Expression of extracellular matrix components and their receptors in the central nervous system during experimental Toxoplasma gondii and Trypanosoma cruzi infection

Alterations in extracellular matrix (ECM) expression in the central nervous system (CNS) usually associated with inflammatory lesions have been described in several pathological situations including neuroblastoma and demyelinating diseases. The participation of fibronectin (FN) and its receptor, the VLA-4 molecule, in the migration of inflammatory cells into the CNS has been proposed. In Trypanosoma cruzi infection encephalitis occurs during the acute phase, whereas in Toxoplasma infection encephalitis is a chronic persisting process. In immunocompromised individuals such as AIDS patients, T. cruzi or T. gondii infection can lead to severe CNS damage. At the moment, there are no data available regarding the molecules involved in the entrance of inflammatory cells into the CNS during parasitic encephalitis. Herein, we characterized the expression of the ECM components FN and laminin (LN) and their receptors in the CNS of T. gondii- and T. cruzi-infected mice. An increased expression of FN and LN was detected in the meninges, leptomeninges, choroid plexus and basal lamina of blood vessels. A fine FN network was observed involving T. gondii-free and T. gondii-containing inflammatory infiltrates. Moreover, perivascular spaces presenting a FN-containing filamentous network filled with a4+ and a5+ cells were observed. Although an increased expression of LN was detected in the basal lamina of blood vessels, the CNS inflammatory cells were a6-negative. Taken together, our results suggest that FN and its receptors VLA-4 and VLA-5 might be involved in the entrance, migration and retention of inflammatory cells into the CNS during parasitic infections.

Human immunodeficiency virus tat gene transfer to the murine central nervous system using a replication-defective herpes simplex virus vector stimulates transforming growth factor beta 1 gene expression.

The high incidence of neurological disorders in patients afflicted with acquired immunodeficiency syndrome (AIDS) may result from human immunodeficiency virus type 1 (HIV-1) induction of chemotactic signals and cytokines within the brain by virus-encoded gene products. Transforming growth factor beta1 (TGF-beta1) is an immunomodulator and potent chemotactic molecule present at elevated levels in HIV-1-infected patients, and its expression may thus be induced by viral trans-activating proteins such as Tat. In this report, a replication-defective herpes simplex virus (HSV)-1 tat gene transfer vector, dSTat, was used to transiently express HIV-1 Tat in glial cells in culture and following intracerebral inoculation in mouse brain in order to directly determine whether Tat can increase TGF-beta1 mRNA expression. dSTat infection of Vero cells transiently transfected by a panel of HIV-1 long terminal repeat deletion mutants linked to the bacterial chloramphenicol acetyltransferase reporter gene demonstrated that vector-expressed Tat activated the long terminal repeat in a trans-activation response element-dependent fashion independent of the HSV-mediated induction of the HIV-1 enhancer, or NF-kappaB domain. Northern blot analysis of human astrocytic glial U87-MG cells transfected by dSTat vector DNA resulted in a substantial increase in steady-state levels of TGF-beta1 mRNA. Furthermore, intracerebral inoculation of dSTat followed by Northern blot analysis of whole mouse brain RNA revealed an increase in levels of TGF-beta1 mRNA similar to that observed in cultured glial cells transfected by dSTat DNA. These results provided direct in vivo evidence for the involvement of HIV-1 Tat in activation of TGF-beta1 gene expression in brain. Tat-mediated stimulation of TGF-beta1 expression suggests a novel pathway by which HIV-1 may alter the expression of cytokines in the central nervous system, potentially contributing to the development of AIDS-associated neurological disease.

Hypothalamic Inflammation And The Central Nervous System Control Of Energy Homeostasis.

The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states.

Behaviour of oligodendrocytes and Schwann cells in an experimental model of toxic demyelination of the central nervous system

Oligodendrocytes and Schwann cells are engaged in myelin production, maintenance and repairing respectively in the central nervous system (CNS) and the peripheral nervous system (PNS). Whereas oligodendrocytes act only within the CNS, Schwann cells are able to invade the CNS in order to make new myelin sheaths around demyelinated axons. Both cells have some limitations in their activities, i.e. oligodendrocytes are post-mitotic cells and Schwann cells only get into the CNS in the absence of astrocytes. Ethidium bromide (EB) is a gliotoxic chemical that when injected locally within the CNS, induce demyelination. In the EB model of demyelination, glial cells are destroyed early after intoxication and Schwann cells are free to approach the naked central axons. In normal Wistar rats, regeneration of lost myelin sheaths can be achieved as early as thirteen days after intoxication; in Wistar rats immunosuppressed with cyclophosphamide the process is delayed and in rats administered cyclosporine it may be accelerated. Aiming the enlightening of those complex processes, all events concerning the myelinating cells in an experimental model are herein presented and discussed.

Association of Trypanosoma vivax in extracellular sites with central nervous system lesions and changes in cerebrospinal fluid in experimentally infected goats

Changes in cerebrospinal fluid (CSF) and anatomical and histopathological central nervous system (CNS) lesions were evaluated, and the presence of Trypanosoma vivax in CNS tissues was investigated through PCR. Twelve adult male goats were divided into three groups (G): G1, infected with T. vivax and evaluated during the acute phase; G2, infected goats evaluated during the chronic phase; and G3, consisting of non-infected goats. Each goat from G1 and G2 was infected with 1.25 x 10(5) trypomastigotes. Cerebrospinal fluid (CSF) analysis and investigation of T. vivax was performed at the 15(th) day post-infection (dpi) in G1 goats and on the fifth day after the manifestation of nervous system infection signs in G2 goats. All goats were necropsied, and CNS fragments from G1 and G2 goats were evaluated by PCR for the determination of T. vivax. Hyperthermia, anemia and parasitemia were observed from the fifth dpi for G1 and G2, with the highest parasitemia peak between the seventh and 21(st) dpi. Nervous system infection signs were observed in three G2 goats between the 30(th) and 35(th) dpi. CSF analysis revealed the presence of T. vivax for G2. Meningitis and meningoencephalitis were diagnosed in G2. PCR were positive for T. vivax in all the samples tested. In conclusion, T. vivax may reach the nervous tissue resulting in immune response from the host, which is the cause of progressive clinical and pathological manifestations of the CNS in experimentally infected goats.

INTENSITY-MODULATED AND 3D-CONFORMAL RADIOTHERAPY FOR WHOLE-VENTRICULAR IRRADIATION AS COMPARED WITH CONVENTIONAL WHOLE-BRAIN IRRADIATION IN THE MANAGEMENT OF LOCALIZED CENTRAL NERVOUS SYSTEM GERM CELL TUMORS

Purpose: To compare the sparing potential of cerebral hemispheres with intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for whole-ventricular irradiation (WVI) and conventional whole-brain irradiation (WBI) in the management of localized central nervous system germ cell tumors (CNSGCTs). Methods and Materials: Ten cases of patients with localized CNSGCTs and submitted to WVI by use of IMRT with or without a ""boost"" to the primary lesion were selected. For comparison purposes, similar treatment plans were produced by use of 3D-CRT (WVI with or without boost) and WBI (opposed lateral fields with or without boost), and cerebral hemisphere sparing was evaluated at dose levels ranging from 2 Gy to 40 Gy. Results: The median prescription dose for WVI was 30.6 Gy (range, 25.2-37.5 Gy), and that for the boost was 16.5 Gy (range, 0-23.4 Gy). Mean irradiated cerebral hemisphere volumes were lower for WVI with IMRT than for 3D-CRT and were lower for WVI with 3D-CRT than for WBI. Intensity-modulated radiotherapy was associated with the lowest irradiated volumes, with reductions of 7.5%, 12.2%, and 9.0% at dose levels., compared with 3D-CRT. Intensity-modulated radiotherapy provided of 20, 30, and 40 Gy, respectively statistically significant reductions of median irradiated volumes at all dose levels (p = 0.002 or less). However, estimated radiation doses to peripheral areas of the body were 1.9 times higher with IMRT than with 3D-CRT. Conclusions: Although IMRT is associated with increased radiation doses to peripheral areas of the body, its use can spare a significant amount of normal central nervous system tissue compared with 3D-CRT or WBI in the setting of CNSGCT treatment. (C) 2010 Elsevier Inc.

Involvement of the central nervous system in patients with dengue virus infection

The findings of a neurological evaluation in 85 patients with confirmed, acute, dengue virus infection are described. Signs of central nervous system involvement were present in IS patients (21.2%). The most frequent neurological symptom was mental confusion. The frequency of neurological involvement did not differ between patients with primary and secondary dengue infection, and the prevalence of central nervous system involvement in dengue fever and dengue hemorrhagic fever also did not differ significantly. The presence of CNS involvement did not influence the prognosis of dengue infection. Dengue viral CSF RNA was found in 7 of 13 patients submitted to a spinal tap, the CSF viral load being less than 1000 copies/ml. PCR was negative in serum samples obtained from three patients on the same day as the CSF samples, suggesting that the dengue virus actively enters the CNS and that the presence of the virus in the CNS does not result from passive crossing of the blood-brain barrier. (C) 2007 Elsevier B.V. All rights reserved.

Oral tolerance reduces Th17 cells as well as the overall inflammation in the central nervous system of EAE mice

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory immune response directed against myelin antigens of the central nervous system. In its murine model, EAE, Th17 cells play an important role in disease pathogenesis. These cells can induce blood-brain barrier disruption and CNS immune cells activation, due to the capacity to secrete high levels of IL-17 and IL-22 in an IL-6 + TGF-beta dependent manner. Thus, using the oral tolerance model, by which 200 mu g of MOG 35-55 is given orally to C57BL/6 mice prior to immunization, we showed that the percentage of Th17 cells as well as IL-17 secretion is reduced both in the periphery and also in the CNS of orally tolerated animals. Altogether, our data corroborates with the pathogenic role of IL-17 and IFN-gamma in EAE, as its reduction after oral tolerance, leads to an overall reduction of pro-inflammatory cytokines, such as IL-1 alpha, IL-6, IL-9, IL-12p70 and the chemokines MIP-1 beta, RANTES, Eotaxin and KC in the CNS. It is noteworthy that this was associated to an increase in IL-10 levels. Thus, our data clearly show that disease suppression after oral tolerance induction, correlates with reduction in target organ inflammation, that may be caused by a reduced Th1/Th17 response. Crown Copyright (c) 2010 Published by Elsevier B.V. All rights reserved.

Toxoplasma gondii: The severity of toxoplasmic encephalitis in C57BL/6 mice is associated with increased ALCAM and VCAM-1 expression in the central nervous system and higher blood-brain barrier permeability

In order to investigate the differential ALCAM, ICAM-1 and VCAM-1 adhesion molecules mRNA expression and the blood-brain barrier (BBB) permeability in C57BL/6 and BALB/c mice in Toxoplasma gondii infection, animals were infected with ME-49 strain. It was observed higher ALCAM on day 9 and VCAM-1 expression on days 9 and 14 of infection in the central nervous system (CNS) of C57BL/6 compared to BALB/c mice. The expression of ICAM-1 was high and similar in the CNS of both lineages of infected mice. In addition, C57BL/6 presented higher BBB permeability and higher IFN-gamma and iNOS expression in the CNS compared to BALB/c mice. The CNS of C578L/6 mice presented elevated tissue pathology and parasitism. In conclusion, our data suggest that the higher adhesion molecules expression and higher BBB permeability contributed to the major inflammatory cell infiltration into the CNS of C57BL/6 mice that was not efficient to control the parasite. (C) 2010 Elsevier Inc. All rights reserved.

CCR2 receptor is essential to activate microbicidal mechanisms to control Toxoplasma gondii infection in the central nervous system

Chemokines comprise a structurally related family of cytokines that regulate leukocyte trafficking. Because infection with Toxoplasma gondii can induce an important inflammatory reaction that, if left uncontrolled, can lead to death, we investigated the role of the chemokine receptor CCR2 in T gondii infection. We orally infected CCR2(-/-) mice with five ME-49 T gondii cysts and monitored morbidity, survival, and immune response thereafter. The CCR2(-/-) mice displayed higher susceptibility to infection as all mice died on day 28 after infection. Despite similar Th1 responses, a more evident anti-inflammatory response was induced in the peripheral organs of CCR2(-/-) mice compared with wild-type C57BL/6 mice. Additionally, CCR2-/- mice presented greater parasitism and a milder inflammatory reaction in their peripheral organs with lesser CD4(+) and MAC-1(+) and greater CD8(+) cell migration. The parasite load decreased in these organs in CCR2(-/-) mice but remained uncontrolled in the central nervous system. Additionally, we observed down-regulated inducible nitric oxide synthase expression in peripheral organs from CCR2(-/-) mice that was associated with a small nitric oxide production by spleen macrophages. In conclusion, in the absence of CCR2, another mechanism is activated to control tissue parasitism in peripheral organs. Nevertheless, CCR2 is essential for the activation of microbicidal mediators that control T gondii replication in the central nervous system.

Involvement of the central nervous system in the chronic form of Chagas` disease

Background and purpose: Apart from the central nervous system parasitic invasion in chagasic immunodeficient patients and strokes due to heart lesions provoked by the disease, the typical neurological syndromes of the chronic phase of Chagas` disease (CD) have not yet been characterized, although involvement of the peripheral nervous system has been well documented. This study aims at investigating whether specific signs of central nervous system impairment might be associated with the disease. Methods: Twenty-seven patients suffering from the chronic form of Chagas` disease (CCD) and an equal number of controls matched for sex, age, educational and socio-cultural background, and coming from the same geographical regions, were studied using neurological examinations, magnetic resonance images, and electroencephalographic frequency analysis. Results: Nineteen patients were at the stage A of the cardiac form of the disease (without documented structural lesions or heart failure). Dizziness, brisk reflexes, and ankle and knee areflexia were significantly more prevalent in the patients than in the controls. The significant findings in quantitative electroencephalogram were an increase in the theta relative power and a decrease in the theta dominant frequency at temporal-occipital derivations. Subcortical, white matter demyelination was associated with diffuse theta bursts and theta-delta slowing in two patients. Conclusions: Our findings suggest a discrete and unspecific functional cortical disorder and possible white matter lesions in CD. The focal nervous system abnormalities in CD documented here did not seem to cause significant functional damage or severely alter the patient`s quality of life. (C) 2008 Elsevier B.V. All rights reserved.

Development of axon pathways in the zebrafish central nervous system

The zebrafish has a number of distinct advantages as an experimental model in developmental biology. For example, large numbers of embryos can be generated in each lay, development proceeds rapidly through a very precise temporal staging which exhibits minimal batch-to-batch variability, embryos are transparent and imaging of wholemounts negates the need for tedious histological preparation while preserving three-dimensional spatial relationships. The zebrafish nervous system is proving a convenient model for studies of axon guidance because of its small size and highly stereotypical trajectory of axons. Moreover, a simple scaffold of axon tracts and nerves is established early and provides a template for subsequent development. The ease with which this template can be visualized as well as the ability to spatially resolve individual pioneer axons enables the role of specific cell-cell and molecular interactions to be clearly deciphered. We describe here the morphology and development of the earliest axon pathways in the embryonic zebrafish central nervous system and highlight the major questions that remain to be addressed with regard to axon guidance.

Current concepts in central nervous system regeneration

A dictum long-held has stated that the adult mammalian brain and spinal cord are not capable of regeneration after injury. Recent discoveries have, however, challenged this dogma. In particular, a more complete understanding of developmental neurobiology has provided an insight into possible ways in which neuronal regeneration in the central nervous system may be encouraged. Knowledge of the role of neurotrophic factors has provided one set of strategies which may be useful in enhancing CNS regeneration. These factors can now even be delivered to injury sites by transplantation of genetically modified cells. Another strategy showing great promise is the discovery and isolation of neural stem cells from adult CNS tissue. It may become possible to grow such cells in the laboratory and use these to replace injured or dead neurons. The biological and cellular basis of neural injury is of special importance to neurosurgery, particularly as therapeutic options to treat a variety of CNS diseases becomes greater. (C) 2002 Published by Elsevier Science Ltd.

Central nervous system involvement in Chagas' disease: an updating

A review was made of the available literature on central nervous system (CNS) involvement in Chagas' disease. Thirty-one works concerning the acute nervous form and 17 others dealing with the chronic nervous form, all presenting neuropathologic studies, were critically analysed. Based on this analysis, an attempt was made to establish the possible natural history of CNS involvement in Chagas' disease. Among others, the following facts stand out: 1) the initial, acute phase of Trypanosoma cruzi infection is usually asymptomatic and subclinical; 2) only a small percentage of cases develop encephalitis in the acute phase of Chagas' disease; 3) the symptomatic acute forms accompanied by chagasic encephalitis are grave, with death ensuing in virtually all cases as a result of the brain lesions per se or of acute chagasic myocarditis, this being usually intense and always present; 4) individuals with the asymptomatic acute form and with the mild symptomatic acute form probably have no CNS infection or, in some cases, they may have discrete encephalitis in sparse foci. In the latter case, regression of the lesions may be total, or residual inflammatory nodules of relative insignificance may persist. Thus, no anatomical basis exists that might characterize the existence of a chronic nervous form of Chagas' disease; 5) reactivation of the CNS infection in the chronic form of Chagas' disease is uncommon and occurs only in immunosuppressed patients.