RESUMEN

Disruption of axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria (CM). Calpains are calcium (Ca2+)-activated cysteine proteases which have been implicated in axonal injury in neurological diseases of various aetiologies. In this study we examined the association between mu- and m-calpain, the specific inhibitor calpastatin, and axonal injury in post mortem brain tissue from patients who died from severe malaria. Calpains were associated with axons labelled for the beta-amyloid precursor protein that detects impaired axonal transport. Elevated levels of calpastatin were rarely observed in injured axons. There were increased numbers of neurones with mu-calpain in the nuclear compartment in severe malaria cases compared with non-neurological controls, and increased numbers of glia with nuclear mu-calpain in CM patients compared with non-CM malaria cases and non-neurological controls. There was marked redistribution of calpastatin in the sequestered Plasmodium falciparum-infected erythrocytes. Responses specific to malaria infection were ascertained following analysis of brain samples from fatal cases with acute axonal injury, HIV encephalitis, and progressive multifocal leucoencephalopathy. Our findings implicate a role for calpains in the modulation of disease progression in CM.

Asunto(s)

Transporte Axonal , Calpaína/metabolismo , Malaria Falciparum/metabolismo , Malaria Falciparum/patología , Complejo SIDA Demencia/metabolismo , Complejo SIDA Demencia/patología , Adulto , Anciano , Axones/enzimología , Axones/patología , Proteínas de Unión al Calcio/metabolismo , Endotelio Vascular/enzimología , Endotelio Vascular/patología , Eritrocitos/parasitología , Eritrocitos/patología , Femenino , Humanos , Inmunohistoquímica , Leucoencefalopatía Multifocal Progresiva/metabolismo , Leucoencefalopatía Multifocal Progresiva/patología , Malaria Falciparum/mortalidad , Masculino , Persona de Mediana Edad , Neuroglía/enzimología , Neuroglía/patología , Neuronas/enzimología , Neuronas/patología , Neuronas/ultraestructura

RESUMEN

In animals, high doses of intramuscular artemether and artemotil have been shown to cause an unusual pattern of selective damage to certain brainstem nuclei, especially those implicated in hearing and balance. We aimed to investigate whether a similar pattern arises in human adults. We examined the brainstems of adults who died after treatment with high dose artemether or quinine for severe falciparum malaria for evidence of a pattern of selective neuronal damage. Neuropathological findings were similar in recipients of quinine (n=15) and artemether (n=6; total artemether doses received 4-44 mg/kg). No evidence was recorded for artemether-induced neurotoxic effects.

Asunto(s)

Antimaláricos/efectos adversos , Artemisininas/efectos adversos , Encefalopatías/inducido químicamente , Encefalopatías/patología , Malaria Falciparum/tratamiento farmacológico , Sesquiterpenos/efectos adversos , Adulto , Antimaláricos/uso terapéutico , Arteméter , Artemisininas/uso terapéutico , Tronco Encefálico/efectos de los fármacos , Tronco Encefálico/patología , Femenino , Humanos , Malaria Falciparum/patología , Masculino , Quinina/efectos adversos , Quinina/uso terapéutico , Sesquiterpenos/uso terapéutico

RESUMEN

Axonal damage has recently been recognized to be a key predictor of outcome in a number of diverse human CNS diseases, including head and spinal cord trauma, metabolic encephalopathies, multiple sclerosis and other white-matter diseases (acute haemorrhagic leucoencephalitis, leucodystrophies and central pontine myelinolysis), infections [malaria, acquired immunodeficiency syndrome (AIDS) and infection with human lymphotropic virus type 1 (HTLV-I) causing HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP)] and subcortical ischaemic damage. The evidence for axonal damage and, where available, its correlation with neurological outcome in each of these conditions is reviewed. We consider the possible pathogenetic mechanisms involved and how increasing understanding of these may lead to more effective therapeutic or preventive interventions.

Asunto(s)

Axones/patología , Enfermedades del Sistema Nervioso Central/patología , Lesión Axonal Difusa/patología , Complejo SIDA Demencia/patología , Adolescente , Adulto , Anciano , Encefalopatías Metabólicas/patología , Isquemia Encefálica/patología , Niño , Preescolar , Traumatismos Craneocerebrales/patología , Infecciones por Deltaretrovirus/patología , Enfermedades Desmielinizantes/patología , VIH-1 , Humanos , Lactante , Malaria Cerebral/patología , Persona de Mediana Edad , Esclerosis Múltiple/patología , Traumatismos de la Médula Espinal/patología

RESUMEN

Damage to neurites with transection of axons and spheroid formation is commonly noted in the central nervous system during viral and autoimmune diseases such as multiple sclerosis, but it remains open whether such changes are caused primarily by immune mechanisms or whether they are secondary to inflammation. The present experiments explored whether neurites can be directly attacked by cytotoxic T lymphocytes (CTLs). Cultured murine neurons induced by interferon-gamma and tetrodotoxin to express major histocompatibility complex class I were pulsed with a dominant peptide of the lymphochoriomeningitis virus envelope glycoprotein (GP33) and then confronted with GP33-specific CD8(+) CTLs. Within 3 hours the neurites developed cytoskeleton breaks with adjacent solitary neuritic spheroids, as documented by confocal examination of the cytoskeletal marker beta-tubulin III. At the same time cytoskeleton staining of the neuronal somata showed no damage. The CTLs selectively attacked neurites and induced segmental membrane disruption 5 to 30 minutes after the establishment of peptide-specific CTL-neurite contact, as directly visualized by live confocal imaging. Thus, major histocompatibility complex class I/peptide-restricted CD8(+) T lymphocytes can induce lesions to neurites, which might be responsible for axonal damage during neuroinflammatory diseases.

Asunto(s)

Antígenos de Histocompatibilidad Clase I/fisiología , Neuritas/fisiología , Linfocitos T Citotóxicos/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/fisiología , Membrana Celular/fisiología , Membrana Celular/ultraestructura , Células Cultivadas , Citoesqueleto/fisiología , Citoesqueleto/ultraestructura , Antígenos de Histocompatibilidad Clase I/metabolismo , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Proteínas Asociadas a Microtúbulos/metabolismo , Neuritas/ultraestructura , Linfocitos T Citotóxicos/inmunología , Tubulina (Proteína)/metabolismo

RESUMEN

Previous work showed that neurons of the CNS are protected against perforin-mediated T cell cytotoxicity, but are susceptible to Fas-mediated apoptosis. In this study, we report that Fas ligand (FasL) expression by neurons is involved in protection against perforin-mediated T cell cytotoxicity. Gene transcripts for FasL were identified in single murine hippocampal neurons by RT-PCR combined with patch clamp electrophysiology, and constitutive expression of FasL protein was confirmed in neurons by immunohistochemistry. Neurons derived from wild-type C57BL/6 (BL6) mice and mutant BL6.gld mice lacking functional FasL were confronted with allogeneic CTLs and continuously monitored in real time for changes in levels of intracellular calcium ([Ca(2+)](i)), an indicator of cytotoxic damage. Perforin-mediated plasma membrane lysis, characterized by rapid, massive [Ca(2+)](i) influx into the target cells within 0.5 h, was not detected in wild-type neurons. In striking contrast, FasL-deficient neurons showed rapid increase in [Ca(2+)](i) within 0.5 h, reflecting perforin-dependent cell lysis. FasL seems to protect neurons by blocking degranulation of CTLs, since CD3-induced release of cytotoxic granules was reduced by coapplication of Fas-specific Abs or rFasL.

Asunto(s)

Citotoxicidad Inmunológica , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/fisiología , Glicoproteínas de Membrana/toxicidad , Neuronas/inmunología , Linfocitos T Citotóxicos/inmunología , Receptor fas/metabolismo , Animales , Apoptosis/genética , Apoptosis/inmunología , Complejo CD3/farmacología , Células Cultivadas , Gránulos Citoplasmáticos/inmunología , Gránulos Citoplasmáticos/metabolismo , Citotoxicidad Inmunológica/genética , Proteína Ligando Fas , Ligandos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Neuronas/citología , Neuronas/metabolismo , Perforina , Proteínas Citotóxicas Formadoras de Poros

RESUMEN

Cerebral malaria (CM) is a major life-threatening complication of Plasmodium falciparum infection in humans, responsible for up to 2 million deaths annually. The mechanisms underlying the fatal cerebral complications are still not fully understood. Many theories exist on the aetiology of human CM. The sequestration hypo-thesis suggests that adherence of parasitized erythrocytes to the cerebral vasculature leads to obstruction of the microcirculation, anoxia or metabolic disturbances affecting brain function, resulting in coma. This mechanism alone seems insufficient to explain all the known features of CM. In this review we focus on another major school of thought, that CM is the result of an over-vigorous immune response originally evolved for the protection of the host. Evidence in support of this second hypothesis comes from studies in murine malaria models in which T cells, monocytes, adhesion molecules and cytokines, have been implicated in the development of the cerebral complications. Recent studies of human CM also indicate a role for the immune system in the neurological complications. However, it is likely that multiple mechanisms are involved in the induction of cerebral complications and both the presence of parasitized erythrocytes in the central nervous system (CNS) and immunopathological processes contribute to the pathogenesis of CM. Most studies examining immunopathological responses in CM have focused on reactions occurring primarily in the systemic circulation. However, these also do not fully account for the development of cerebral complications in CM. In this review we summarize results from human and mouse studies that demonstrate morphological and functional changes in the resident glial cells of the CNS. The degree of immune activation and degeneration of glial cells was shown to reflect the extent of neurological complications in murine cerebral malaria. From these results we highlight the need to consider the potentially important contribution within the CNS of glia and their secreted products, such as cytokines, in the development of human CM.

Asunto(s)

Sistema Nervioso Central/inmunología , Malaria Cerebral/inmunología , Malaria Cerebral/patología , Animales , Sistema Nervioso Central/patología , Citocinas/inmunología , Modelos Animales de Enfermedad , Humanos

RESUMEN

Immunohistochemical techniques have been used to investigate specific patterns of potentially reversible cellular injury, DNA damage, and apoptosis in the brainstems of Vietnamese patients who died of severe Plasmodium falciparum malaria. The degree and pattern of neuronal and glial stress responses were compared between patients with cerebral and non-cerebral malaria (CM), and appropriate non-malaria infected controls. The following markers were examined: (i) heat shock protein 70 (HSP70), for reversible injury; (ii) heme oxygenase-1, for oxidative stress; (iii & iv) two DNA-repair proteins, poly(ADP) ribose polymerase (PARP) and DNA-dependent protein kinase catalytic subunit; (v) poly(ADP) ribose, an end-product of PARP activity; and (vi) caspase-3-active, for apoptosis. Stress responses were found in a range of cell types as reflected by the widespread expression of HSP70. Oxidative stress predominated in the vicinity of vessels and haemorrhages. Some degree of DNA damage was found in the majority of malaria patients, but the distribution and frequency of the damage was much less than that observed in controls with irreversible neuronal injury. Similarly, caspase-3-active expression, as a measure of apoptosis, was no higher in the majority of malaria patients than the negative control cases, although 40% of CM cases expressed caspase-3-active in a small number of neurones of the pontine nuclei or within swollen axons of the pontocerebellar and corticospinal tracts. In conclusion, cells within the brainstem of all patients who died from severe malaria showed staining patterns indicative of considerable stress response and reversible neuronal injury. There was no evidence for a specific pattern of widespread irreversible cell damage in those patients with cerebral malaria.

Asunto(s)

Tronco Encefálico/patología , Proteínas de Unión al ADN , Malaria Cerebral/patología , Adulto , Apoptosis , Tronco Encefálico/enzimología , Tronco Encefálico/parasitología , Caspasa 3 , Caspasas/análisis , Causas de Muerte , Proteína Quinasa Activada por ADN , Femenino , Proteínas HSP70 de Choque Térmico/análisis , Hemo Oxigenasa (Desciclizante)/análisis , Hemo-Oxigenasa 1 , Humanos , Malaria Cerebral/metabolismo , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Neuroglía/patología , Proteínas Nucleares , Poli Adenosina Difosfato Ribosa/análisis , Poli(ADP-Ribosa) Polimerasas/análisis , Proteínas Serina-Treonina Quinasas/análisis , Vietnam

RESUMEN

Apoptosis of inflammatory cells plays a crucial role in the recovery from autoimmune CNS disease. However, the underlying mechanisms of apoptosis induction are as yet ill-defined. Here we report on the neuronal expression of FasL and its potential function in inducing T-cell apoptosis. Using a combination of facial nerve axotomy and passive transfer encephalomyelitis, the fate of CD4+ encephalitogenic T cells engineered to express the gene for green fluorescent protein was followed. FasL gene transcripts and FasL protein were detected in neurons by in sit-hybridization and immunohistochemistry. T cells infiltrating preferentially the injured brain parenchyma were found in the immediate vicinity of FasL expressing neurons and even inside their perikarya. In contrast to neurons, T cells rapidly underwent apoptosis. In co-cultures of hippocampal nerve cells and CD4 T lymphocytes, we confirmed expression of FasL in neurons and concomitant induction of T-cell death. Antibodies blocking neuronal FasL were shown to have a protective effect on T-cell survival. Thus, FasL expression by neurons in neuroinflammatory diseases may constitute a pivotal mechanism underlying apoptosis of encephalitogenic T cells.

Asunto(s)

Linfocitos T CD4-Positivos/fisiología , Encefalomielitis/etiología , Glicoproteínas de Membrana/fisiología , Neuronas/metabolismo , Animales , Anticuerpos/farmacología , Apoptosis , Encéfalo/patología , Encéfalo/fisiopatología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Técnicas de Cocultivo , Encefalomielitis/patología , Nervio Facial/citología , Nervio Facial/metabolismo , Proteína Ligando Fas , Expresión Génica , Proteínas Fluorescentes Verdes , Hipocampo/citología , Inmunohistoquímica , Hibridación in Situ , Indicadores y Reactivos , Proteínas Luminiscentes/genética , Glicoproteínas de Membrana/inmunología , Neuronas Motoras/metabolismo , Neuronas/fisiología , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas Lew

RESUMEN

Microglial activation and redistribution toward blood vessels are some of the earliest observable events occurring within the central nervous system (CNS) during fatal murine cerebral malaria (FMCM). To investigate stimuli that might modulate microglial reactivity during FMCM we have performed two experimental manipulations and observed microglial responses in retinal whole mounts. First, to determine whether increased blood-brain barrier (BBB) permeability in the absence of the malaria parasite initiates the microglial changes, BBB function was compromised experimentally by intracarotid injection of arabinose and retinae were examined 12, 24, or 36 hours later. Second, to determine whether the immune response against the malaria parasite modulates microglial reactivity, infected mice were treated with dexamethasone before day 4 postinoculation. This treatment regime ameliorates cerebral complications without affecting parasite growth. We observed that increased BBB permeability was sufficient to elicit thickening of microglial processes and redistribution of microglia toward the vasculature, characteristic of the early stages of FMCM. However, despite the presence of plasma constituents in the CNS for up to 36 hours, microglia with amoeboid and vacuolated morphology were not observed. Dexamethasone treatment inhibited the up-regulation of alpha-D-galactose expression and reactive morphological changes in microglia during FMCM. These results suggest that disruption of the CNS milieu by entry of plasma constituents, or circulating malaria parasites in the absence of an immune response, by themselves are insufficient to induce the reactive microglial changes that are characteristic of FMCM. In addition, dexamethasone-sensitive event(s), presumably associated with immune system activation, occurring within the first few days of malaria infection are essential for the development of reactive microglia and subsequent fatal neurological complications.

Asunto(s)

Barrera Hematoencefálica/efectos de los fármacos , Dexametasona/farmacología , Malaria Cerebral/patología , Microglía/patología , Plasmodium berghei , Retina/patología , Animales , Arabinosa/farmacología , Permeabilidad Capilar/efectos de los fármacos , Recuento de Células , Disacáridos/metabolismo , Modelos Animales de Enfermedad , Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/metabolismo , Ratones , Ratones Endogámicos CBA , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/parasitología , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/patogenicidad , Retina/efectos de los fármacos , Retina/metabolismo , Retina/parasitología , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

Induction of MHC class I genes in neurons of the central nervous system requires signals by pro-inflammatory cytokines, in particular IFN-gamma, and the blockade of electric activity, which is known to suppress induction of MHC related genes in a highly ordered, but unusual fashion [1], [2]. The present experiments explore the immunological function of neuronal MHC class I antigens expressed under permissive conditions. MHC class I proteins were induced in electrically silenced murine hippocampal neurons by treatment with the sodium channel blocker tetrodotoxin and recombinant IFN-gamma, conditions which also resulted in the induction of Fas molecules. The MHC class I positive neurons were challenged with CD8+ cytotoxic T lymphocytes (CTL) specific for the H2-Db binding peptide GP33, a dominant epitope of the lymphocytic choriomeningitis virus envelope glycoprotein, or with alloreactive CTL. Single primed neurons, attacked by GP33-specific CTL, were continuously monitored for changes in intracellular calcium ([Ca2+]i), an indicator of cytotoxic damage. MHC class I-induced neurons pulsed with the GP33 peptide, but not a control peptide, showed a gradual and sustained increase in [Ca2+]i within 3 h following attack by GP33-specific CTL, while in astrocytes [Ca2+]i elevation was rapid. The slow course of the neuronal response was consistent with a delayed apoptotic killing mechanism rather than rapid granule-mediated plasma membrane lysis. Indeed, the attacked neurons bound annexin V, indicating membrane alterations preceding apoptotic cell death. In further support of apoptotic cell death, this sustained increase of [Ca2+]i levels was also observed following attack by perforin-deficient CTL, but was not detected in neurons derived from mutant lpr mice, which lack functional Fas molecules.

Asunto(s)

Apoptosis , Antígenos de Histocompatibilidad Clase I/fisiología , Virus de la Coriomeningitis Linfocítica/inmunología , Glicoproteínas de Membrana/fisiología , Neuronas/patología , Linfocitos T Citotóxicos/inmunología , Proteínas Virales/inmunología , Receptor fas/fisiología , Animales , Calcio/metabolismo , Proteína Ligando Fas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Perforina , Proteínas Citotóxicas Formadoras de Poros , Ratas

RESUMEN

Fatal murine cerebral malaria (FMCM) is an immunopathological process. The depletion of CD4+ T cells, or the administration of antioxidants or antibodies against certain cytokines, protect the mice against cerebral complications. We previously have shown that astrocytes, microglia, and monocytes play a role in the development of FMCM, suggesting that an active immune response occurs locally within the central nervous system. We now have investigated the functional involvement of glia and monocytes in FMCM by assessing 1) the production, 2) the temporal appearance, and 3) the cellular source of cytokine mRNA and protein in the brain. Brain sections from uninfected and FMCM mice were analyzed for the presence of cytokine mRNA and protein by in situ hybridization and immunohistochemistry. Tumor necrosis factor (TNF)-alpha mRNA and protein were associated with microglia and astrocytes, monocytes, and the cerebral vascular endothelium in FMCM mice but not uninfected animals. TNF-alpha mRNA was first detected several days before the animals showed cerebral symptoms and died. Interleukin (IL)-1 beta mRNA was found in the brains of both uninfected and FMCM mice. However, IL-1 beta protein was associated only with monocytes, the meningeal vascular endothelium, and neurons in the fronto-parietal cortex in the FMCM brains. No IL-4 or IL-6 mRNAs were detected in either group. These results provide the strongest evidence to date that cytokines, in particular TNF-alpha, produced locally in the central nervous system play a role in the pathogenesis of FMCM.

Asunto(s)

Astrocitos/metabolismo , Encéfalo/inmunología , Encéfalo/metabolismo , Malaria Cerebral/metabolismo , Malaria Cerebral/mortalidad , Microglía/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Astrocitos/patología , Encéfalo/patología , Interleucina-1/biosíntesis , Interleucina-1/genética , Malaria Cerebral/patología , Ratones , Ratones Endogámicos CBA , Microglía/patología , Plasmodium berghei , ARN Mensajero/biosíntesis , Factor de Necrosis Tumoral alfa/genética

RESUMEN

Microglia are pluripotent members of the macrophage/monocyte lineage that can respond in several ways to pathological changes in the central nervous system. To determine their role in the pathogenesis of fatal murine cerebral malaria (FMCM) we have conducted a detailed study of the changes in morphology and distribution of retinal microglia during the progression of the disease. Adult CBA/T6 mice were inoculated with Plasmodium berghei ANKA. These mice died 7 days post inoculation (p.i.) with the parasite while exhibiting cerebral symptoms, increased permeability of the blood-brain barrier, and monocyte adherence to the vascular endothelium. Mice were injected i.v. with Monastral blue 2 h prior to sacrifice to identify "activated" monocytes, and their isolated retinae were incubated with the Griffonia simplicifolia (GS) lectin or reacted for the nucleoside diphosphatase enzyme to visualize microglia and the vasculature. Changes in microglial morphology were seen within 2-3 days p.i., that is, at least 3 days prior to the onset of cerebral symptoms and 4 days before death. Morphological changes included retraction of ramified processes, soma enlargement, an increasingly amoeboid appearance, and vacuolation. There was also increased staining intensity and redistribution of "activated" microglia toward retinal vessels, but no increase in density of NDPase-positive cells. The GS lectin only labeled a small population of microglia in the uninfected adult mouse retina. However, there was a striking increase in the focal density of GS-positive microglia during the progression of the disease. Extravasation of monocytes also was observed prior to the onset of cerebral symptoms. These results provide the first evidence that microglial activation is a critical component of the pathological process during FMCM.

Asunto(s)

Malaria Cerebral/etiología , Malaria Cerebral/inmunología , Microglía/parasitología , Ácido Anhídrido Hidrolasas/metabolismo , Animales , Biomarcadores , Tamaño de la Célula , Modelos Animales de Enfermedad , Ojo/irrigación sanguínea , Ojo/inmunología , Ojo/parasitología , Histocitoquímica , Lectinas , Malaria Cerebral/metabolismo , Ratones , Ratones Endogámicos CBA , Microglía/enzimología , Monocitos/inmunología , Monocitos/parasitología , Retina/citología , Retina/enzimología , Retina/inmunología

RESUMEN

To determine whether astrocytes play a critical role in the pathogenesis of experimental murine cerebral malaria (EMCM), we examined changes in astrocyte morphology and distribution, using retinal wholemounts, in three models: a fatal cerebral malaria (CM) model, in which mice die showing cerebral symptoms; a "resolving" model, in which mice exhibit mild cerebral symptoms, but then recover; and a non-CM model, in which cerebral symptoms are not seen. In the fatal model, retinal astrocytes lost their even distribution from day 3 post-inoculation (p.i.) with malaria parasites, progressing to gliosis (day 5 p.i.), well before the onset of cerebral symptoms on day 6-7 p.i. At the terminal stage of the disease there was a loss of astrocyte processes contacting retinal vessels, often along vessel segments containing adherent monocytes. These features occurred in a mild form in the resolving model and were absent in the non-CM models. To investigate the mechanisms underlying these astrocytic changes, we carried out two experimental manipulations. Firstly, since dexamethasone ameliorates cerebral complications in the fatal CM model, the astrocytic response was monitored after dexamethasone treatment on days 0 and 1 p.i., or days 3 and 4 p.i. Second, to determine whether increased blood-retinal barrier (BRB) permeability initiates the astrocyte changes, breakdown of the BRB was induced experimentally by intra-carotid injection of arabinose and astrocyte morphology and distribution were examined 12, 24, and 48 h later. Retinal astrocytes in both the dexamethasone- and the arabinose-treated groups showed loss of even astrocyte distribution but no loss of astrocyte ensheathment of vessels. It is concluded that: i) astrocytes are involved in the pathogenesis of EMCM, since these changes are only prominent in the fatal model and occur substantially before the onset of cerebral symptoms; ii) the initial changes in astrocyte distribution may be a consequence of the increase in BRB permeability; and iii) the immune response triggered by the malaria parasite may be responsible for the loss of astrocyte ensheathment of vessel segments.

Asunto(s)

Astrocitos/fisiología , Barrera Hematorretinal , Malaria Cerebral/fisiopatología , Retina/fisiología , Degeneración Retiniana/fisiopatología , Animales , Arabinosa/farmacología , Astrocitos/ultraestructura , Barrera Hematorretinal/efectos de los fármacos , Bromodesoxiuridina/metabolismo , Dexametasona/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/farmacología , Glucocorticoides/farmacología , Inmunohistoquímica , Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/patología , Ratones , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Monocitos/efectos de los fármacos , Ratas , Retina/ultraestructura , Degeneración Retiniana/patología