RESUMO
Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum-mitochondria interface, which might be an astrocyte-based form of long-term depression.
Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Receptores sigma/metabolismo , Envelhecimento/metabolismo , Animais , Citosol/metabolismo , Camundongos Transgênicos , Mitocôndrias/metabolismo , Neurotransmissores/metabolismo , Ratos Sprague-Dawley , Frações Subcelulares/metabolismo , Transcrição Gênica , Regulação para Cima , Receptor Sigma-1RESUMO
CASE REPORT: A 14-year-old girl presented with 1 cm large whitened lesion on the ventral surface of the tongue, appeared from 1 month. Past history showed congenital dyserythropoietic anemia type II. The lesion was excised and microscopic and immunohistochemical analyses were compatible with benign Abrikossoff tumor. Total body MRI was negative. After six months the patient presented a second tongue lesion and four months later another large painful lesion in the soft palate, with the same istological diagnosis. In addition, she had other multiple lesions: two apperead at pharyngeal level (not biopsied) that remain stable over time, and one at the pituitary gland. CONCLUSION: Granular cell tumors, with or without multiple lesions, are rare in children. About 50% of cases involve the head and neck region, with the tongue being the most affected site. Therapy is based on the surgical excision of the lesions; however some tumor forms, although their histological aspect of benignity, often have an important infiltrative power, making the therapeutic approach difficult, as in our case.
Assuntos
Anemia Diseritropoética Congênita , Tumor de Células Granulares , Adolescente , Feminino , Tumor de Células Granulares/complicações , Tumor de Células Granulares/cirurgia , Humanos , Imageamento por Ressonância Magnética , Recidiva Local de NeoplasiaRESUMO
Attention has focused on particular neurons as the source of nitric oxide (NO) within the parenchyma of the CNS. In contrast, glial cells have been viewed mainly as potential reservoirs of L-arginine, the substrate for nitric oxide synthase (NOS), and as likely targets for neuronally derived NO because of their proximity and their expression of soluble guanylyl cyclase (sGC). However, it is becoming evident that astrocytes display both constitutive and inducible NOS activity under various conditions, and that activated microglia express an inducible NOS. The NO-producing capacity of oligodendrocytes is not yet known. Glial-derived NO has significant implications for CNS pathophysiology, given the anatomical location and abundance of these cells, and the wide variety of potential interactions that NO can have with cellular biochemistry. Our intention here is to evaluate the evidence for NO production from non-neuronal CNS sources and thus prompt discussion about potential 'nitrinergic' roles for glial cells.
Assuntos
Sistema Nervoso Central/metabolismo , Neuroglia/metabolismo , Óxido Nítrico/metabolismo , Aminoácido Oxirredutases/metabolismo , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/enzimologia , Humanos , Óxido Nítrico SintaseRESUMO
Bisphosphonates (BPs) are commonly used in the treatment of myeloma-associated osteolytic lesions. Recent reports have suggested that BPs may also exert direct antitumor effects on myeloma cells. Here, we show that the treatment of myeloma cell lines with the combination of the potent BP zoledronate and dexamethasone inhibits cell growth and synergistically induces apoptotic cell death, providing a rationale for potential applications in vivo.
Assuntos
Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Dexametasona/toxicidade , Difosfonatos/toxicidade , Imidazóis/toxicidade , Sinergismo Farmacológico , Citometria de Fluxo/métodos , Humanos , Mieloma Múltiplo , Células Tumorais Cultivadas , Ácido ZoledrônicoRESUMO
Choline acetyltransferase (ChAT) activity is present in isolated cerebral capillaries, where it has been considered to be a marker for perivascular cholinergic nerve terminals. However, ChAT-like immunoreactivity has been visualized in endothelial cells. This finding raised the possibility that at least part of the biochemically detected ChAT has a nonneuronal origin. To evaluate the relative contribution of endothelial cells and nerve fibers to the total acetylcholine (ACh)-synthesizing capacity of cerebral capillaries, ChAT activity and ACh release were measured in capillaries and in purified endothelial cells isolated from bovine cerebral cortex. Isolated capillaries showed ChAT activity, which was inhibited by 2-benzoylethyl trimethylammonium to the same extent as cerebral ChAT. When preincubated with [3H]choline, these capillaries presented a calcium-dependent enhancement in tritium release upon electrical field stimulation. Purified endothelial cells had minor ChAT activity and lacked the ability to release tritium in response to electrical stimulation, although the endothelial markers alkaline phosphatase, gamma-glutamyltranspeptidase, and 1,1'-dioctadecyl-1,3,3',3'-tetramethyl-iodocarbocyanide perchlorate-labeled acetylated low-density lipoprotein uptake were fully preserved. These data indicate that, within isolated cerebral capillaries, ACh is synthesized and released by a periendothelial structure. The fact that ACh release is provoked by electrical stimulation and by a calcium-dependent mechanism strongly suggests that cerebrovascular ACh has a neuronal origin.
Assuntos
Capilares/enzimologia , Córtex Cerebral/enzimologia , Colina O-Acetiltransferase/biossíntese , Animais , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/citologia , Colina O-Acetiltransferase/metabolismo , Endotélio/enzimologiaRESUMO
Cerebral cortical microvessels are innervated by cholinergic fibers that are probably involved in the regulation of local cerebral blood flow and blood-brain barrier permeability. The possibility exists that the cholinergic terminals associated with the cortical microvasculature belong to neurons from the nucleus basalis magnocellularis (NBM), where 70% of the cortical cholinergic projections originate. To test this hypothesis, ibotenic acid (25 nmol) was injected unilaterally in the NBM in rats, and 14 days later, choline acetyltransferase (ChAT) activity was measured in the frontoparietal cortex and in a blood vessel fraction isolated from this region. Lesions of the NBM resulted in a 50% decrease of cortical ChAT as compared with control or sham-operated hemispheres; however, no changes were observed in the ChAT activity associated with cortical microvessels. These results indicate that, in rat cerebral cortex, the perivascular cholinergic terminals do not originate in the basal forebrain.
Assuntos
Gânglios da Base/enzimologia , Capilares/enzimologia , Córtex Cerebral/irrigação sanguínea , Colina O-Acetiltransferase/metabolismo , Animais , Córtex Cerebral/enzimologia , Masculino , Neurônios/enzimologia , Ratos , Ratos EndogâmicosRESUMO
The marked impairment in cerebrovascular endothelial nitric oxide synthase (eNOS) function that develops after ovariectomy may relate to the observation that the abundance of cerebral vascular eNOS and its endogenous inhibitor, caveolin-1, vary in opposite directions with chronic changes in estrogen status. The authors endeavored, therefore, to establish a link between these correlative findings by independently manipulating, in ovariectomized female rats, eNOS and caveolin-1 expression, while monitoring agonist (acetylcholine)-stimulated eNOS functional activity. In the current study, the authors showed that individually neither the up-regulation of eNOS (through simvastatin treatment), nor the down-regulation of caveolin-1 (through antisense oligonucleotide administration) is capable of restoring eNOS function in pial arterioles in vivo in these estrogen-depleted rats. Only when eNOS up-regulation and caveolin-1 down-regulation are combined is activity normalized. These results establish a mechanistic link between the estrogen-associated divergent changes in the abundance of caveolin-1 and eNOS protein and eNOS functional activity in cerebral arterioles.
Assuntos
Caveolinas/fisiologia , Circulação Cerebrovascular/fisiologia , Endotélio Vascular/fisiologia , Óxido Nítrico Sintase/fisiologia , Acetilcolina/farmacologia , Animais , Arteríolas/fisiologia , Caveolina 1 , Estradiol/farmacologia , Feminino , Óxido Nítrico Sintase Tipo III , Ratos , Ratos Sprague-Dawley , Vasodilatadores/farmacologiaRESUMO
The authors studied whether cyclic AMP (cAMP), a widespread regulator of inflammation, modulates the cytokine-mediated expression of the intercellular adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), and the inflammatory nitric oxide synthase 2 (NOS-2), in primary and immortalized brain endothelial cell cultures (GP8.3 cell line). When measured by enzyme-linked immunosorbent assay (ELISA), ICAM-1 was constitutively expressed and was up-regulated twofold by interleukin-1beta, with no effect of interferon-gamma. The NOS-2 activity, assessed by nitrite accumulation, was absent from untreated cultures but was induced by interleukin-1beta and interferon-gamma acting synergistically. Stimulation of cAMP-dependent pathways with forskolin or dibutyryl cAMP decreased ICAM-1 protein expression, whereas it increased NOS-2 protein expression. For both ICAM-1 and NOS-2, mRNA expression correlated with protein expression. Blockade of NOS activity with L-N-monomethylargiuine (L-NMMA) did not alter ICAM-1 expression, indicating that the nitric oxide released by NOS-2 did not cause the down-regulation of ICAM-1. Analysis of NFKB activation indicated that cAMP acted through a mechanism other than inhibition of nuclear translocation of NFKB. The authors conclude that cAMP modulates the expression of proinflammatory molecules in brain endothelium. This suggests that inflammatory processes at the blood-brain barrier in vivo may be regulated by perivascular neurotransmitters via cAMP.
Assuntos
Circulação Cerebrovascular , AMP Cíclico/fisiologia , Endotélio Vascular/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Óxido Nítrico Sintase/metabolismo , Animais , Linhagem Celular Transformada , Células Cultivadas , Endotélio Vascular/citologia , Homeostase , Molécula 1 de Adesão Intercelular/genética , Interferon gama/farmacologia , Interleucina-1/farmacologia , Masculino , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Oxaliplatin (L-OHP), a diaminocyclohexane platinum derivative, is an active and well tolerated anticancer drug which is presently used in the treatment of gastrointestinal tumours. Since the efficacy of L-OHP in the treatment of multiple myeloma (MM) has not yet been evaluated, we studied the antiproliferative activity of this compound in vitro in a panel of MM cell lines (XG1, XG1a, U266 and IM-9). We found that L-OHP inhibited the growth of MM cells at therapeutically achievable concentrations (IC(50): 5-10 microM after 24 h of exposure) and was more active than Cisplatin (CDDP) or Carboplatin (CBDCA). The activity of L-OHP was apparently not affected by interleukin-6 (IL-6), the major growth and survival factor of MM cells. We also found that L-OHP induced apoptotic cell death. We demonstrated that the combination of L-OHP with Dexamethasone (Dex) resulted in the enhancement of the anti-myeloma effects. L-OHP and Dex both induced poly adenosine diphosphate (ADP)-ribose polymerase (PARP) cleavage and this induction was enhanced by the combined treatment. L-OHP-induced apoptosis correlated with caspase-3 cleavage, but this correlation could not be demonstrated in Dex-treated cells. Taken together, these in vitro results provide a rationale for the experimental use of L-OHP in the treatment of MM patients and suggest therapeutic combinations of potential value.
Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3 , Caspases/metabolismo , Divisão Celular/efeitos dos fármacos , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Citometria de Fluxo , Humanos , Interleucina-6/farmacologia , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Oxaliplatina , Poli(ADP-Ribose) Polimerases/metabolismo , Células Tumorais CultivadasRESUMO
Here we show that lipopolysaccharide (LPS) induction of glial inducible nitric oxide synthase (iNOS) requires membrane (m) and soluble (s) forms of CD14. In glial cell cultures, an anti-rat CD14 monoclonal antibody detected CD14 protein in whole cells and cell lysates, and reduced LPS-dependent iNOS expression. Glial cells and normal brain tissue expressed CD14 mRNA, as revealed by isolation of a rat CD14 clone (rCD14) from an astrocyte cDNA library and RT-PCR analysis. Finally, serum the ED(50) of LPS required for glial iNOS expression, and antibodies against sCD14 blocked the potentiating effect of serum.
Assuntos
Astrócitos/enzimologia , Receptores de Lipopolissacarídeos/fisiologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase/biossíntese , Sequência de Aminoácidos , Animais , Sequência de Bases , Células Cultivadas , Indução Enzimática , Humanos , Soros Imunes/imunologia , Receptores de Lipopolissacarídeos/genética , Dados de Sequência Molecular , RNA Mensageiro/análise , RatosRESUMO
Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD.
Assuntos
Apoptose/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Citocinas/metabolismo , Neurônios/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Western Blotting , Caspase 3 , Caspases/biossíntese , Sobrevivência Celular/efeitos dos fármacos , Cerebelo/citologia , Cerebelo/enzimologia , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Lipopolissacarídeos/farmacologia , Neurônios/enzimologia , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo II , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacologia , Prostaglandinas Sintéticas/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiazinas/farmacologia , Fatores de TempoRESUMO
The brain can protect itself from ischemia and/or hypoxia by two distinct mechanisms which probably involve two separate systems of neurons in the CNS. One, which mediates a reflexive neurogenic neuroprotection, emanates from oxygen-sensitive sympathoexcitatory reticulospinal neurons of the RVLM. These cells, excited within seconds by reduction in blood flow or oxygen, initiate the systemic vascular components of the oxygen conserving (diving) reflex. They profoundly increase rCBF without changing rCGU and, hence, rapidly and efficiently provide the brain with oxygen. Upon cessation of the stimulus the systemic and cerebrovascular adjustments return to normal. The system mediating reflex protection projects via as-yet-undefined projections from RVLM to upper brainstem and/or thalamus to engage a small population of neurons in the cortex which appear to be dedicated to transducing a neuronal signal into vasodilation. It also appears to relay the central neurogenic vasodilation elicited from other brain regions, including excitation of axons innervating the FN. This mode of protection would be initiated under conditions of global ischemia and/or hypoxemia because the signal is detected by medullary neurons. The second neuroprotective system is represented in intrinsic neurons of the cerebellar FN and mediates a conditioned central neurogenic neuroprotection. The response can be initiated by excitation of intrinsic neurons of the FN and does not appear dependent upon RVLM. The pathways and transmitters that mediate the effect are unknown. The neuroprotection afforded by this network is long-lasting, persisting for almost two weeks, and is associated with reduced excitability of cortical neurons and reduced immunoreactivity of cerebral microvessels. This mode of neuroprotection, moreover, is not restricted to focal ischemia, as we have demonstrated that it also protects the brain against global ischemia and excitotoxic cell death. That the brain may have neuronal systems dedicated to protecting itself from injury, at first appearing to be a novel concept, is, upon reflection, not surprising since the brain is not injured in naturalistic behaviors characterized by very low levels of rCBF, diving and hibernation. An understanding of the pathways, transmitters, and molecules engaged in such protection may provide new insights into novel therapies for a range of disorders characterized by neuronal death.
Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Hipóxia Encefálica/fisiopatologia , Precondicionamento Isquêmico , Vasodilatação/fisiologia , Animais , Encéfalo/fisiopatologia , HumanosRESUMO
The choline analogue ethylcholine mustard aziridinium ion (AF64A) produces both neuronal and non-neuronal alterations in the rat retina. The possible involvement of the retinal capillaries in the origin of the apparently non-specific lesions has been investigated. Two hours after a single intraocular injection of 5 nmol AF64A, ultrastructural alterations were observed in neurons of the inner nuclear layer and the ganglion cell layer, where cholinergic cells are located. One week later, the number of cholinergic neurons, identified by choline acetyltransferase immunohistochemistry, was decreased to 65% of control, the neurons located in the inner nuclear layer being more sensitive than those in the ganglion cell layer. The same dose of AF64A also induced ultrastructural changes in retinal capillaries, which showed a significant increase in the number of pinocytotic vesicles and microvilli in the endothelial cells, 2-5 h after the toxin administration. One day later, arterioles and capillaries presented contracted profiles and the lumen was occasionally lost. The sensitivity of endothelial cells to the toxic effects of AF64A may be explained by the presence in the cerebral endothelium of a choline transport mechanism with an affinity close to that of cerebral synaptosomes. In vitro, both neuronal and endothelial choline uptake systems were equally sensitive to the toxin inhibitory effect. The early and severe vascular alterations induced in the retinal microvessels by AF64A may produce changes in blood perfusion and capillary permeability that could account for the apparently non-specific histological damage.
Assuntos
Aziridinas/farmacologia , Capilares/fisiologia , Colina O-Acetiltransferase/metabolismo , Colina/análogos & derivados , Fármacos Neuromusculares Despolarizantes/farmacologia , Células Fotorreceptoras/fisiologia , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Animais , Capilares/efeitos dos fármacos , Capilares/ultraestrutura , Colina/farmacologia , Técnicas Imunoenzimáticas , Células Fotorreceptoras/efeitos dos fármacos , Pinocitose , Ratos , Ratos Endogâmicos , Retina/efeitos dos fármacos , Retina/ultraestrutura , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/ultraestrutura , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/fisiologia , Sinaptossomos/ultraestruturaRESUMO
Protein kinases associated with ribosomes in the brains of suckling (4-10 days) and adult (2 months) rats were extracted from ribosomal fraction with 0.5 M KCl. The different protein kinase activities were characterized by their ability to phosphorylate three exogenous substrates: casein, histone IIs and histone IIIs in the presence of different modulators. Ribosomal salt wash fractions contain a high casein kinase activity which was partially inhibited by heparin and stimulated by calmodulin in the presence of Ca2+, indicating the presence of casein kinase I and II and calcium/calmodulin-dependent kinases. Cyclic AMP and cyclic GMP-dependent kinases and protein kinase C (calcium/phospholipids-dependent kinase) were also present. No differences were found in the casein kinase activities of suckling and adult animals, but histone kinase activities were higher in adult than in suckling animals. To identify initiation factor 2 kinases, purified factor from adult brains was used as a protein marker. In addition to the phosphorylation of both factor subunits alpha and beta by casein kinase I or II, an increased phosphorylation was detected of alpha subunit in the presence of cyclic AMP, and beta subunit, in the presence of Ca2+/calmodulin or Ca2+/phospholipids. Present results reinforce our hypothesis that, as occurs in other eukaryotic cells, the decreased rate of protein synthesis during brain development may be regulated by phosphorylation of initiation factor 2.
Assuntos
Envelhecimento/metabolismo , Encéfalo/enzimologia , Proteínas Quinases/metabolismo , Ribossomos/enzimologia , Animais , Encéfalo/crescimento & desenvolvimento , Caseínas/metabolismo , Fosforilação , Ratos , Ratos Endogâmicos , Frações Subcelulares/enzimologia , eIF-2 QuinaseRESUMO
Incubation of C6 astrocytoma cells with bacterial endotoxin (lipopolysaccharide; LPS) plus interferon-gamma (IFN-gamma), or with a combination of cytokines (TNF-alpha, IL1-beta, and IFN-gamma) leads to high levels of inducible nitric oxide synthase (iNOS) expression. Previous results demonstrated a requirement for tyrosine kinase (TK) activities for iNOS induction. In the present study, a set of structurally related TK inhibitors, the tyrphostins (TYRs), were used to characterize possible differences between LPS and cytokine iNOS induction. All TYRs tested suppressed both types of induction. However, dose-response curves revealed significant differences in the IC50 values obtained for some TYRs (T25 and T56), and significant differences in the IC50 potency rank order when comparing inhibition of LPS versus cytokine-dependent iNOS induction. These results are consistent with differential TK utilization by the LPS versus cytokine pathways of iNOS induction, and establish a basis for developing further selective inhibitors of iNOS expression.
Assuntos
Neuroglia/enzimologia , Óxido Nítrico Sintase/biossíntese , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirfostinas , Animais , Neoplasias Encefálicas/metabolismo , Citocinas/farmacologia , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Glioma/metabolismo , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico/metabolismo , Nitrilas/farmacologia , Ratos , Células Tumorais CultivadasRESUMO
The mathematical simulation of the evacuation process has a wide and largely untapped scope of application within the aircraft industry. The function of the mathematical model is to provide insight into complex behaviour by allowing designers, legislators, and investigators to ask 'what if' questions. Such a model, EXODUS, is currently under development, and this paper describes its evolution and potential applications. EXODUS is an egress model designed to simulate the evacuation of large numbers of individuals from an enclosure, such as an aircraft. The model tracks the trajectory of each individual as they make their way out of the enclosure or are overcome by fire hazards, such as heat and toxic gases. The software is expert system-based, the progressive motion and behaviour of each individual being determined by a set of heuristics or rules. EXODUS comprises five core interacting components: (i) the Movement Submodel -- controls the physical movement of individual passengers from their current position to the most suitable neighbouring location; (ii) the Behaviour Submodel -- determines an individual's response to the current prevailing situation; (iii) the Passenger Submodel -- describes an individual as a collection of 22 defining attributes and variables; (iv) the Hazard Submodel -- controls the atmospheric and physical environment; and (v) the Toxicity Submodel -- determines the effects on an individual exposed to the fire products, heat, and narcotic gases through the Fractional Effective Dose calculations. These components are briefly described and their capabilities and limitations are demonstrated through comparison with experimental data and several hypothetical evacuation scenarios.
Assuntos
Acidentes Aeronáuticos/psicologia , Comportamento/fisiologia , Simulação por Computador , Sistemas Inteligentes/instrumentação , Incêndios , Humanos , Modelos Teóricos , SoftwareRESUMO
Expression of the calcium-independent nitric oxide synthase (NOS2) contributes to damage in neurologic disease and trauma. The effects of local anesthetics on NOS2 expression have not been examined. The authors tested the effects of four local anesthetics on the expression of NOS2 in immunostimulated rat C6 glioma cells. Incubation with local anesthetics alone did not induce nitrite accumulation; however, the nitrite production induced by stimulation with bacterial endotoxin lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was increased in a dose-dependent manner by bupivacaine (maximal 3-fold at 360 microM), tetracaine (maximal 7-fold at 360 microM), and lidocaine at higher doses (5-fold increase at 3.3 mM). Significant increases in nitrite production were observed in concentrations of bupivacaine or tetracaine as low as 120 microM, which correspond to 30 microg/mL (.003% weight/volume). In contrast, ropivacaine had little effect on nitrite production (160% of control values) and only at the highest concentration (3.3 mM, corresponding to 890 microg/mL or 0.089% w/v) tested. Increased nitrite production was not caused by cytotoxic effects of the drugs used, as assessed by release of intracellular lactate dehydrogenase. Increased nitrite production was accompanied by increased NOS2 catalytic activity, steady state mRNA levels, and promoter activation. These results demonstrate that submillimolar doses of two commonly used local anesthetics can increase glial NOS2 expression.
Assuntos
Anestésicos Locais/farmacologia , Neuroglia/enzimologia , Óxido Nítrico Sintase/biossíntese , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Indução Enzimática/efeitos dos fármacos , Glioma/metabolismo , Indicadores e Reagentes , Neuroglia/efeitos dos fármacos , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Ratos , Células de Schwann/efeitos dos fármacos , Células de Schwann/enzimologia , Células Tumorais CultivadasAssuntos
Antineoplásicos Hormonais/farmacologia , Apoptose/efeitos dos fármacos , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Inibidores do Crescimento/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Sinergismo Farmacológico , Humanos , Interleucina-6/análogos & derivados , Células Tumorais CultivadasAssuntos
Aminoácido Oxirredutases/biossíntese , Astrócitos/enzimologia , Citocinas/farmacologia , Expressão Gênica/efeitos dos fármacos , Isoflavonas/farmacologia , Neuroglia/enzimologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Aminoácido Oxirredutases/antagonistas & inibidores , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Genisteína , Glioma , Interferon gama/farmacologia , Interleucina-1/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase , RNA Mensageiro/biossíntese , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
During the last decade, interest has grown in the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) in neurodegeneration, particularly in pathologies such as Alzheimer's (AD) and Parkinson's (PD) disease. Evidence from epidemiological studies has indicated a decreased risk for AD and PD in patients with a history of chronic NSAID use. However, clinical trials with NSAIDs in AD patients have yielded conflicting results, suggesting that these drugs may be beneficial only when used as preventive therapy or in early stages of the disease. NSAIDs may also have salutary effects in other neurodegenerative diseases with an inflammatory component, such as multiple sclerosis and amyotrophic lateral sclerosis. In this review we analyze the molecular (cyclooxygenases, secretases, NF-kappaB, PPAR, or Rho-GTPasas) and cellular (neurons, microglia, astrocytes or endothelial cells) targets of NSAIDs that may mediate the therapeutic function of these drugs in neurodegeneration.