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At least 19 recordsLinked to original sources
PubMed1988

Observations on exsudation of fibronectin, fibrinogen and albumin in the brain after carotid infusion of hyperosmolar solutions. An immunohistochemical study in the rat indicating longlasting changes in the brain microenvironment and multifocal nerve cell injuries.

An immunohistochemical study was carried out on rat brain to determine if a transient opening of the blood-brain barrier (BBB), leading to extravasation of serum albumin, is also associated with exudation and cellular uptake of fibronectin and fibrinogen. Both of them might exert important biological effects provided that they pass the BBB and come into contact with cells of the brain parenchyma. Hyperosmolar solutions of urea or mannitol were infused in the carotid artery for 30 s to open the BBB and the animals were killed at various time intervals thereafter. Formaldehyde-fixed, paraffin-embedded material was used for immunohistochemical demonstration of extravasated proteins by an avidin-biotin peroxidase technique. Multifocal, often confluent areas of widely different sizes with signs of albumin extravasation were observed both in the grey and the white matter of the cerebral hemispheres exposed to the hyperosmolar solutions. Much less pronounced changes were observed in rats given an intracarotid saline infusion alone. Immunoreactive material indicating extravasation of fibronectin and fibrinogen was present in the infused cerebral hemispheres but albumin immunoreactivity was much more widespread. Reaction product was observed in vascular walls, presumably in extracellular spaces and in nerve cells. Immunoreactivity in the perikaryon of neurons formed different patterns in various cells. A granular type most probably represents accumulation of the proteins in lysosomal organelles after pinocytotic uptake into the neuron. The second so-called diffuse variety is presumably the result of a severe nerve cell injury with an uncontrolled leakage of proteins into the cytoplasm. Our results indicate that vascular walls, extracellular spaces, glial cells and neurons will be exposed to extravasated fibronectin and fibrinogen as well as to albumin and that antigenic sites in such compounds remain for a long period after the BBB opening. In addition, there are indications that carotid infusions of hyperosmolar solutions may cause nerve cell injuries in regions with BBB opening. These findings have obvious clinical and experimental significance.

Animals↗
PubMed2025

Effect of acupuncture on brain microenvironment in rats with post-stroke limb spasticity based on single-cell transcriptome sequencing technology.

OBJECTIVE: To investigate the possible mechanisms by which acupuncture improves post-stroke limb spasticity using single-cell sequencing technology. METHODS: Thirty-two rats were randomly assigned to four groups: Control, Sham, Model, and Acupuncture. The middle cerebral artery occlusion (MCAO) model was established, and the acupuncture groups received acupuncture treatment. After treatment, brain morphological changes and the degree of neurological impairment were assessed. The effect of acupuncture on the proportion of brain cell types in the ischemic penumbra of MCAO rats was analyzed using single-cell transcriptomics, and the expression and enrichment of differentially expressed genes were examined. Finally, selected differential genes were validated by Western blot and quantitative real-time polymerase chain reaction. RESULTS: Triphenyltetrazolium chloride staining showed that the infarct area in MCAO rats was significantly reduced after acupuncture. Garcia scoring, hematoxylin-eosin staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling demonstrated that acupuncture reduced brain damage. Enzyme-linked immunosorbent assay results showed that acupuncture significantly decreased serum inflammatory factors, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Single-cell transcriptome analysis revealed marked changes in cell type proportions between the Acupuncture and Model groups. A total of 207 differential genes were identified, including 157 upregulated and 50 downregulated genes. Analysis of macrophage-specific differential genes in the ischemic penumbra showed enrichment in Gene Ontology terms such as Ras protein signal transduction and regulation of GTPase activity, and Kyoto Encyclopedia of Genes and Genomes pathways including lysosome, axon guidance, and mitogen-activated protein kinase signaling. S100a8 and leukocyte specific transcript 1 (LST1) were identified as key differential genes. CONCLUSION: These findings suggest that the key differential genes S100a8 and LST1 may alleviate post-stroke limb spasticity by regulating the inflammatory response in the ischemic penumbra.

Animals↗
PubMed1977

Calcium modulation in brain extracellular microenvironment demonstrated with ion-selective micropipette.

Changes in extracellular Ca2+ concentration were directly measured in the rat cerebellum, using an ion-selective micropipette. Extracellular K+ was measured simultaneously with a second ion-selective micropipette. The potential reference barrels of the ion electrodes also provided fast field and slow potentials. During repetitive stimulation of the parallel fiber--Purkinje cell cerebellar circuit, extracellular Ca2+ fell to about 80% of base line concentration. During the spreading depression of Leão, extracellular Ca2+ fell to about 10% of base line; decreases of this magnitude also occurred during terminal anoxia. In all cases extracellular K+ increased substantially. These results show that extracellular Ca2+ is modulated during neuronal activity in the central nervous system and that under some conditions the Ca2+ change can be extreme. Given the well-established and antagonistic effects of reduce extracellular Ca2+ on axonal excitability and synaptic transmission, these results suggest that Ca2+ modulation in the brain cell microenvironment may be a significant parameter in the behavior of neuronal ensembles.

Animals↗
PubMed1987

Calcium diffusion in the brain cell microenvironment.

A review of some of the literature on Ca2+ diffusion in free media and a variety of nervous tissues is presented. In the majority of tissue studies the apparent diffusion coefficient of Ca2+ is three to nine times smaller than that in a free aqueous medium. The methodology of using pressure microejection and Ca2+ ion-selective microelectrodes to measure Ca2+ diffusion is discussed. Our ongoing studies of Ca2+ diffusion in the cerebral cortex of the rat, using these methods, also confirm that Ca2+ diffusion is mainly influenced by the tortuosity of the tissue rather than other factors such as binding to extracellular charge sites or uptake.

Animals↗
PubMed1986

Dynamic variations of the brain cell microenvironment in relation to neuronal hyperactivity.

Neuronal hyperactivity has been shown to cause transient changes in ionic concentrations as well as in the volume of the extracellular space (ECS). During enhanced neuronal activity in the sensorimotor cortex of the cat, increases in the extracellular K+ concentration to a ceiling value of 10 mM have been observed concomitant with decreases in the Na+ concentration of similar magnitude. Simultaneously, the Cl- concentration rose steadily during the enhanced neuronal activity, and the extracellular space decreased by about 30%. A mathematical model allowed the interpretation of these concentration and volume changes as results of K+ release by active neurons in exchange for Na+, removal of K+ from the ECS by spatial glial buffering and movements of KCl into glial cells, as well as cell swelling due to metabolically induced transient increases in cellular osmolarity. Similar mechanisms have also been found to operate in gliotic scar tissue, where glial cells appeared to function the same way as in normal cortex, in rat hippocampal slices, and in preparations studied by other investigators.

Animals↗
PubMed1987

Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect.

The form and function of blood vessels are determined by the cells that constitute their microenvironment. Brain tissue around tumors contains varying numbers of tumor cells that could influence local capillaries to lose their blood-brain barrier (BBB), as they do in the tumor itself. Microvascular permeability cannot be measured directly in humans but can be inferred from a knowledge of vessel ultrastructure. The authors have examined the vascular ultrastructure associated with the BBB in human peritumoral brain tissue for evidence of BBB compromise and to correlate BBB features with the cellular components of the vessel microenvironment. Light microscopic examination of brain tissue samples in patients with primary brain tumors showed that the tissue lying beyond the visible edge of the tumor ranged from essentially normal to grossly infiltrated with tumor cells. Although some of the vessels were structurally normal, the microvessels as a group had elongated junctional clefts (unfused regions) and an increase in the density of endothelial vesicles. Furthermore, the cleft index (the percentage of the junctional profile that is unfused) varied directly with the local cell density. A subpopulation of vessels enveloped by a layer of tumor cells was grossly abnormal. However, vessels that were not immediately invested by tumor cells also showed some abnormalities. It is concluded that tumor cells infiltrating peritumoral brain tissue cause blood vessels to take on some of the structural characteristics of leaky vessels. Since direct contact is not required, and since the degree of abnormality correlates with the number of tumor cells in the environment, the authors suggest that this inductive influence is exerted over a distance and is dependent on the concentration of the inducing factors.

Adult↗
PubMed2026

Spatial analysis reveals the evolving organization of IDH-mutant glioma.

Adult diffuse gliomas are composed of malignant cell states interwoven with the non-malignant brain microenvironment. Here, we combine spatial transcriptomics and spatial proteomics of isocitrate dehydrogenase (IDH)-mutant gliomas to define organizational principles across histological grades. In low-grade tumors, spatial organization is shaped by underlying brain anatomy. We identify a functional white-gray matter junction that restricts cortical invasion and is associated with marked changes in tumor composition and cellular phenotypes. This junction is preferentially traversed by oligodendrocyte progenitor (OPC)-like malignant cells, suggesting a role in tumor expansion. In contrast, tumors with intermediate histological features are largely disorganized, with few recurring interactions between cancer cell states and microenvironmental cell types. In high-grade tumors, hypoxia-associated structure emerges, resembling IDH-wild-type glioblastoma. Together, these findings reveal two independent axes of spatial organization-from anatomy-driven structure in low-grade tumors to hypoxia-driven organization in high-grade tumors-and establish a framework linking tumor grade to recurrent spatial interactions.

Isocitrate Dehydrogenase↗
PubMed1987

Brain surface invasion and metastasis of murine malignant melanoma variants.

Mouse B16 melanoma sublines were selected sequentially for their abilities to colonize brain meninges and leptomeninges of C57BL/6 mice. After 14 selections subline B16-B14b was established that formed significantly more brain tumor colonies than the parental B16 line. Examination of brains at various times after intravenous or intra-arterial injection of B16 cells by electron microscopy revealed that B14b melanoma cells lodged in small brain blood vessels, proliferated and invaded through vessel walls into brain parenchyma and also along small blood vessels at perivascular sites. Invasion into brain parenchyma was characterized by extension of melanoma cell filopodia resulting in fragmentation and sometimes enfulgment of glial and neural cells. Analysis of cell surface proteins of B16 melanoma sublines revealed increased exposure of a Mr approximately 90,000 glycoprotein on the high brain-colonizing cells. Antibodies against the Mr approximately 90,000 glycoprotein reacted with a variety of human melanoma cell lines and with some fetal and adult tissues, indicating that this melanoma-associated component is not species-, tumor- or tissue-specific. The glycoprotein could be a cell surface receptor important in the survival and growth properties of melanoma cells in brain microenvironments.

Animals↗
PubMed1985

Tightness of the blood-brain barrier and evidence for brain interstitial fluid flow in the cuttlefish, Sepia officinalis.

Cephalopod molluscs have complex brains and behaviour, yet little is known about the permeability of their blood-brain interface. The accompanying paper characterized the fluid compartments of the brain and presented evidence for restricted permeability of the blood-brain interface to albumin. The present paper investigates the permeability of the interface to small non-electrolytes. [14C]Polyethylene glycol (PEG, mol. wt. 4000), and [51Cr]EDTA (mol. wt. 342) were injected intravenously or intramuscularly, and their penetration into brain and muscle studied up to 48 h. Tracers equilibrated with muscle interstitial fluid (ISF) at relatively short times, but in brain ISF reached only 0.5-0.65 X their plasma concentration. This is qualitative evidence for the presence in brain of a barrier to these molecules and an efficient drainage mechanism for ISF. Quantitative treatment of the uptake data allows calculation of the permeability X surface area product (PS) and the permeability coefficient (P). For the brain PS and P are in the range 1-3 X 10(-4) ml g-1 min-1 and 1-3 X 10(-8) cm s-1 respectively, (PEG), and 3 X 10(-4) ml g-1 min-1 and 3-4 X 10(-8) cm s-1 respectively (Cr-EDTA). The P values are close to those reported for mammalian brain. Assuming that the lack of equilibration in brain is due to ISF flow, the rate of flow can be calculated. Values for vertical and optic lobe are approximately 0.2 microliter g-1 min-1, again close to those reported for mammalian brain. It is concluded that the tightness of the Sepia blood-brain barrier approaches that of mammals, and a flowing ISF system is present. An association between a tight barrier and higher central nervous system integrative function is suggested. The significance of these findings for the evolution of control of the brain microenvironment is discussed.

Animals↗
PubMed2026

Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.

Glioblastoma (GBM) is one of the most aggressive and lethal primary brain tumors in adults, characterized by dynamic clonal evolution and extensive genomic, cellular, spatial, and microenvironmental heterogeneity. Multi-omics studies have revealed that GBM follows complex evolutionary trajectories involving genetic, epigenetic, transcriptional, and immune-microenvironmental remodeling as tumors grow, adapt to the brain microenvironment, and acquire therapeutic resistance. Increasing evidence suggests that GBM may originate from aberrant neural stem or progenitor cells, including those residing in the subventricular zone, and that glioblastoma stem cells (GSCs) contribute to tumor propagation, heterogeneity, and recurrence. A key conceptual challenge is to reconcile hierarchical cancer stem cell models, in which GSCs are viewed as relatively stable tumor-propagating subpopulations, with dynamic state plasticity models, in which stem-like properties can be reversibly acquired or lost during transitions among proneural-like, mesenchymal-like, invasive, and therapy-tolerant states. Recent advances in single-cell profiling, spatial transcriptomics, lineage tracing, organoid culture, 3D bioprinting, genetically engineered models, and artificial intelligence (AI)-assisted computational modeling have substantially improved the ability to study these processes. However, no currently available model fully recapitulates human GBM heterogeneity, recurrence, treatment history, and tumor-microenvironment interactions. Therefore, model selection should be guided by clearly defined mechanistic questions rather than by reliance on any single platform. This review summarizes current advances in in vitro, ex vivo, in vivo, and computational models for studying GBM evolution and heterogeneity, and discusses how integrated model pipelines may improve preclinical drug testing, treatment-response prediction, and precision neuro-oncology.

Humans↗
PubMed1990

A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat.

Morphometric changes in the rat lateral ventricle choroid plexus epithelium and endothelium and in the ventricular ependyma were studied between 16 days gestation and 30 days after birth, using stereological techniques. The epithelial apical surface density increased from 0.6 to 3.3 microns 2/microns 3 and the mitochondrial volume fraction from 3.2 to 7.6% during this period. The endothelial fenestrations increased from 0.05 to 0.39 micron-1. These changes may be related to postnatal increases in choroid plexus function. Morphological changes in basolateral surface density, cell height and nucleus and glycogen volume fraction have also been measured. The development of the lateral ventricle choroid plexus was qualitatively similar to the fourth ventricle plexus reported previously, but small quantitative differences occurred. The ventricular ependyma also showed a significant increase in mitochondrial volume fraction after birth, though to a lesser extent than the plexus epithelium. The total apical surface area of the choroid plexuses was estimated at 75 cm2 for 30-day-old rats. This figure, which takes into account the apical microvilli, is much greater than previous estimates and is similar to the surface area of the cerebral capillaries (155 cm2), and suggests that the choroid plexuses may play a more important role in the regulation of the brain microenvironment than previously thought.

Animals↗
PubMed1989

A morphological study of the neuroblastoma-glioma hybrid cell line, NG108-15, in culture and after grafting to the adult rat brain.

NG108-15 cells were implanted into adult rat neocortex 10 days after nucleus basalis lesions which had partially denervated this site. Before implantation, NG108-15 cells displayed highly differentiated characteristics, including neurite extension and neurofilament expression. After grafting, however, NG108-15 cells became highly mitotic and lost their differentiated features such as neurofilament immunoreactivity. It is concluded that anaplastic changes, presumed to be induced in these cells by the injured brain microenvironment, are not conductive to using this cell line as a potential donating source of neural tissue for transplantation.

Animals↗
PubMed1991

Extracellular alkalinization evoked by GABA and its relationship to activity-dependent pH shifts in turtle cerebellum.

1. The effect of gamma-aminobutyric acid (GABA) on extracellular pH (pHo) was investigated in the turtle cerebellum, in vitro, using double-barrelled, H(+)-selective microelectrodes. Responses evoked by GABA were compared with pHo shifts evoked by repetitive stimulation of the parallel fibres. 2. In media buffered with 35 mM-HCO3- and 5% CO2, superfusion of GABA (1 mM) elicited an abrupt alkaline shift in the molecular layer, which averaged 0.05 +/- 0.02 pH units (+/- S.D., range 0.02-0.12 pH units). pHo often recovered in the continued presence of GABA, and displayed a rebound acidification upon wash-out. 3. The GABA-evoked alkaline shift was blocked by picrotoxin and was mimicked by the GABAA agonists isoguvacine and muscimol. The GABAB agonist baclofen did not elicit an alkaline shift. Alkaline shifts evoked by stimulation of the parallel fibres were unaffected by picrotoxin. 4. In nominally HCO3(-)-free solutions, buffered with 35 mM-HEPES, superfusion of GABA caused either no pHo change or a slow acid shift. In contrast, the alkaline shift evoked by stimulation of the parallel fibres became enhanced in HEPES-buffered media. 5. The alkaline shift evoked by GABA was accompanied by an increase in extracellular K+ ([K+]o) which averaged 1.7 mM above baseline. Experimental elevation of [K+]o to a comparable level always caused a pure acid shift in the extracellular space. 6. The GABA-evoked alkaline shift persisted when synaptic transmission was blocked using 4 mM-kynurenic acid or saline prepared with nominally zero Ca2+ and 10 mM-Mg2+. The alkaline shift evoked by repetitive stimulation of the parallel fibres was completely abolished in these media. 7. Although the GABA-evoked alkaline shift was blocked in nominally HCO3(-)-free media, substitution of 35 mM-formate for HCO3- restored the GABA response. Superfusion of 1 mM-GABA in formate saline produced an alkaline shift of 0.040 +/- 0.034 pH units. 8. These results indicate that gating of GABAA channels in the vertebrate CNS gives rise to an HCO3- efflux which can significantly increase the pH of the brain microenvironment. However, this mechanism cannot account for the extracellular alkalinization caused by parallel fibre stimulation. Extracellular alkaline shifts capable of modulating local synaptic operations may therefore be a consequence of either excitatory or inhibitory synaptic transmission.

Animals↗
PubMed1990

[Spreading depression--cortical reactions: disorders of the extracellular microenvironment].

Changes of brain cell microenvironment in the cerebral cortex of the rat were studied during spreading depression (SD) elicited by KCl application or local cooling. The question was whether the behavior of extracellular ion concentrations, especially of K+, could give some information about the triggering mechanisms of SD at the site where the phenomenon originates in the tissue. SDs elicited by KCl and recorded far from their original sites were associated with disturbances of extracellular ion concentrations and of tissue pO2 and pCO2 showing characteristic time sequences. Under these conditions none of the parameters studied changed before SD development. When an SD was elicited by local cooling extracellular K+ concentration ([K+]0) increased steeply in the mostly cooled cortical layers prior to SD initiation and formed a plateau of about 10 mmol/l resembling the ceiling level for K+ associated with ictal seizure activity. The front of the SD wave moved down slowly to the white matter. Thereby the rectangular rise in [K+]0 prior to SD progressively flattened and finally disappeared. The results suggest that SD evoked by local cooling originates from a primary increase of [K+]0 to the K+ ceiling level and by a secondary breakdown of the mechanisms being responsible for this type of K(+)-regulation. The mechanisms mentioned may be responsible for all kinds of SD-triggering.

Animals↗
PubMed1985

In vivo measurement of brain tumor pH using [11C]DMO and positron emission tomography.

In vivo measurements of regional brain tissue/tumor pH (rpH) have been accomplished in 9 patients with primary or metastatic brain tumors using [11C]dimethyloxazolidinedione [( 11C]DMO) and positron emission tomography. Tumor rpH values ranged from 6.88 to 7.26, whereas gray matter and white matter rpH values ranged from 6.74 to 7.09 and from 6.77 to 7.03, respectively. Our results, which are consistent with reported [14C]DMO autoradiographic measurements of brain and tumor pH, suggest that the pH microenvironment of brain tumors is not more "acidic" than that of normal gray or white matter.

Adult↗
PubMed2026

Leveraging single-cell and spatial omics for brain tumour insights to improve therapeutic strategies.

Single-cell and spatial omics (SPOs) technologies have advanced how healthcare physicians characterise brain tumours by enabling detailed understanding of their cellular architecture, functional states, and microenvironmental dynamics. These approaches provide high-resolution detection of tumour heterogeneity and allow precise analysis of the brain tumour microenvironment. Their application has also led to the discovery of novel biomarkers used for early brain tumour detection, prognosis, and improved tumour stratification. Furthermore, integrative multi-omic analyses have revealed new therapeutic targets, clarified mechanisms of drug resistance, and uncovered molecular pathways underpinning treatment failure. By bridging cellular-level insights with spatial context, SPOs hold significant promise for advancing personalised diagnostics, predicting therapeutic response, and guiding the development of targeted interventions for brain tumours. Despite these advances, several limitations constrain the full translational potential of SPOs, including high experimental costs, substantial computational demands, lack of standardised protocols, and challenges in data integration and reproducibility. Addressing these barriers through scalable bioinformatic pipelines, consensus experimental frameworks, and cost-effective platforms remains critical for broadening accessibility and enabling clinical adoption.

Brain Neoplasms↗
PubMed1990

Development of the blood-brain barrier.

The microenvironment of the CNS is important for neuronal function, and the blood-brain barrier is involved in its maintenance. The barrier is present in a complex cellular system at the level of the tight junctions between endothelial cells. The unique properties of the endothelial cells in the CNS compared with those present in other organs are not predetermined by brain-specific endothelial precursors but are induced by the neural environment during the development of the vascular system. Astrocytes that tightly appose endfeet onto the abluminal side of brain capillaries seem to be important for the induction and maintenance of the endothelial barrier.

Animals↗