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At least 775 records · Page 43Linked to original sources
PubMed2002

Morphine induces apoptosis of human microglia and neurons.

Apoptosis plays a critical role in normal brain development and in a number of neurodegenerative diseases. Recently, opiates have been shown to promote apoptotic death of cells of the immune and nervous systems. In this study, we investigated the effect of morphine on apoptosis of primary human fetal microglial cell, astrocyte and neuronal cell cultures. Exposure of microglia and neurons to 10(-6) M morphine potently induced apoptosis of these brain cells (approximately fourfold increase above untreated control cells). In contrast to microglia and neurons, astrocytes were completely resistant to morphine-induced apoptosis. Concentration-response and time-course studies indicated that neurons were more sensitive than microglia to morphine's effect on apoptosis. Naloxone blocked morphine-induced apoptosis suggesting involvement of an opiate receptor mechanism. Potent inhibition (>70%) of apoptosis by an inhibitor of caspase-3 as well as co-localization of active caspase-3 and DNA fragmentation in microglia or neurons treated with morphine indicated that caspase-3 is involved in the execution phase of morphine-induced apoptosis. The results of these in vitro studies have implications regarding the potential effect of opiates on fetal brain development and on the course of certain neurodegenerative diseases.

Analgesics, Opioid↗
PubMed1997

Analysis of B7-1 and B7-2 costimulatory ligands in cultured mouse microglia: upregulation by interferon-gamma and lipopolysaccharide and downregulation by interleukin-10, prostaglandin E2 and cyclic AMP-elevating agents.

Recent evidence indicates that membrane-bound costimulatory molecules of the B7 family are important for T-cell activation and are upregulated in IFN gamma-stimulated human microglia and in multiple sclerosis active lesions. In this study we have performed a detailed analysis of B7-1 and B7-2 expression and regulation in cultured mouse glial cells using immunocytochemical and semi-quantitative reverse transcriptase-polymerase chain reaction techniques. In an immortalized mouse microglial cell line (BV-2), expression of B7-1 and B7-2 was enhanced by interferon-gamma (IFN gamma). IFN gamma was a weak inducer of B7-2 mRNA and immunoreactivity in microglia primary cultures obtained from the neonatal mouse brain, whereas lipopolysaccharide, tumour necrosis factor-alpha, colony-stimulating factors and interleukin-1 beta did not affect microglial B7-2 expression. Combined IFN gamma and lipopolysaccharide treatment very effectively upregulated the B7-2 gene expression and immunoreactivity in microglia, but not in astrocytes. In both glial cell types, expression of B7-1 was not induced by any of the above agents. Among known microglia/macrophage deactivators, interleukin-10, prostaglandin E2 and cAMP-elevating agents, but not transforming growth factor-beta 1 and interleukin-4, inhibited B7-2 transcripts and immunoreactivity in IFN gamma/LPS-stimulated microglia, thus suggesting possible paracrine and autocrine mechanisms for regulating the expression of this important T-cell costimulatory signal in the brain.

Animals↗
PubMed1997

Ia expression and antigen presentation by glia: strain and cell type-specific differences among rat astrocytes and microglia.

Astrocytes from experimental allergic encephalomyelitis (EAE)-susceptible Lewis rats expressed higher levels of Interferon-gamma-inducible Ia than astrocytes from EAE-resistant Brown Norway (BN) rats, whereas BN microglia expressed higher Ia than Lewis at both mRNA and protein levels. Lewis astrocytes induced proliferation of MBP-specific T cells selected on Lewis background as efficiently as Lewis thymocytes, whereas BN astrocytes were much less efficient in stimulating T cells selected in the presence of BN thymocytes. Microglia, irrespective of strain, induced only weak proliferative responses of these T cells despite the high expression of Ia. Antigen-stimulated T cells underwent apoptosis in the presence of microglia but not astrocytes. Thus, astrocyte-mediated proliferation of MBP-specific T cells may contribute to the development of EAE, while microglia-induced T cell apoptosis may downregulate immunopathological processes in the brain.

Animals↗
PubMed1999

Increased interleukin-6 expression by microglia from brain of aged mice.

Over expression of inflammatory cytokines in the brain may establish a state that is permissive to the onset of neurodegenerative disease. Because the occurrence of certain neurodegenerative diseases increases with age, in the present study we examined the expression of the inflammatory cytokine, interleukin-6 (IL-6), in the brain of aged mice. In an initial experiment, IL-6 was measured in crude protein extracts from brains of juvenile (1-month-old), adult (3-month-old), and aged (24-month-old) male BALB/c mice. The concentration of IL-6 in crude protein extracts from the cerebellum, cerebral cortex, and hippocampus increased with age. The increase in IL-6 was discrete, as levels in the hypothalamus were not age-dependent. To begin evaluating spontaneous IL-6 production in aging, glial cells were cultured from brains of neonate, adult, and aged mice. An age-associated increase in IL-6 mRNA and supernatant IL-6 concentration was evident, indicating glia from aged mice spontaneously express high levels of IL-6 relative to glia from adult and neonate mice. Flow cytometric analysis revealed that cultures established from aged brain compared to either adult or neonate brain comprised more microglia (i.e., MAC-1-positive cells). Furthermore, the proportion of microglia that was positive for IL-6 increased with age, whereas the proportion of astrocytes that were positive for IL-6 was not age-dependent. The present results suggest that IL-6 increases in the mouse brain with age, and that microglia cultured from aged mice spontaneously produce more IL-6 than those from neonate or adult mice. Therefore, microglia may contribute to the increased level of IL-6 present in aged brain.

Aging↗
PubMed1999

Comparison of C1q-receptors on rat microglia and peritoneal macrophages.

A comparison of the expression and ligand specificity of the C1q (first complement component) receptor on rat microglia and peritoneal macrophages was made. This revealed that radiolabelled C1q was competed from the peritoneal macrophages with intact C1q, and additively displaced by calf-skin collagen and purified C1q globular heads, suggesting the presence of at least two receptors. This was in contrast to microglia, where radiolabelled C1q was displaced with intact C1q and to a modest degree with collagen, but not with globular heads. Taken together, this implies that under these conditions, peritoneal macrophages and microglia both express a C1q receptor which binds to the collagen-like region, and that peritoneal macrophages additionally express a molecule which binds to the globular head of C1q. Analysis of the ligand bound by these cells reflected the differences observed in the competitive binding experiments, with the novel identification of naturally-occurring peptides from the globular head of C1q bound to the peritoneal macrophages, but not the microglia.

Amino Acid Sequence↗
PubMed2003

Microglia in the olfactory bulb of rats during postnatal development and olfactory nerve injury with zinc sulfate: a lectin labeling and ultrastrucutural study.

Using isolectin (GSA I-B4) as a marker, this study examined the possible alterations of lectin-labeled membranous glycoproteins in microglial cells in the olfactory bulb of normal development and under experimentally induced degeneration. In light microscopy, several morphological types of microglial cells representing different degrees of cell differentiation were distributed in the bulb laminae. A gradient of microglial differentiation extending from the intermediate to superficial and intermediate to deep occurs in the bulb layers. The differentiation gradient and lectin labeling pattern of microglial cells in the developing bulb resembled those in other areas of the brain tissues. Differentiating microglia showed a gradual diminution of lectin staining when the nascent round cells transformed into the mature ramified cells. Microglia in the external plexiform layer of the olfactory bulb were the first to mature and the cells expressed very weak lectin reactivity. In mature or adult rats, some microglial cells showing intense lectin labeling were observed in the olfactory nerve layer, granule cell layer and subependymal layer. Ultrastructurally, lectin labeling was localized at the trans saccules of the Golgi apparatus. Microglial cells in other bulb laminae, however, exhibited a negative reaction for the isolectin at the Golgi apparatus. Following intranasal irrigation of zinc sulfate, some microglial cells in the olfactory nerve layer and glomerular layer were activated to become phagocytic cells with increased lectin labeling at their ramified processes. GSA I-B4 staining was also localized at their trans saccules of the Golgi apparatus. The lectin labeling pattern of these phagocytic cells resembled that of differentiating microglia in postnatal bulbs, suggesting that bulb microglia in the lesioned sites were activated through cell dedifferentiation into macrophages.

Animals↗
PubMed2001

Lactoferrin is synthesized by activated microglia in the human substantia nigra and its synthesis by the human microglial CHME cell line is upregulated by tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment.

The presence of the iron-binding protein lactoferrin (Lf) in some specific areas of the central nervous system and particularly in the normal human substantia nigra, where it is found in dopaminergic (DA) neurons and some glial cells, led us to investigate Lf synthesis in this area. Lf mRNA were identified using in situ hybridization and found in small ameboid cells. These cells were identified using immunocytochemistry as activated microglia since they exhibited macrophage markers such as the CD68 and the CR1 antigens. Double immunofluorescent labeling confirmed that the two Lf immunostained cell populations were activated microglia and DA neurons. Since activated microglia contained both Lf and its messenger, these cells are the Lf producing cells. The presence of Lf in DA neurons in which no Lf messengers were visible, might be due to an endocytosis mechanism, DA neurons probably internalizing Lf produced in microglial cells located in their neighborhood. In neuropathological disorders, such as Alzheimer's and Parkinson's diseases, inflammatory process and oxidative stress are events that contribute to neuronal death. Since Lf concentration increases during these pathologies, we studied the level of Lf expression under these different stresses and showed, using RT-PCR, that the immortalized human embryonic microglial CHME cell line produced Lf transcripts under tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment whereas untreated cells did not. These data confirm that Lf is produced only when microglia are activated.

1-Methyl-4-phenylpyridinium↗
PubMed2002

Hypoxia induces nitric oxide production in mouse microglia via p38 mitogen-activated protein kinase pathway.

In vitro exposure of microglial cells to hypoxia induces cellular activation. Also, in vivo studies of glial activation following ischemic hypoxia have shown that neuronal cell death is followed by microglial activation. Thus, it is likely that toxic inflammatory mediators produced by activated microglial cells under hypoxic conditions may exacerbate neuronal injury following cerebral ischemia. Nitric oxide (NO), which is known to be produced by activated microglia, may participate in this process. In the current work, we sought to determine whether and how the production of NO and the expression of inducible NO synthase (iNOS) are triggered by hypoxia in microglial cells. Exposure of established microglial cell lines as well as primary mouse microglial cultures to mild hypoxia (8 h) followed by reoxygenation (24 h) induced the production of NO and TNFalpha, indicating that hypoxia could lead to the inflammatory activation of microglia. Hypoxic induction of NO was accompanied by iNOS induction. Moreover, hypoxia induced the activation of p38 MAPK, but not ERK or JNK/SAPK, in BV-2 mouse microglial cells. SB203580, a specific inhibitor of p38 MAPK, blocked the hypoxic induction of NO and iNOS. Taken together, our results indicated that hypoxia could induce inflammatory activation of microglia, and the hypoxic induction of NO production in microglia is mediated through p38 MAPK pathway. Thus, during cerebral ischemia, hypoxia may not only directly damage neurons, but may also promote neuronal injury indirectly via microglial activation.

Animals↗
PubMed1998

Lipopolysaccharide-induced expression of IP-10 mRNA in rat brain and in cultured rat astrocytes and microglia.

Using mRNA differential display technique, we have found a differentially expressed band in rat brain, designated HAP2G1, which was the strongest one induced in response to peripheral administration of lipopolysaccharide (LPS). Sequence analysis showed that HAP2G1 cDNA is the rat homologue of the human alpha-chemokine IP-10. Using RT-PCR technique and in situ hybridization, we demonstrate that IP-10 mRNA was expressed only in brain tissue of rats treated with LPS and not in control brain tissue. Using semi-quantitative PCR, we found that both cultured astrocytes and microglia express IP-10 mRNA after treatment with LPS. LPS-induced IP-10 mRNA reached peak levels in rat brain and in cultured microglia at approximately 3 h after treatment with LPS. At 10 h, IP-10 mRNA was markedly decreased, and at 24 h it was low but still detectable by PCR or in situ hybridization. In contrast to unstimulated microglia, unstimulated astrocytes constitutively expressed IP-10 mRNA at a low level. Increased IP-10 expression could possibly be involved in the microglia response to inflammatory stimuli in vivo.

Animals↗
PubMed1999

Inhibitory effects of indomethacin on interleukin-1 and nitric oxide production in rat microglia in vitro.

Indomethacin, as a nonsteroidal antiinflammatory drug, is reported to be effective in some degree in the prevention and treatment of Alzheimer's disease (AD). Effects of indomethacin on proinflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor alpha and nitric oxide (NO) on rat microglia in vitro were investigated. The biological activities of IL-1 were assayed by thymocyte proliferation assay and the activities of TNG-alpha, by L929 cytotoxicity assay. NO concentration was represented by nitrite and determined by Griess reaction. Indomethacin inhibited IL-1 and NO production by rat microglia stimulated at the concentration of 0.1-10 micromol/l. However, it did not show any inhibitory effect on TNF-alpha production by resting and LPS-stimulated rat microglia. The results suggest that the mechanism by which indomethacin might be beneficial in treatment of AD might be due to the inhibition IL-1 and NO production from microglia.

Animals↗
PubMedDate not supplied

Microglia, scavenger receptors, and the pathogenesis of Alzheimer's disease.

The senile plaque is the pathological hallmark of Alzheimer's disease. Senile plaques are composed of beta amyloid fibrils, associated with activated microglia, astrocytes, and dystrophic neurons. We have recently identified class A scavenger receptors as the main receptors mediating the interaction of microglia with beta amyloid fibrils. Adhesion of microglia to beta amyloid fibrils leads to immobilization of these cells on the fibrils, and induces them to produce reactive oxygen species. We propose that interactions of microglial scavenger receptors with fibrillar beta amyloid may stimulate the microglia to secrete apolipoprotein E and complement proteins, which may further contribute to neurotoxicity and neuronal degeneration. Therefore, microglial scavenger receptors may be novel targets for therapeutic interventions in Alzheimer's disease.

Alzheimer Disease↗
PubMed2000

Regional distribution of cortical microglia parallels that of neurofibrillary tangles in Alzheimer's disease.

It has been postulated that microglia contribute to the development of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). We compared the distribution of microglia with that of NFT in both AD and non-AD cases. In AD cases, we found that the extent of area covered by Ricinus communic agglutinin-1 labeled microglia generally paralleled NFT frequency and distribution. Microglia occupied the greatest area in tangle-rich periallocortex/allocortex, a lesser area in association cortex, and the smallest area in tangle-poor primary cortex. Interestingly, this pattern was also present in non-AD cases where there were few to no NFT. These findings suggest that regional variations in microglial distribution may constitute, at least in part, a template for the development of NFT.

Aged↗
PubMed2001

Identification of protein kinase C isoforms involved in interferon-gamma-induced expression of inducible nitric oxide synthase in murine BV2 microglia.

Microglia are major inflammatory cells of the brain. It has been known that interferon-gamma (IFN-gamma) induces nitric oxide (NO)/inducible nitric oxide synthase (iNOS) in microglia, and that protein kinase C (PKC) mediates the action of IFN-gamma. In this study, we investigated isoforms of PKC that are involved in IFN-gamma-induced activation of microglia using BV2 murine microglial cells. NO release/iNOS expression in IFN-gamma -treated BV2 cells was reduced in the presence of PKC inhibitors (Gö 6976 and BIM), and by long-term pre-treatment (48 h) of cells with phorbol-12-myristate-13-acetate (PMA) or thymeleatoxin. PMA depleted alpha, beta, delta, and epsilon isoforms, and thymeleatoxin depleted alpha, beta, and epsilon isoforms although gamma, eta, iota, lambda, theta, mu, and zeta were also detected in these cells. Furthermore, IFN-gamma phosphorylated alpha and epsilon on their tyrosine residues. These results suggested that alpha and epsilon could be the major PKC isoforms involved in signaling pathways of IFN-gamma to induce NO/iNOS expression in BV2 microglia.

Animals↗
PubMed2001

Beta-amyloid peptide induces the expression of voltage dependent outward rectifying K+ channels in rat microglia.

Upregulation of voltage-dependent outward rectifying K+ (Kv) channels has been reported in activated microglia. Since beta-amyloid peptide (A beta) is known to activate microglia, we tested whether the exposure of cultured rat microglia to A beta fragment 25-35 (A beta 25-35) induced the Kv current. A beta 25-35 in 5-200 nM concentration range significantly increased Kv current density, while there was small change in inward rectifying K+ current density. The full length A beta peptide (A beta 1-42) also increased Kv current. However, the control peptide, A beta 35-25, did not induce Kv current. Most of the Kv current induced by A beta was specifically blocked by the presence of antisense deoxyoligonucleotides against Kv1.3, and Kv1.5. Thus, it is concluded that we have identified Kv1.3 and Kv1.5 as the channel types expressed in A beta-treated microglia.

Alzheimer Disease↗
PubMed2001

Synergistic apoptosis induced by bacterial endotoxin lipopolysaccharide and high glucose in rat microglia.

The present study investigates whether bacterial lipopolysaccharide (LPS) in the presence of increased levels of glucose induced synergistic cytotoxicity in primary cultured microglia. Significant cytotoxicity was only observed while the concentrations of LPS were increased to 10 microg/ml. D-glucose concentration-dependently (25-125 mM) generated cytotoxicity. Synergistic apoptosis of microglia was seen by LPS in the presence of increased levels of D-glucose. This synergistic cytotoxicity was attenuated by the use of superoxide dimutase and catalase, suggesting the involvement of oxidative free radicals. Collectively, the present results suggest that increased ambient levels of glucose rendered microglia vulnerable to LPS insults, and led to a synergistic apoptosis. The findings here may be important in certain patho-physiological implications in which hyperglycemia exacerbated the ambient functions contributed by microglia, and may provide new insight into a novel therapeutic intervention.

Animals↗
PubMed2003

Specific uptake of Abeta1-40 in rat brain occurs in astrocyte, but not in microglia.

In the brain of a patient with Alzheimer's disease, beta amyloid peptide (Abeta) is thought to be taken up by glial cells such as astrocyte and microglia to be degraded. However, it is unclear whether the Abeta is absorbed by astrocyte or microglia. The purpose of our study is to determine which type of glial cell, astrocyte or microglia, can take up Abeta. Beta amyloid 1-40 (Abeta1-40) was directly infused into the frontal cortex or hippocampus for 14 days. Dual-labeling immunohistochemistry for Abeta1-40 with an astrocytic (GFAP) or microglial (CD11b) marker was performed to examine co-localization of Abeta1-40 and glial markers. In the Abeta1-40 infused site, immunoreactivity of Abeta1-40 was observed only in astrocytes, not in microglia. In addition, Abeta40-1, a reverse peptide of Abeta1-40, was not taken up by astrocytes. These results suggested that the astrocyte-specific uptake of Abeta occurred in the rat brain.

Amyloid beta-Peptides↗
PubMed1998

Changes in proton currents in murine microglia induced by cytoskeletal disruptive agents.

Voltage-gated proton currents (IPR) were investigated in cultured murine microglia using the whole-cell configuration of the patch clamp technique. At a gradient of 1.5 between intracellular (pHi = 6.0) and extracellular pH (pHo = 7.5) values, outward IPR were detected at depolarizing potentials, while the activation threshold of IPR was -40 mV. Time-dependent activation of IPR was fitted by a single exponential with a time constant of 661 ms at +40 mV. An increase in the activation time constant of IPR was seen after exposure of microglia to the cytoskeletal disruptive agents cytochalasin D or colchicine. Moreover, the current density of IPR was significantly reduced by 49% in cells treated with cytochalasin D and by 27% in cells treated with colchicine for 24 h. In contrast, voltage-dependence of steady-state activation of IPR was unchanged after disruption of the cytoskeleton. Exposure of microglia to the cytoskeletal stabilizers phalloidin and taxol did not affect IPR of microglia.

Action Potentials↗
PubMed1998

Expression of FAC1 in activated microglia during Alzheimer's disease.

The presence of reactive microglia and astrocytes is a common observation in Alzheimer's disease brain. Microglia are present within the numerous beta-amyloid containing neuritic plaques, whereas reactive astrocytes usually surround the plaque perimeter. These glial cells express and secrete numerous neurotrophic and neurotoxic factors that contribute to the etiology of the disease. The molecular mechanisms that dictate glial cell activation and subsequent alternative gene expression are currently unknown. In the present study we determine that activated microglia in AD brain express the FAC1 protein, a developmentally regulated gene product, while astrocytes fail to express significant levels of FAC1 protein. Since FAC1 is a putative DNA binding protein, expression in microglia during AD suggests that FAC1 participates in the regulation of alternative gene expression.

Aged↗