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Results for “brain microenvironment”

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At least 91 records · Page 5Linked to original sources
PubMed2000

Ascorbate regulation and its neuroprotective role in the brain.

Ascorbic acid (vitamin C) occurs physiologically as the ascorbate anion: a water-soluble antioxidant that is found throughout the body. However, despite the high, homeostatically regulated levels of brain ascorbate, its specific functions in the CNS are only beginning to be elucidated. Certainly, it acts as part of the intracellular antioxidant network, and as such is normally neuroprotective. There is also evidence that it acts as a neuromodulator. A possibly unique role it might have is as an antioxidant in the brain extracellular microenvironment, where its concentration is modulated by glutamate-ascorbate heteroexchange at glutamate uptake sites. Ongoing studies of ascorbate and glutamate transporters should lead to rapid progress in understanding ascorbate regulation and function.

Animals↗
PubMed2004

Experimental radiobiological investigations into radiosurgery: present understanding and future directions.

LARS LEKSELL BEGAN radiobiological investigations to study the effect of high-dose focused radiation on the central nervous system more than 5 decades ago. Although the effects of radiosurgery on the brain tumor microenvironment are still under investigation, radiosurgery has become a preferred management modality for many intracranial tumors and vascular malformations. The effects and the pathogenesis of biological effects after radiosurgery may be unique. The need for basic research concerning the radiobiological effects of high-dose, single-fraction, ionizing radiation on nervous system tissue is crucial. Information from those studies would be useful in devising strategies to avoid, prevent, or ameliorate damage to normal tissue without compromising treatment efficacy. The development of future applications of radiosurgery will depend on an increase in our understanding of the radiobiology of radiosurgery, which in turn will affect the efficacy of treatment. This article analyzes the current state of radiosurgery research with regard to the nature of central nervous system effects, the techniques developed to increase therapeutic efficacy, investigations into the use of radiosurgery for functional disorders, radiosurgery as a tool for investigations into basic central nervous system biology, and the additional areas that require further investigation.

Animals↗
PubMed2003

Microdialysis of dopamine interpreted with quantitative model incorporating probe implantation trauma.

Although microdialysis is widely used to sample endogenous and exogenous substances in vivo, interpretation of the results obtained by this technique remains controversial. The goal of the present study was to examine recent criticism of microdialysis in the specific case of dopamine (DA) measurements in the brain extracellular microenvironment. The apparent steady-state basal extracellular concentration and extraction fraction of DA were determined in anesthetized rat striatum by the concentration difference (no-net-flux) microdialysis technique. A rate constant for extracellular clearance of DA calculated from the extraction fraction was smaller than the previously determined estimate by fast-scan cyclic voltammetry for cellular uptake of DA. Because the relatively small size of the voltammetric microsensor produces little tissue damage, the discrepancy between the uptake rate constants may be a consequence of trauma from microdialysis probe implantation. The trauma layer has previously been identified by histology and proposed to distort measurements of extracellular DA levels by the no-net-flux method. To address this issue, an existing quantitative mathematical model for microdialysis was modified to incorporate a traumatized tissue layer interposed between the probe and surrounding normal tissue. The tissue layers are hypothesized to differ in their rates of neurotransmitter release and uptake. A post-implantation traumatized layer with reduced uptake and no release can reconcile the discrepancy between DA uptake measured by microdialysis and voltammetry. The model predicts that this trauma layer would cause the DA extraction fraction obtained from microdialysis in vivo calibration techniques, such as no-net-flux, to differ from the DA relative recovery and lead to an underestimation of the DA extracellular concentration in the surrounding normal tissue.

Animals↗
PubMed1995

Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum.

A quantitative description of the behavior of a neurotransmitter in the brain extracellular microenvironment requires an understanding of the relative importance of diffusion versus uptake processes. This paper models the behavior of dopamine released from a small iontophoresis electrode and its voltammetric detection by a carbon fiber sensor 100 microns away as a basis for developing a new paradigm for measuring dopamine kinetics in intact rat neostriatum. The diffusion equation incorporating uptake, characterized by a maximum velocity Vmax and a Michaelis-Menten constant Km, was transformed to an integral equation and solved numerically for the dopamine concentration, C. Analytical solutions were derived for limiting cases of a steady-state free-boundary problem when C >> Km and the linear time-dependent problem when C << Km. These solutions were compared with complete numerical solutions, both for normal uptake (Vmax = 0.2 or 0.8 microM s-1; Km = 0.15 microM), and in the presence of the uptake blocker nomifensine (Km = 6 microM). The results suggest that an experimental strategy for the quantitative analysis of dopamine, and other compounds, in living tissue is to fit a family of concentration versus time curves generated with different iontophoretic current strengths and recorded with a microsensor, to the numerical solution of the diffusion-uptake equation.

Animals↗
PubMed1994

Cerebral microvascular responses to endothelins: the role of ETA receptors.

The regulatory role of endothelins in cerebral microvessels was investigated in a recently developed model system which allows the study of small cerebral vessels in their normal microenvironment. Using brain slices of the rat neocortex, it was shown that the isopeptide endothelin-3 (ET-3) had no effect on cerebral microvessels, while the isopeptide endothelin-1 (ET-1) produced a potent, dose-dependent vasoconstriction. When a recently developed antagonist of ETA receptors (cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp]; ETant) was administered prior to treatment with ET-1, the vasoconstrictor response to ET-1 was inhibited in a dose-dependent manner. When ETant was administered after the establishment of a constriction by ET-1, the constrictor response to ET-1 was partially reversed, and this effect was weaker than that seen in the pre-treatment paradigm. These findings indicate that constrictor responses to ET-1 in cerebral microvessels are mediated by ETA receptors. Inasmuch as endothelins have been implicated in pathological forms of vasoconstriction in the CNS, the present findings also suggest that endothelin antagonists may be useful in the treatment of cerebral ischemia.

Amino Acid Sequence↗
PubMed2005

A finite-element model of the mechanical effects of implantable microelectrodes in the cerebral cortex.

The viability of chronic neural microelectrodes for electrophysiological recording and stimulation depends on several factors, including the encapsulation of the implant by a reactive tissue response. We postulate that mechanical strains induced around the implant site may be one of the leading factors responsible for the sustained tissue response in chronic implants. The objectives of this study were to develop a finite-element model of the probe-brain tissue interface and analyze the effects of tethering forces, probe-tissue adhesion and stiffness of the probe substrate on the interfacial strains induced around the implant site. A 3D finite-element model of the probe-brain tissue microenvironment was developed and used to simulate interfacial strains created by 'micromotion' of chronically implanted microelectrodes. Three candidate substrates were considered: (a) silicon, (b) polyimide and (c) a hypothetical 'soft' material. Simulated tethering forces resulted in elevated strains both at the tip and at the sharp edges of the probe track in the tissue. The strain fields induced by a simulated silicon probe were similar to those induced by a simulated polyimide probe, albeit at higher absolute values for radial tethering forces. Simulations of poor probe-tissue adhesion resulted in elevated strains at the tip and delamination of the tissue from the probe. A tangential tethering force results in 94% reduction in the strain value at the tip of the polyimide probe track in the tissue, whereas the simulated 'soft' probe induced two orders of magnitude smaller values of strain compared to a simulated silicon probe. The model results indicate that softer substrates reduce the strain at the probe-tissue interface and thus may also reduce tissue response in chronic implants.

Animals↗
PubMed1993

Hippocampal extracellular space micro-EEG--high frequency oscillations.

The hippocampal extracellular space electro-magnetic field interactions and related integrative mechanisms are important factors in the make-up of the micro-EEG. Combinations of ion currents give rise to complex patterns of neuronal electrical activity in the brain cell microenvironment, the extracellular space. The flow of ions through populations of ion channels in the neuronal plasma membrane and give rise to trans membrane ion currents. It is the sum of various currents flowing at any point in time that determines the neurons membrane potential. The multiple ion channels with their diverse and interacting regulatory mechanisms allow the neuron to modulate its electrical properties in complex ways of high frequency oscillations and electrical fields. Some of the hippocampal neurons have ionic conductances organized to endow them with auto rhythmicity. In many neurons the kinetics of these ionic voltage dependent conductances are such that the cells may respond preferentially to inputs at a certain frequency or frequencies acting as a resonators.

Amygdala↗
PubMedDate not supplied

[Fatty acid composition of aminophospholipids of the protein microenvironment in synaptosome plasma membranes in the rat brain].

Fatty acid composition of the aminophospholipids present in protein microenvironment of the plasmatic synaptic membranes was studied by covalent binding method. The analysis of fatty acids was carried out by gas liquid chromatography. Aminophospholipid fatty acids in the protein microenvironment were found to be more unsaturated compared to the lipids of the free bilayer. The fatty acids of the aminophospholipids present in the protein microenvironment of the plasmatic synaptic membranes were compared to those of rhodopsin microenvironment in photoreceptor membrane. The obtained results are discussed from the point of view of the signal transmission in the excitable membranes.

Animals↗
PubMed1994

Brain maturation and high-energy phosphate diffusivity: alteration in cytosolic microenvironment and effective viscosity.

Maturational changes in intracellular brain phosphocreatine (PCr) transport were investigated using 31P-nuclear magnetic resonance diffusion spectroscopy. The diffusivities of PCr showed significant maturational facilitation in rat brain in vivo. Physicochemical analysis of the cytosol microenvironment as a multicomponent solution, where one of the components is a dilute polymer, indicated that the observed developmental facilitation of PCr diffusivity is likely to be due to a decline in the concentration of the free amino acid taurine. Changes in the concentrations of biopolymers (i.e., proteins or lipids) have only little effect, if any, on PCr diffusivity. PCr diffusivity values of rat brain measured in vivo showed excellent quantitative agreement with the predicted values estimated using a model for multicomponent diffusion. The study confirmed that the taurine/N-acetylaspartate exchange observed during postnatal development of rat brain plays a major, it not unique, role in maturational facilitation of intracellular high-energy phosphate transport.

Albumins↗
PubMed2006

Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent.

A major challenge not yet addressed by current therapeutic interventions for Alzheimer's disease (AD) is the regeneration of lost neurons and neural circuitry to restore cognitive function. Therapies that lead to cessation of the degenerative process still leave the brain riddled with deteriorated neural circuits and reduced neuron number. The discovery of neurogenesis in the adult brain and the regenerative potential of neural stem cells holds the promise for restoration of neural populations and regeneration of neural circuits necessary for cerebral function. While the regenerative potential of neural stem cells is great, so too is the challenge of delivering neural stem cells to the brain. Basic science analyses and human trials indicate that constituents of microenvironments within the brain determine the neurogenic potential, phenotypic differentiation of neural stem cells and magnitude of the neural stem cell pool. Multiple analyses have documented that dentate neurogenesis is regulated by multiple growth factors which are abundant during development and which dramatically decline with age. While the cause(s) of age-associated decline in neurogenesis remains to be fully determined, loss in growth factors, FGF-2, IGF-1 and VEGF, in the microenvironment of the subgranular zone (SGZ) are prime contributors to the reduced neurogenic potential. The decline in dentate neurogenesis can be observed as early as middle age. In the aged and AD brain, both the pool of neural stem cells and their proliferative potential are markedly diminished. In parallel, the level of potential regenerative factors is diminished in the brains of Alzheimer's patients compared to age-matched controls. Our efforts have been directed towards discovery and development of small, blood brain barrier penetrant molecules to promote endogenous proliferation of neural stem cells within the brain. These endeavors have led to the discovery that the neurosteroid alloprognanolone (APalpha) is a potent and highly efficacious proliferative agent in vitro and in vivo of both rodent and human neural stem cells. Results of our in vitro studies coupled with our more recent analyses in the triple transgenic mouse model of AD suggest that APalpha is a promising strategy for promoting neurogenesis in the aged brain and potentially for restoration of neuronal populations in brains recovering from neurodegenerative disease or injury. A brief overview of issues impacting the therapeutic potential of neurogenesis and the factors used to promote neurogenesis in the aging and degenerating brain is presented. Also included is a review of our current research into the neurogenic potential of the small molecule, blood brain barrier penetrating, neurosteroid allopregnanolone (APalpha).

Aging↗
PubMed1990

Cellular and molecular aspects of neurocarcinogenesis.

Although the morphology of neural tumors induced in rats by N-ethyl-N-nitrosourea (NEU) and related alkylating agents has been extensively investigated, their histogenesis and the molecular basis of malignant transformation are still largely unknown. This review gives an account of the interaction of neurocarcinogenic agents with cellular DNA, the possible role of promutagenic O6-alkyldeoxyguanine and their deficient repair by the cerebral O6-alkylguanine-DNA alkyltransferase. A new experimental model is described in which neural tumors are induced in fetal brain transplants. Pregnant rats received a single iv dose of NEU (50 mg/kg) on the 14th day of gestation. One day later, suspensions were prepared from the fetal forebrain and stereotactically injected into the caudoputamen of adult rats. After additional exposure to NEU of the host animals 8 days and 9 weeks post transplantation, all rats developed brain tumors within the neural graft. Histopathologically, all neoplasms were classified as olidogdendrogliomas. Other neoplasms typically induced by NEU transplacentally (astrocytomas, mixed gliomas, ependymomas) were absent. The selective induction of oligodendrogliomas indicates that neoplastic transformation in the nervous system can occur in a differentiated glial cell or a precursor cell committed to oligodendrocytic differentiation, and that transformation of a pluripotential stem cell is not necessary. Transplacental exposure of the donor fetuses to NEU alone, i.e., without additional postgrafting exposure, did not produce brain tumors in any of the experimental animals indicating that in the microenvironment of fetal brain transplants the multistep development of gliomas requires additional mutational events. Malignant schwanomas perinatally induced by NEU carry a point mutation in the transmembrane domain of the neu gene. The mode of oncogene activation in NEU-induced CNS gliomas has not yet been elucidated. We have used cerebral grafting techniques to study the effects of known oncogenes on the developing nervous system, taking advantage of efficient gene transfer by replication-defective retroviral vectors and of the extraordinary capacity of fetal CNS to differentiate in and fully integrate with the host brain. Rats carrying transplants exposed in vitro to the polyoma medium T-antigen developed endothelial hemangiomas in the graft which often led to fatal cerebral hemorrhage within 13-50 days after transplantation. Introduction of the viral src gene caused astrocytic and mesenchymal tumors after latency periods of 2-6 months. Following infection of fetal donor cells with a vector encoding the v-myc oncogene, only a single embryonal CNS tumor was observed whereas exposure to v-H-ras produced a low incidence of gliomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2026

Unraveling the Enigma of Melanoma Brain Metastasis: New Molecular Insights and Therapeutic Directions.

Melanoma, a highly aggressive and metastatic cancer, poses significant challenges due to its propensity to spread to distant organs, with brain metastasis representing a particularly devastating complication. This review synthesizes preclinical and clinical evidence on the molecular, cellular, and microenvironmental mechanisms driving melanoma metastasis, emphasizing mechanisms of blood-brain barrier traversal, tumor-stroma co-option, and brain-specific genomic and transcriptional programs. We summarize advances in therapeutic strategies to combat melanoma brain metastasis including novel small molecules, immunotherapies, and combination approaches tailored for brain metastases. The review also highlights the immunological landscape of the brain, translational models, and multidisciplinary clinical management strategies. Finally, we identify critical research gaps, including the need for brain metastasis-specific clinical trials, AI-driven predictive models, and preventive strategies, to guide future efforts in improving outcomes for patients with melanoma brain metastasis.

Humans↗
PubMed2001

Transplantation of brain cells assembled around a programmable synthetic microenvironment.

Cell therapy is a promising method for treatment of hematopoietic disorders, neurodegenerative diseases, diabetes, and tissue loss due to trauma. Some of the major barriers to cell therapy have been partially addressed, including identification of cell populations, in vitro cell proliferation, and strategies for immunosuppression. An unsolved problem is recapitulation of the unique combinations of matrix, growth factor, and cell adhesion cues that distinguish each stem cell microenvironment, and that are critically important for control of progenitor cell differentiation and histogenesis. Here we describe an approach in which cells, synthetic matrix elements, and controlled-release technology are assembled and programmed, before transplantation, to mimic the chemical and physical microenvironment of developing tissue. We demonstrate this approach in animals using a transplantation system that allows control of fetal brain cell survival and differentiation by pre-assembly of neo-tissues containing cells and nerve growth factor (NGF)-releasing synthetic particles.

Animals↗
PubMed1984

Blood-brain interfaces in vertebrates: a comparative approach.

The neuronal microenvironment in the vertebrate brain is isolated from plasma by a series of selective membranes, including the blood-brain barrier, the choroid plexus, and the meningeal barrier. This review deals with the structure and function of these selective membranes in the different vertebrate classes. Present knowledge indicates that all vertebrates have brain barrier membranes and, further, that functional characteristics of these membranes are basically similar in all the vertebrate classes. The blood-brain barrier (or capillary-glial complex) and the meningeal barrier have many of the properties of a tight epithelium, including the presence of tight junctions and specific transport mechanisms. The choroidal epithelium is a typical secretory epithelium. The functional significance of the specialized membranes located at the blood-brain interface is considered, and we suggest that the phylogenetic development of a blood-brain barrier provided neurons of the vertebrate brain with a unique extracellular milieu optimal both for synaptic communication and for nonsynaptic communication via the entire extracellular space.

Adaptation, Physiological↗
PubMed1977

Age-related change in the neuronal microenvironment: penetration of ruthenium red into extracellular space of brain in young adult and senescent rats.

The volume of the extracellular space, which contributes to the microenvironment of neurons, is diminished in the brains of senescent (as compared to adult) rats and an age-related change in its composition has been hypothesized. To test this hypothesis we have compared the penetration of ruthenium red, a polyanion selectively distributed in the extracellular space, into the dentate gyri of young adult and senescent Fischer 344 rats. Slices of hoppocampal formation were fixed by immersion, first in a glutaraldehyde solution containing ruthenium red, then in a solution of osmium tetroxide containind examined by electron microscopy. Dense particles of ruthenium red reaction product were readily localized in intercellular channels and synaptic clefts and the depth of penetration of ruthenium red in 25-month-old rats, as compared with 3-month-old animals, was found. These data indicate an age-related change in the charge density of the intercellular channels in the dentate gyrus of 25-month-old rats. They suggest a primary age-related change in the charg density of extracellular macromoledules, presumed to be primarily glycosaminoglycans, with a consequent change in water binding capacity and volume of the extracellular space.

Aging↗
PubMed2002

Uncoupling of virus-induced inflammation and anti-viral immunity in the brain parenchyma.

Non-neuroadapted influenza virus confined to the brain parenchyma does not induce antigen-specific immunity. Nevertheless, infection in this site upregulated major histocompatibility complex (MHC) class I and MHC class II expression and recruited lymphocytes to a perivascular compartment. T cells recovered from the brain had an activated/memory phenotype but did not respond to viral antigens. In contrast, T cells recovered from the brain after infection in a lateral cerebral ventricle, which is immunogenic, showed virus-specific responses. As with infectious virus, influenza virus-infected dendritic cells elicited virus-specific immunity when inoculated into the cerebrospinal fluid but not when inoculated into the brain parenchyma. Thus, inflammation and dendritic cell function were both uncoupled from immune priming in the microenvironment of the brain parenchyma and neither was sufficient to overcome immunological privilege.

Animals↗