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PubMed2001

Sequential and opposite regulation of two outward K(+) currents by ET-1 in cultured striatal astrocytes.

In the brain, astrocytes represent a major target for endothelins (ETs), a family of peptides that can be released by several cell types and that have potent and multiple effects on astrocytic functions. Four types of K(+) currents (I(K)) were detected in various proportions by patch-clamp recordings of cultured striatal astrocytes, including the A-type I(K), the inwardly rectifying I(K IR), the Ca(2+)-dependent I(K) (I(K Ca)), and the delayed-rectified I(K) (I(K DR)). Variations in the shape of current-voltage relationships were related mainly to differences in the proportion of these currents. ET-1 was found to regulate with opposite effects the two more frequently recorded outward K(+) currents in striatal astrocytes. Indeed, this peptide induced an initial activation of I(K Ca) (composed of SK and BK channels) and a delayed long-lasting inhibition of I(K DR). In current-clamp recordings, the activation of I(K Ca) correlated with a transient hyperpolarization, whereas the inhibition of I(K DR) correlated with a sustained depolarization. These ET-1-induced sequential changes in membrane potential in astrocytes may be important for the regulation of voltage gradients in astrocytic networks and the maintenance of K(+) homeostasis in the brain microenvironment.

4-Aminopyridine↗
PubMed1998

Functional specialization and topographic segregation of hippocampal astrocytes.

Astrocytes have been suggested to play several roles in the complex control of brain microenvironment. However, they have been generally considered to constitute a homogeneous population of cells. Here we show that at least three electrophysiologically distinct types of astrocytes can be found in the mature hippocampus. These subpopulations of glia were characterized by expression of different ion currents. In astrocytes exposed to elevated K+, Cs+ prevented influx of K+ only in cells with inwardly rectifying currents (IIR). The topographic distribution of glia with Cs+-sensitive inward rectifying currents (involved in K+ buffering) was nonuniform. Cs+-sensitive astrocytes were predominantly found in CA3 radiatum, whereas most CA1 astrocytes were Cs+-insensitive. Functional significance of the spatial segregation of glial cells with inward rectification was addressed in slices that were bathed in Cs+-containing media. Under these conditions, neuronal stimulation induced spontaneous epileptiform activity, which first appeared in CA3 and was then synaptically propagated to CA1. Intracellular labeling of astrocytes with biocytin revealed that CA1 astrocytes are characterized by a high degree of cell-to-cell coupling; in contrast, cell labeling in CA3 revealed smaller groups and occasionally individual cells. Three individual biocytin-labeled cells had electrophysiological properties indistinguishable from Cs+-sensitive astrocytes but had morphology typical of oligodendroglia. These results provide evidence for a role of K+ uptake via IIR into astrocytes. The segregated expression of potassium channels in a subpopulation of astrocytes suggests that functionally specialized cell types are involved in K+ homeostasis.

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↗
PubMed1983

Alkaline and acid transients in cerebellar microenvironment.

1. Extracellular pH (pHo) was measured in the cerebellar cortex of the rat using a recently developed liquid membrane ion-selective micropipette (ISM). pHo was determined during stimulus-evoked neuronal activity, elevated extracellular potassium concentration, [K+]o, spreading depression (SD), and complete ischemia. In many experiments [K+]o was simultaneously determined. 2. A train of local surface stimuli (LOC) produced an initial alkaline shift in pHo from a base line of 7.20-7.30 to 7.25-7.35. This was followed by a long-lasting acid phase that reached a plateau of 7.05-7.15 after 64 s of stimulation. pHo decrease was related to stimulus frequency, intensity, and duration. 3. Superfusion with Ringer solution containing manganese ions rapidly abolished parallel fiber-induced Purkinje cell synaptic depolarization together with the alkaline shifts while enhancing the acid shifts. 4. Superfusion of the cerebellar cortex with Ringer solution containing increasingly elevated [K+] progressively lowered pHo to a plateau of 6.95-7.05. The acidification occurred in the presence of ouabain but was reversed on return to the normal [K+]o or with the addition of the glycolytic blocker, fluoride. Stimulus-evoked alkaline shifts were enhanced by K+-Ringer superfusion. These experiments suggested that the acid shift was due to the metabolic production of an anion, possibly lactate. 5. Elevation of [K+]o above 8-12 mM often produced oscillation in pHo and [K+]o with a period of about 40 s. Sometimes these oscillations ended in a spontaneous SD or SD could be evoked by stimulation. Under these conditions of raised [K+]o, the SD consisted of a very pronounced alkaline transient followed by a small, long-lasting acid shift. When SD was induced by conditioning the cerebellum with proprionate or lowered NaCl, the alkaline phase was reduced and the acid enhanced. 6. Complete ischemia began with a progressive decrease of pHo and rise in [K+]o. When [K+]o reached 12 mM, a second more rapid rise in [K+]o to 40 mM or more occurred. This was correlated with 0.1-0.2 pHo transient increase similar to that seen during SD. pHo eventually reached a plateau of 6.60-6.80, close to neutrality. 7. Superfusion with Ringer solution containing acetazolamide immediately altered pHo homeostasis by increasing base-line pHo by about 0.10 and enhanced the induced pHo changes. These results suggest that carbonic anhydrase (CA) is important for acute buffering of the brain extracellular microenvironment. 8. The above results were interpreted in terms of changes in extracellular strong ion concentration differences ( [SID]o), extracellular concentration of total weak acid ( [Atot]o) and partial pressure of CO2 (Pco2) in the brain microenvironment. The results indicate that neuronal activity produces changes in many of the constituents of the microenvironment.

Acetazolamide↗
PubMed1983

Diffusion in the slice microenvironment and implications for physiological studies.

The brain cell microenvironment includes the extracellular space surrounding the cell together with the cellular elements that define the space. The dense packing of cells in the mammalian nervous system ensures that the extracellular space is narrow but highly complex in geometry. Recent studies with ion-selective micropipettes have revealed that the cerebellar slice can support changes in [K+]o that resemble those seen in the intact preparation. In the slice, [K+]o responses of individual cells can even be resolved. Studies with iontophoretic techniques and quantitative analysis in the slice have shown that the extracellular space has diffusion properties, characterized by a volume fraction and a tortuosity, that are very similar to those seen in the intact animal. These data confirm that the microenvironment in the slice is comparable to that in the intact animal. The diffusion parameters can be used to make predictions about the time necessary for substances to diffuse into slices under various conditions. Such estimates, together with other studies, indicate that it is probably inadvisable to use slices with thicknesses in excess of 300--400 micrometers, and that the bathing conditions can be critical in maintaining slice viability.

Animals↗
PubMed1994

Neuromediators in the cerebellar blood-brain barrier and its microenvironment. Immunocytochemical demonstration of taurine, glycine, serotonin, thiamin and AATase.

Cerebral capillaries represent the responsible structure for the establishment of the Blood-Brain Barrier (BBB). It is known that in the Central Nervous System a relationship exists between neuronal activity and microvascular blood flow and permeability. Our analysis demonstrates the presence of several putative neuromediators-taurine. glycine, serotonin, thiamine and aspartate-in endothelial cells of the rat cerebellar cortex capillaries, as well as in the perivascular glia, neuronal bodies, dendrites and axon terminals that come in close contact with the basement membrane surrounding capillary wall. Our results support the conclusion of other biochemical and pharmacological studies on the relationship between these neuromediators and microvascular function in the Central Nervous System.

Animals↗
PubMed2004

Changes in diffusion through the brain extracellular space.

ECS (extracellular space) works as the microenvironment of brain cells. Diffusion through ECS may be described through an effective diffusion coefficient, D (e), which in turn depends on ECS porosity, epsilon, and tortuosity, T. In the present research, diffusion data together with epsilon and T were collected from the specialized literature and analysed to seek a correlation of T versus epsilon. On the basis of D (e) data, upper and lower T boundaries were defined and related to topologically 'dense' and 'loose' cell arrangement. A possible range for T variation was obtained for ECS, with epsilon ranging from 0.05 to 0.6. A tortuosity index ( n ) in the form of T and epsilon logarithmic ratio was introduced. This index may be adopted for recalculation of T or epsilon if only one of these parameters is known. As a result of data analysis and modelling, it was concluded that, upon different external conditions, for instance oxygen depletion, the ECS porosity decreases and cells (presumably through membrane rearrangements) adjust the void space to keep the diffusion within a defined range, which gives the living tissue the ability to maintain the diffusion level up to two or more times higher than in conventional granular bed packing. Thus, even with a dramatic ECS decrease, the cellular system is still able to support a given diffusion by decreasing the value of T. The obtained results clearly show the existence of three data clusters: a region of normal brain functioning, both for young and adult brains, for values of epsilon comprised between 0.15 and 0.30, and two regions of abnormal brain behaviour to the left and to the right of the normal region, corresponding to different states (aging, tumours, anoxia, brain death, etc.). The present approach allows defining the optimal range of epsilon and T to assure the best ECS diffusion efficiency for a specified macromolecule. This might be important in brain clinical treatment.

Animals↗
PubMed2006

A potent serotonin-modulating compound AP-267 attenuates morphine withdrawal-induced blood-brain barrier dysfunction in rats.

The possibility that a serotonin 5-HT2c receptor-modulating compound, AP-267, will influence spontaneous morphine withdrawal symptoms and the alterations in the brain fluid microenvironment was examined in a rat model. Daily administration of morphine (10 mg/kg, i.p.) for 10 days resulted in dependence of rats as seen by loss of analgesic response. On the 11th day, no morphine administration was given. This resulted in profound withdrawal symptoms 24 h after morphine withdrawal. The magnitude and severity of these symptoms were increased further 48 h after withdrawal. Measurement of the blood-brain barrier (BBB) permeability, a measure of perturbed brain fluid microenvironment showed leakage of Evans blue and radioiodine tracers in several parts of the brain in rats showing withdrawal symptoms. Whereas, rats treated with AP-267 either on the 1st day or 2nd day morphine withdrawal showed much less symptoms and leakage of the BBB. Taken together, these observations suggest that (a) stress associated with the withdrawal symptoms are sufficient enough to induce breakdown of the BBB function, and (b) modulation of serotonin 5-HT2c receptors may have some protective influence on the stress symptoms and the BBB disruption.

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↗
PubMed1996

Enzyme-linked immunosorbent assay quantification of cytokine concentrations in human meningiomas.

OBJECTIVE: To gain insight into the network of cytokine gene expression in the brain tumor microenvironment, we investigated the presence of the following cytokines in freshly excised brain tumors: interleukin (IL)-1 beta, IL-2, IL-4, and IL-6. METHODS: Tumor specimens from nine meningiomas were grown as tissue explants. The supernatants from the explants were tested for the presence of the aforementioned cytokines via the enzyme-linked immunosorbent assay method. RESULTS: IL-6, which is thought to stimulate acute protein phase synthesis, neovascularization, and cell proliferation, was found in all of the samples in greater concentrations than the other cytokines tested. IL-1 beta, another stimulatory cytokine thought to be involved in acute protein phase synthesis and cell proliferation, was also found in 100% of the samples tested, in concentrations significantly lower than those of IL-6. As expected, the presence of IL-2 and IL-4 was not detectable in any of the samples. CONCLUSION: This study is the first to clearly determine the relative concentrations of IL-1 beta and IL-6, using enzyme-linked immunosorbent assay quantification. These findings are an important precursor to future studies using antibodies to IL-1 beta and IL-6 and antibodies to IL-6 receptors to modulate neoplastic growth both in vitro and in vivo.

Cell Division↗
PubMed2001

Adrenomedullin in the cerebral circulation.

The central nervous system requires an effective autoregulation of cerebral circulation in order to meet the critical and unusual demands of the brain. In addition, cerebral microvessels has a unique feature, the formation of the blood-brain barrier, which contributes to the stability of the brain parenchymal microenvironment. Many factors are known to be involved in the regulation of cerebral circulation and blood-brain barrier functions. In the last few years a new potential candidate, adrenomedullin, a hypotensive peptide was added to this list. Adrenomedullin has a potent vasodilator effect on the cerebral vasculature, and it may be implicated in the pathologic mechanism of cerebrovascular diseases. In this review, we describe current knowledge about the origin and possible role of adrenomedullin in the regulation of cerebral circulation and blood-brain barrier functions.

Adrenomedullin↗
PubMed1996

Preparation of giant myelin vesicles and proteoliposomes to register ionic channels.

Myelin vesicles, reconstituted liposomes with proteolipid protein (PLP), the main protein component of myelin, and electrophysiological patch-clamp are potentially powerful tools to study the role of myelin in functional ionic channels. However, technical difficulties in the vesiculation of myelin and the small size of the vesicles obtained do not permit the application of micropipettes for current recordings. From a suspension of purified myelin we have prepared oligolamellar vesicles (mean diameter of 144 nm) using the so-called French pressure system. From this preparation we obtained giant myelin vesicles approximately 10 microns in mean diameter, using a dehydration-rehydration procedure. Qualitative analysis of proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed no significant loss of any component in these vesicles due to pressure, in comparison with non-vesiculated myelin. A way of preparing giant liposomes of approximately 80-100 microns and proteoliposomes of approximately 30 microns in mean diameter, using the same dehydration-rehydration procedure, is also reported. Reconstitution of purified PLP in giant liposomes was confirmed by fluorescent labeling of PLP and by fluorescence microscopy. The current recordings from these vesicles prove the validity of these methods and provide significant evidence of the existence of ionic channels in myelin membranes and the possibility that PLP functions as a channel. The physiological significance and characterization of these channels remain yet unresolved. These results have a special significance for elucidating the molecular role of myelin in the regulation of neural activity and in the brain ion microenvironment.

Animals↗
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↗
PubMed1992

Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view.

This new view of the immunoreactivity of the normal brain is based on three key components. First, there is an active and highly-regulated communication between the brain and the central immune organs. Secondly, the connection from the brain to the draining nodes is much larger than previously appreciated. And third, the blood-brain barrier, by virtue of its selective permeability properties, contributes to the regulation of immunoregulatory cells and molecules in the brain cell microenvironment.

Albumins↗
PubMed1992

Interactions of phospholipids and free fatty acids with antidepressant recognition binding sites in rat brain.

The lipid microenvironment of cell membranes has been shown to regulate both neurotransmitter and hormone receptors. Preincubation of cortical synaptosomal membranes of rat brain with phospholipase A2 (PLA2) increases the number of [3H]imipramine ([3H]IMI) high affinity binding sites without altering Kd (Bmax control: 2.53 +/- 0.28 pmol/mg protein vs Bmax PLA2: 3.66 +/- 0.26 pmol/mg protein). The displacement curves of [3H]IMI binding in synaptosomal membranes with other tricyclic antidepressants are not affected by the presence of PLA2. The effect of PLA2 was prevented by incubation with EGTA (2 x 10(-3)) or bovine serum albumin (BSA; 1:1). In addition, end products of catalytic activity of PLA2 such as unsaturated fatty acids (arachidonic or oleic acids) mimicked the effect of PLA2. These effects were entirely prevented by preincubation with BSA. The in vitro addition of the acidic phospholipid phosphatidylserine isolated from bovine brain (BC-PS) produced a similar increase in Bmax. This action was also blocked by addition of BSA. On the other hand, palmitic acid, a saturated fatty acid, and lysophosphatidylserine (lysoPS) or lysophosphatidylethanolamine (lysoPE) failed to modify [3H]IMI binding sites. The chronic administration of tricyclic antidepressant (AD) resulted in a 25% decrease in [3H]IMI binding sites in synaptosomal membranes. Preincubation of these AD-treated membranes with PLA2 did not alter [3H]IMI binding, whereas the addition of unsaturated free fatty acids (FFA) produced a greater increase in the density of [3H]IMI binding sites in comparison with control membranes. Taken together, these findings suggest that unsaturated free fatty acids could play an important role in the regulation of the number of [3H]IMI high affinity binding sites in the mammalian brain.

Amitriptyline↗
PubMed2006

Cross-priming of T cells to intracranial tumor antigens elicits an immune response that fails in the effector phase but can be augmented with local immunotherapy.

Central nervous system (CNS) tumors are thought to be poorly immunogenic. However, whether defective anti-tumor immunity is a consequence of a relative failure of T cell priming versus a deficient effector phase of the anti-tumor immune response is not clear. We utilized a well-defined model system of B16 melanoma expressing the model antigen SIY-GFP to evaluate tumor antigen cross-priming and tumor rejection from the CNS versus subcutaneous compartments. We observed that B16-SIY cells implanted in the CNS were capable of inducing T cell priming as measured by IFN-gamma ELISPOT in the spleen. Cross-priming occurred in the absence of detectable systemic dissemination of the tumor. Despite the induction of a T cell response, CNS tumors grew progressively and were fatal, whereas the same tumor implanted in the flank was rejected. To study the effector phase of the immune response in more detail, in vitro primed 2C/RAG2-/- TCR transgenic CD8+ cells, which recognize the SIY peptide, were adoptively transferred. In addition, the CNS microenvironment was modulated by intracranial delivery of IL-2. While mice that received primed 2C cells alone showed an increase in survival, co-administration of intracranial IL-2 led to a marked prolongation of survival, with 20% of mice surviving at least 120 days. Our results demonstrate that CD8+ T cell cross-priming does indeed occur in response to a CNS tumor, but that manipulation of the brain tumor microenvironment may be necessary to support the effector phase of the anti-tumor immune response.

Abdominal Neoplasms↗
PubMed1993

Cytokine gene expression in primary brain tumours, metastases and meningiomas suggests specific transcription patterns.

To obtain an insight into the network of cytokine gene transcription in the brain tumour microenvironment, we investigated the expression of genes encoding for interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta 1, -beta 2 and -beta 3 in freshly excised brain tumour samples and autologous peripheral blood mononuclear cells. Tissue specimens from 15 primary brain tumours, three brain metastases, five meningiomas, autologous peripheral blood mononuclear cells (PBMC) and three brain tumour cell lines were tested by reverse polymerase chain reaction. Despite the presence of T-lymphocytes, cytokine gene transcripts typically detectable upon T cell receptor triggering could not be observed in central nervous system tumours of diverse histology. In primary brain neoplasms, transcription of genes encoding for the inhibitory cytokines TGF-beta and IL-10 was detectable in more than 50% of samples. IL-6 transcripts could only be detected in malignant gliomas. In brain metastases, virtually no cytokine gene transcripts could be observed. Surprisingly, TGF-beta transcripts were also detected in all meningiomas. Thus, transcription of genes encoding for inhibitory factors appears to prevail in primary brain neoplasms.

Adolescent↗