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PubMed2003

Identification of gene products suppressed by human immunodeficiency virus type 1 infection or gp120 exposure of primary human astrocytes by rapid subtraction hybridization.

Neurodegeneration and human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) are the major disease manifestations of HIV-1 colonization of the central nervous system (CNS). In the brain, HIV-1 replicates in microglial cells and infiltrating macrophages and it persists in a low-productive, noncytolytic state in astrocytes. Astrocytes play critical roles in the maintenance of the brain microenvironment, responses to injury, and in neuronal signal transmission, and disruption of these functions by HIV-1 could contribute to HAD. To better understand the potential effects of HIV-1 on astrocyte biology, the authors investigated changes in gene expression using an efficient and sensitive rapid subtraction hybridization approach, RaSH. Primary human astrocytes were isolated from abortus brain tissue, low-passage cells were infected with HIV-1 or mock infected, and total cellular RNAs were isolated at multiple time points over a period of 1 week. This approach is designed to identify gene products modulated early and late after HIV-1 infection and limits the cloning of genes displaying normal cell-cycle fluctuations in astrocytes. By subtracting temporal cDNAs derived from HIV-1-infected astrocytes from temporal cDNAs made from uninfected cells, 10 genes displaying reduced expression in infected cells, termed astrocyte suppressed genes (ASGs), were identified and their suppression was confirmed by Northern blot hybridization. Both known and novel ASGs, not reported in current DNA databases, that are down-regulated by HIV-1 infection are described. Northern blotting confirms suppression of the same panel of ASGs by treatment of astrocytes with recombinant HIV-1 envelope glycoprotein, gp120. These results extend our previous analysis of astrocyte genes induced or enhanced by HIV-1 infection and together they suggest that HIV-1 and viral proteins have profound effects on astrocyte physiology, which may influence their function in the CNS.

AIDS Dementia Complex↗
PubMed2005

T-Cells and excitotoxicity: HIV-1 and other neurodegenerative disorders.

Until recently the central nervous system (CNS) was considered an immune-privileged site, however, technological and immunological advances have resulted in the CNS being reclassified as an "immune-specialized site." The immune cells, particularly T-cells, continuously patrol the brain and are involved in neuroimmune responses. As such, any changes in the brain microenvironment could affect the physiological functioning of T-cells. Particularly, neurotransmission- associated abnormalities, such as excitotoxicity associated with hypersecretion of glutamate, could severely affect the neuroimmune function of T-cells. Excitotoxicity is involved in the pathogenesis of a number of neurodegenerative disorders. The specific excitotoxicity triggered by the excitatory amino acid neurotransmitter, glutamate, is considered a key mechanism involved in neuronal death. The inability of brain immune cells to overcome these aberrant changes is an active area of investigation. In the systemic circulation, glutamate is inversely related to the number of CD4+ T-cells; however, the effects of elevated glutamate and glutamate-induced exicitotoxicity on cells homing in the brain are critical for understanding neuropathogenesis of neurodegenerative disorders.

AIDS Dementia Complex↗
PubMed2004

Glycerophosphoinositol and dexamethasone improve transendothelial electrical resistance in an in vitro study of the blood-brain barrier.

The blood-brain barrier (BBB) maintains the homeostasis of the brain microenvironment, which is crucial for neuronal activity and function. Under pathological conditions, the BBB may fail due to yet unknown mechanisms. BBB failure is accompanied by an increase in the transendothelial permeability to substances such as sucrose that are normally extruded. Furthermore, altered BBB function may also lead to development of abnormal drug extrusion mechanisms including expression of multiple drug resistance proteins. Therefore, it is not surprising that strategies have been developed to "repair" the BBB in order to restore normal brain homeostasis and penetration/extrusion of pharmacologically active (noxious) substances. To this end, steroidal hormones and synthetic analogues such as dexamethasone (DEX) have been used to counteract BBB failure. However, several side effects limit the usefulness of steroid treatment in humans leading to the quest for developing novel strategies for BBB repair. We here show that, in an in vitro model of the BBB based on a co-culture of endothelial cells (EC) and glia, the natural compound glycerophosphoinositol (GPI) may replicate the effects of DEX. Thus, GPI in concentrations ranging from 3 to 100 microM promoted both BBB formation and repair in a dose dependent fashion. Similar effects were obtained with an elevated dose of DEX (10 microM); at higher concentrations (100 microM), DEX was cytotoxic. We conclude that the endogenous anti-inflammatory agent GPI may ameliorate BBB function with efficacy comparable to that of steroids, but with significantly fewer side effects. Further experiments will confirm the efficacy of this treatment in vivo and elucidate the pathways that lead to BBB repair after exposure to GPI.

Animals↗
PubMed2006

Imaging of cortical astrocytes using 2-photon laser scanning microscopy in the intact mouse brain.

A number of studies over the past decade have shown that astrocytes, the supportive cells of the brain, play important roles in synaptic transmission including regulating the strength of both excitatory and inhibitory synapses. A major challenge for the future is to define the role of astrocytes in complex tasks, such as functional hyperemia and sensory processing, as well as their contribution to acute and degenerative diseases of the nervous system. Multiphoton imaging approaches are ideally suited to study electrically non-excitable astrocytes. We here discuss novel in vivo studies aimed at defining the role of astrocytes in normal and pathological brain function. With a better understanding of the role astrocytes play in information processing and regulation of the brain microenvironment in vivo, and the understanding that astrocytes are heavily implicated in the pathology of many diseases such as epilepsy, Alzheimer's and Parkinson's diseases, astrocytes provide a promising target for future drug therapy approaches.

Animals↗
PubMed2003

Constitutive patterns of RANTES, MCP-1 and MIP-1 alpha expression at the mRNA and protein level during postnatal development of the rat brain.

The importance of chemokines seems to extend far beyond their well-known role as mediators of an inflammatory response. The most interesting hypothesis is that these molecules may influence the migration of progenitor cells during development. Primary sensory neurones have been shown to migrate towards RANTES in vitro. Recent evidence has revealed that MCP-1, MIP-1alpha and MIP-1beta are potent chemoattractants for glial cell populations. The exact role of the constitutive appearance of chemokines in the CNS during postnatal development is still largely unknown. The intention was to show whether constitutive temporal and spatial profiles of RANTES, MCP-1 and MIP-1alpha expression vary during the postnatal development of the rat brain. RT-PCR was used to assess the levels of mRNA production at different developmental stages. Semi-quantitative analysis of the immunofluorescence signal from glial cells harbouring chemokines was used to determine the spatial-temporal patterns of protein expression. It has been shown here that all chemokines are constitutive factors within the brain microenvironments where the postnatal migration phenomenon occurs. The chemokines were characterised by variable temporal patterns of mRNA production and distinct spatial-temporal patterns of protein appearance. This may support the differences between RANTES, MCP-1 and MIP-1alpha functional significance in vivo in terms of influence on the migration of distinct cell populations.

Animals↗
PubMed2006

Gene therapy, cell transplantation and stroke.

The use of neuroteratocarcinoma cells for transplantation therapy in stroke has emerged as a strategy for cell replacement therapy that has begun its transition from basic science laboratories to a clinical setting. Procurement logistics and novel neuroprotective functions associated with these cells allow neuroteratocarcinoma cells to serve as efficacious alternatives to using fetal cells as donor cell grafts for stroke therapy, although the optimal transplantation regimen must still be determined. In particular, the limitations of current stroke treatments and management reveal an urgent need to examine the efficacy of experimental treatments, such as neural transplantation, in order to develop better treatment therapies. This chapter will discuss the characteristics of NT2N cells, the role of the host brain microenvironment and NT2N cell grafts, laboratory research and clinical trials for the intracerebral transplantation of NT2N cells in stroke, the mechanisms underlying the grafts' effects, and NT2N cell grafts and the need for immunosuppression. This chapter will also highlight some of the most recent findings regarding NT2N cells.

Adult↗
PubMed1993

O2A progenitor cells transplanted into the neonatal rat brain develop into oligodendrocytes but not astrocytes.

The differentiation of the bipotential O2A progenitor cell into an oligodendrocyte or a type 2 astrocyte has been well documented in cell cultures of various regions of the central nervous system. The appropriate tools to prove its existence in vivo have been lacking. We report on an in vitro-in vivo approach that combines stable labeling of an enriched population of cultured O2A progenitors by the fluorescent dye fast blue, followed by their transplantation into neonatal rat brains, which allowed us to study the influence of the brain microenvironment on their lineage decision. The grafted cells survived well and 21 days after grafting nearly all were positive for the oligodendroglial marker galactocerebroside. Surprisingly, the fast blue-positive grafted cells did not stain for the astroglial marker glial fibrillary acidic protein. These results indicate that the O2A progenitor's plasticity is restricted by the in vivo environment, resulting in the developmental exclusion of the type 2 astrocyte initially described in vitro.

Aging↗
PubMed1999

Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia.

Traumatic brain injury (TBI) can be associated with memory impairment, cognitive deficits, or seizures, all of which can reflect altered hippocampal function. Whereas previous studies have focused on the involvement of neuronal loss in post-traumatic hippocampus, there has been relatively little understanding of changes in ionic homeostasis, failure of which can result in neuronal hyperexcitability and abnormal synchronization. Because glia play a crucial role in the homeostasis of the brain microenvironment, we investigated the effects of TBI on rat hippocampal glia. Using a fluid percussion injury (FPI) model and patch-clamp recordings from hippocampal slices, we have found impaired glial physiology 2 d after FPI. Electrophysiologically, we observed reduction in transient outward and inward K(+) currents. To assess the functional consequences of these glial changes, field potentials and extracellular K(+) activity were recorded in area CA3 during antidromic stimulation. An abnormal extracellular K(+) accumulation was observed in the post-traumatic hippocampal slices, accompanied by the appearance of CA3 afterdischarges. After pharmacological blockade of excitatory synapses and of K(+) inward currents, uninjured slices showed the same altered K(+) accumulation in the absence of abnormal neuronal activity. We suggest that TBI causes loss of K(+) conductance in hippocampal glia that results in the failure of glial K(+) homeostasis, which in turn promotes abnormal neuronal function. These findings provide a new potential mechanistic link between traumatic brain injury and subsequent development of disorders such as memory loss, cognitive decline, seizures, and epilepsy.

Animals↗
PubMed2002

Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin.

The quality of the blood-brain barrier (BBB), represented mainly by endothelial tight junctions (TJ), is now believed to be dependent on the brain microenvironment and influenced by the basal lamina of the microvessels. In the highly vascularized glioblastoma multiforme (GBM), a dramatic increase in the permeability of blood vessels is observed but the nature of basal lamina involvement remains to be determined. Agrin, a heparan sulfate proteoglycan, is a component of the basal lamina of BBB microvessels, and growing evidence suggests that it may be important for the maintenance of the BBB. In the present study, we provide first evidence that agrin is absent from basal lamina of tumor vessels if the TJ molecules occludin, claudin-5 and claudin-1 were lacking in the endothelial cells. If agrin was expressed, occludin was always localized at the TJ, claudin-5 was frequently detected, whereas claudin-1 was absent from almost all vessels. Furthermore, despite a high variability of vascular phenotypes, the loss of agrin strongly correlated with the expression of tenascin, an extracellular matrix molecule which has been described previously to be absent in mature non-pathological brain tissue and to accumulate in the basal lamina of tumor vessels. These results support the view that in human GBM, BBB breakdown is reflected by the changes of the molecular compositions of both the endothelial TJ and the basal lamina.

Agrin↗
PubMed2005

Autocrine peptide mediators of cerebral endothelial cells and their role in the regulation of blood-brain barrier.

A unique feature of cerebral endothelial cells (CECs) is the formation of the blood-brain barrier (BBB), which contributes to the stability of the brain microenvironment. CECs are capable of producing several substances mediating endothelium-dependent vasorelaxation or vasoconstriction, regulating BBB permeability, and participating in the regulation of cell-cell interactions during inflammatory and immunological processes. The chemical nature of these mediators produced by CECs ranges from gaseous anorganic molecules (e.g. nitric oxide) through lipid mediators (e.g. prostaglandins) to peptides. Peptide mediators are a large and diverse family of bioactive molecules which can elicit multiple effects on cerebral endothelial functions. In this review, we summarize current knowledge of peptide mediators produced by CECs, such as adrenomedullin, angiotensin, endothelin and several others and their role in the regulation of BBB functions.

Animals↗
PubMed2002

Breakdown of the blood-brain barrier and neuropathological changes induced by Phoneutria nigriventer spider venom.

The blood-brain barrier (BBB) is responsible for selective flux of substances between blood and brain. The selective permeability of the BBB is crucial for the maintenance of the brain microenvironment homeostasis, and alterations in the barrier may be involved in many pathophysiological processes. Phoneutria nigriventer armed spider venom produces excitatory signals and symptoms in humans, and its recognized neurotoxic action suggests a potential ability to alter BBB permeability. The aim of the present study was to investigate the capacity of P. nigriventer venom (PNV) in promoting BBB breakdown in adult rats. After intravenous injection of 850 micro g/kg of the whole venom, BBB lesions were evaluated after 18 h to 9 days by ultrastructural methods using the extracellular tracer lanthanum nitrate. Clinical signs and symptoms of rats showed acute neurotoxicity, with some of the animals presenting convulsions, but which were clinically resolved by 12 h post-envenoming. The results showed that PNV is able to increase BBB permeability, particularly in the hippocampus. Changes were first detected in arterioles and post-capillary venules 18 h to 5 days after venom inoculation. The increased permeation of the extracellular tracer peaked on day 1, representing about 42% of the examined vessels (P<0.01). This appeared to occur by both transendothelial and intercellular routes, i.e., by pinocytic transport and through interendothelial junctions. Concomitantly, the surrounding tissue showed vasogenic edema and swollen astrocytic processes, without inflammatory infiltrates. The peak of the edema occurrence was observed on day 3, in about 60% of the vessels (P<0.001). Enhanced capillary permeability was observed on day 9, and affected 36% of all capillaries (P<0.05). The affected capillaries were characterized by increased number of pinocytotic vesicles, which, in addition, were filled with the extracellular tracer, but without visible transport through the interendothelial pathway. This study demonstrates that systemic PNV inoculation induces BBB breakdown through trans- and paracellular routes. It is concluded that BBB breakdown is an event not associated with the acute neurotoxicity exhibited by the rats.

Animals↗
PubMed1982

Physiological and ultrastructural evidence for an extracellular anion matrix in the central nervous system of an insect (Periplaneta americana).

The efflux of radiocations (22Na, 2K and 45Ca) and of radiochloride occur as two-stage processes from intact cockroach nerve cords. It is suggested that the initial, fast fraction of efflux comes mainly from the superficial connective tissue layer, the neural lamella, and the clefts between the underlying layer of neuroglia, the perineurium. This is deduced from the lack of effect of a metabolic inhibitor and sodium-transport inhibitors on the fast component of 22Na efflux (which contrast with their effects both on the size an the half-time of the slow component) and from the typically extracellular ratios between the fast components of substantial increase in the fast fractions of 22Na and 45Ca efflux but only a small increase in 36Cl efflux: effects which would be expected if the addition to the fast fraction consisted of ions maintained in Donnan equilibrium with fixed anionic sites within the extracellular system. The presence of such anionic sites is also indicated by lanthanum-binding in the extracellular matrix and by the previous histochemical demonstration of hyaluronic acid in the matrix by Ashhurst and Costin. It is suggested that the anionic glycosaminoglycans provide an extracellular cation reservoir which could serve a role in short-term ionic homeostasis of the brain microenvironment.

Animals↗
PubMed1995

The microglial cell. A historical review.

Effectively, modern research has confirmed Hortega's view of the origin of the microgliacyte from circulating monocytes of the monocyte-macrophage series that invade the brain during embryonic and early postnatal life. Their phagocytic capacity is exercised during the brain remodelling that marks brain maturation. They then convert to the ramified resting microglial cell visualized in the silver carbonate staining technique of Hortega and by modern lectin-binding methods. In response to injury, reactive microglia exhibit hypertrophy and hyperplasia, and may or may not go on to form typical lipid-laden phagocytes. Activated microglia show upregulation of the many marker antigens they share with circulating monocytes, including the major histocompatibility class (MHC) class II antigens that bespeak their immunocompetent nature. However, MHC class I and II expression and development of immunohistochemical positivity for cytoplasmic and plasma membrane antigens that characterize the monocyte-macrophage do not necessarily indicate an immunological response though there is ample evidence that microglia can serve as antigen-presenting cells. Rather, microglia are extraordinarily sensitive to changes in the brain microenvironment, whatever the nature of the exciting mechanism or substance. They may be considered to serve an ever alert, protective and supportive function that can be assembled rapidly to deal with infections, physical injuries, physiologic changes and systemic influences. In addition to elaboration and secretion of cytokines with varied actions, e.g., suppression of astrogliosis, they secrete factors, including nerve growth factor, which are supportive of neurons. They have an important role in iron metabolism and the storage of iron and ferritin. They may promote central nervous system regeneration. They are prominently involved in such pathologic processes as the acquired immunodeficiency syndrome, multiple sclerosis, prion diseases and the degenerative disorders, e.g., Alzheimer's disease and Parkinson's disease. With aging, they grow more numerous, become richer in iron and ferritin and exhibit phenotypic alteration, e.g., the expression of MHC class II antigens that are not ordinarily demonstrable immunohistochemically in the resting state. The rate of growth of our knowledge of microglia during the last decade has been exponential and continues.

Animals↗
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

Endothelin Opens Potassium Channels in Glial Cells.

Endothelin-1 (ET-1), an autocrine hormone synthesized by astrocytes, and endothelin-3 (ET-3), a highly homologous peptide produced by neurons, have both been shown previously to cause proliferation of these astrocytes in culture [Supattapone et al. (1989) Biochem. Biophys. Res. Commun., 165, 1115 - 1122; MacCumber et al. (1990) Proc. Natl. Acad. Sci. USA, 87, 2359 - 2363]. We now demonstrate, using 86Rb+ influx assays and single channel patch-clamp recording, that both endothelins-ET-3 and ET-1-can also open a charybdotoxin-sensitive, calcium-activated K+ channel of 15 - 40 pS in glial cells. The opening of this channel may be important for the regulation of [K+] in the brain microenvironment. Thus, the endothelins may be a general mediator of astroglial response to neuronal injury.

Journal Article↗
PubMed2006

Immune privilege and HIV-1 persistence in the CNS.

Human immunodeficiency virus-1 (HIV-1) neuroinvasion occurs early (during period of initial viremia), leading to infection of a limited amount of susceptible cells with low CD4 expression. Protective cellular and humoral immunity eliminate and suppress viral replication relatively quickly due to peripheral immune responses and the low level of initial central nervous system (CNS) infection. Upregulation of the brain protective mechanisms against lymphocyte entry and survival (related to immune privilege) helps reduce viral load in the brain. The local immune compartment dictates local viral evolution as well as selection of cytotoxic lymphocytes and immunoglobulin G specificity. Such status can be sustained until peripheral immune anti-viral responses fail. Activation of microglia and astrocytes, due to local or peripheral triggers, increases chemokine production, enhances traffic of infected cells into the CNS, upregulates viral replication in resident brain macrophages, and significantly augments the spread of viral species. The combination of these factors leads to the development of HIV-1 encephalitis-associated neurocognitive decline and patient death. Understanding the immune-privileged state created by virus, the brain microenvironment, and the ability to enhance anti-viral immunity offer new therapeutic strategies for treatment of HIV-1 CNS infection.

Central Nervous System↗
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↗