls for a comprehensive assessment of the health risks of susceptible populations to Nd2O3, such as pregnant women. It may providing theoretical basis for preventing and controlling neodymium-induced harm in children by examing the repair mechanism of the damage through probiotic intervention.

The role of histohematologic barriers and the possibility of using polarization biomedical optics methods in the diagnosis of autoimmune thyroiditis

Background. Violation of the integrity of the histohematologic barriers (blood-brain, blood-testis, blood-ocular, blood-labyrinth, blood-thyroid) leads to autoimmune damage to these organs. One of the manifestations of the latter is autoimmune thyroiditis, the structural and quantitative changes of which can be more informatively accurately assessed by polarization biomedical optics. The purpose of the study was to substantiate the possibility of using polarization biomedical optics methods in the diagnosis of autoimmune thyroiditis based on the use of pathophysiological analysis of blood-brain barrier integrity disorders. Materials and methods. Two groups of patients were studied: control group 1 — healthy donors (n = 51), study group 2 — people with autoimmune thyroiditis (n = 51) who underwent a puncture biopsy of the thyroid gland for diagnostic purposes. Instrumental laser methods were used: polarization, interference, multifractal. The statistical parameters of polarization ellipticity maps, polarization ellipticity of phase and multifractal spectra of digital microscopic images of native thyroid histological sections in patients with autoimmune thyroiditis were quantified: mean, dispersion, asymmetry, and kurtosis. The probability of differences compared to the controls, taken as 100 %, was evaluated using the Student’s parametric test (p &lt; 0.05). Results. A significant increase in the mean and variance at inhibition of the asymmetry and kurtosis of polarization ellipticity, as well as in the mean and variance at reduction of the asymmetry and kurtosis of polarization ellipticity of phase digital microscopic images of thyroid native histological sections was revealed. There were a significant increase in dispersion and a decrease in the asymmetry and kurtosis of multifractal spectra of polarization ellipticity maps of digital microscopic images of native histological sections. Conclusions. A significant increase in the biophysical optical parameters of digital microscopic images of thyroid native histological sections from patients with autoimmune thyroiditis was found due to the growth of connective tissue in the interstitium as a result of an autoimmune inflammation. There was a significant inhibition of the asymmetry and kurtosis of the ellipticity of polarization of phase digital and multifractal spectra of polarization ellipticity maps of microscopic images of native histological sections in patients with autoimmune thyroiditis due to a decrease in the amount of colloids as a crystalline component caused by damage to the blood-thyroid barrier.