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CNS Pathology (cns + pathology)
Selected AbstractsSeizure-Promoting Effect of Blood,Brain Barrier DisruptionEPILEPSIA, Issue 4 2007Nicola Marchi Summary:,Purpose: It is generally accepted that blood,brain barrier (BBB) failure occurs as a result of CNS diseases, including epilepsy. However, evidences also suggest that BBB failure may be an etiological factor contributing to the development of seizures. Methods: We monitored the onset of seizures in patients undergoing osmotic disruption of BBB (BBBD) followed by intraarterial chemotherapy (IAC) to treat primary brain lymphomas. Procedures were performed under barbiturate anesthesia. The effect of osmotic BBBD was also evaluated in naive pigs. Results: Focal motor seizures occurred immediately after BBBD in 25% of procedures and originated contralateral to the hemisphere of BBBD. No seizures were observed when BBB was not breached and only IAC was administered. The only predictors of seizures were positive indices of BBBD, namely elevation of serum S100, levels and computed tomography (CT) scans. In a porcine model of BBBD, identical procedures generated an identical result, and sudden behavioral and electrographic (EEG) seizures correlated with successful BBB disruption. The contribution of tumor or chemotherapy to acute seizures was therefore excluded. Conclusion: This is the first study to correlate extent of acute BBB openings and development of seizures in humans and in a large animal model of BBB opening. Acute vascular failure is sufficient to cause seizures in the absence of CNS pathologies or chemotherapy. [source] CD4+CD25, effector T-cells inhibit hippocampal long-term potentiation in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2007Gil M. Lewitus Abstract During neuroinflammation T-cells invade the CNS, and may lead to the development and progression of several pathologies, of which multiple sclerosis is the most common. In these pathologies neuroinflammation is often associated with cognitive dysfunction. Using mouse hippocampal slices, we show here that CD4+CD25, T-cells inhibit long-term potentiation (LTP) induced by high-frequency stimulation. The T-cell-mediated inhibition of LTP can be prevented by blockade of ,-aminobutyric acid (GABA)A receptors. These findings provide additional insight into the multiple functions of T-cells in CNS pathologies. [source] Expression of plasminogen activator inhibitor-1 and protease nexin-1 in human astrocytes: Response to injury-related factorsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2010Karin Hultman Abstract Astrocytes play a diverse role in central nervous system (CNS) injury. Production of the serine protease inhibitors (serpins) plasminogen activator inhibitor-1 (PAI-1) and protease nexin-1 (PN-1) by astrocytes may counterbalance excessive serine protease activity associated with CNS pathologies such as ischemic stroke. Knowledge regarding the regulation of these genes in the brain is limited, so the objective of the present study was to characterize the effects of injury-related factors on serpin expression in human astrocytes. Native human astrocytes were exposed to hypoxia or cytokines, including interleukin-6 (IL-6), IL-1,, tumor necrosis factor-, (TNF-,), IL-10, transforming growth factor-, (TGF-,), and TGF-, for 0,20 hr. Serpin mRNA expression and protein secretion were determined by real-time RT-PCR and ELISA, respectively. Localization of PAI-1 and PN-1 in human brain tissue was examined by immunohistochemistry. Hypoxia and all assayed cytokines induced a significant increase in PAI-1 expression, whereas prolonged treatment with IL-1, or TNF-, resulted in a significant down-regulation. The most pronounced induction of both PAI-1 and PN-1 was observed following early treatment with TGF-,. In contrast to PAI-1, the PN-1 gene did not respond to hypoxia. Positive immunoreactivity for PAI-1 in human brain tissue was demonstrated in reactive astrocytes within gliotic areas of temporal cortex. We show here that human astrocytes express PAI-1 and PN-1 and demonstrate that this astrocytic expression is regulated in a dynamic manner by injury-related factors. © 2010 Wiley-Liss, Inc. [source] NMDA receptor antagonists: tools in neuroscience with promise for treating CNS pathologiesTHE JOURNAL OF PHYSIOLOGY, Issue 1 2007Georg Köhr No abstract is available for this article. [source] Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic PotentialCHEMMEDCHEM, Issue 6 2007Novella Romanelli Abstract The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between ,4,2 and ,7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials. [source] Constraint-induced movement therapy (CIMT): Pediatric applicationsDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2009Kathleen Brady Abstract The purpose of this article is to describe theoretical and research bases for constraint-induced movement therapy (CIMT), to discuss key features and variations in protocols currently in use with children, and to review the results of studies of efficacy. CIMT has been found to be an effective intervention for increasing functional use of the hemiparetic upper extremity in adults with chronic disability from stroke. CIMT developed out of behavioral research on the phenomenon of "learned nonuse" of an upper extremity, commonly observed following sensory and/or motor CNS injury, in which failure to regain use persists even after a period of partial recovery. CIMT includes three key elements: (1) constraining the use of the less-impaired upper extremity (UE); (2) intensive, repetitive daily therapist-directed practice of motor movements with the impaired UE for an extended period (2,3 weeks); and (3) shaping of more complex action patterns through a process of rewarding successive approximations to the target action. Mechanisms responsible for success are thought to be separate but complementary, that is, operant conditioning (reversal of learned nonuse) and experience-driven cortical reorganization. CIMT has recently been extended to children with hemiparesis secondary to perinatal stroke or other CNS pathology. Numerous case studies, as well as a small number of randomized controlled or controlled clinical trials have reported substantial gains in functional use of the hemiplegic UE following CIMT with children. Protocols vary widely in terms of type of constraint used, intensity and duration of training, and outcome measures. In general, all report gains in functional use, with minimal or no adverse effects. Continued research is needed, to clarify optimal protocol parameters and to further understand mechanisms of efficacy. © 2009 Wiley-Liss, Inc. Dev Disabil Res Rev 2009;15:102,111. [source] Characterization of CD8-positive macrophages infiltrating the central nervous system of rats with chronic autoimmune encephalomyelitisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2009Keiko Hiraki Abstract CD8+ macrophages appear in the central nervous system (CNS) under various pathological conditions such as trauma and ischemia. Furthermore, macrophages expressing CD8 were found in CNS lesions of chronic, but not acute, experimental autoimmune encephalomyelitis (EAE). To further characterize cells with this phenotype, we examined CD8+ macrophages/monocytes in the CNS and peripheral organs during the course of acute and chronic EAE that had been induced by immunization of rats with myelin basic protein and myelin oligodendrocyte glycoprotein, respectively. Counting CD8+ macrophages in CNS lesions revealed that their numbers increased reaching about 60% of total infiltrating macrophages in chronic EAE, while CD8+ macrophages remained less than 5% throughout the course of acute EAE. Unexpectedly, however, higher abundance of CD8+ monocytes/macrophages in the peripheral blood was found in both acute and chronic EAE. Real-time polymerase chain reaction analysis revealed no significant difference in the levels of chemokines and chemokine receptors of blood CD8+ monocytes between acute and chronic EAE. mRNA expression of perforin, a cytotoxic substance, was up-regulated in CD8+ monocytes compared with that of CD8, monocytes in both acute and chronic EAE. These findings suggest that activated CD8+ macrophages may play a cytotoxic role in chronic EAE lesions and that cells other than CD8+ monocytes/macrophages determined the difference in CNS pathology between acute and chronic EAE. Analysis of CD8+ monocytes/macrophages may provide useful information to permit further dissect the pathomechanisms of multiple sclerosis and to develop effective immunotherapies against autoimmune diseases in the CNS. © 2008 Wiley-Liss, Inc. [source] What is the basis of transmissible spongiform encephalopathy induced neurodegeneration and can it be repaired?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2002J. R. FraserArticle first published online: 8 APR 200 Once an animal becomes infected with a prion disease, or transmissible spongiform encephalopathy (TSE), the progression of infection is relentless and inevitably fatal, although often with such prolonged incubation periods that an alternative cause of death can intervene. Infection has been compared to ,setting a clock' which then runs inexorably as the disease spreads, usually through the lymphoreticular system and then via peripheral nerves to the central nervous system (CNS), although the mechanism controlling the protracted progression is not known. Clinical disease develops as characteristic degenerative changes in the CNS progress, but the molecular basis for this pathology is not clear, particularly the relationship between the deposition of abnormal PrP and neuronal dysfunction. Recent research has identified several means of slowing (if not stopping) the clock when infection has not yet reached the CNS; although the potential for later stage therapies seems limited, neuroprotective strategies which have been shown to be effective in other neurodegenerative conditions may also ameliorate TSE induced CNS pathology. This review focuses on our current knowledge of the key events following infection of the CNS and the opportunities for intervention once the CNS has become infected. [source] Intrathecal pathogenic anti,aquaporin-4 antibodies in early neuromyelitis optica,ANNALS OF NEUROLOGY, Issue 5 2009Jeffrey L. Bennett MD Objective The serum of most neuromyelitis optica (NMO) patients contains autoantibodies (NMO-IgGs) directed against the aquaporin-4 (AQP4) water channel located on astrocyte foot processes in the perivessel and subpial areas of the brain. Our objectives were to determine the source of central nervous system (CNS) NMO-IgGs and their role in disease pathogenesis. Methods Fluorescence-activated cell sorting and single-cell reverse transcriptase polymerase chain reaction were used to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the cerebrospinal fluid (CSF) of an NMO patient after a first clinical attack. Monoclonal recombinant antibodies (rAbs) were generated from the paired heavy and light chain sequences and tested for target specificity and Fc effector function. The effect of CSF rAbs on CNS immunopathology was investigated by delivering single rAbs to rats with experimental autoimmune encephalomyelitis (EAE). Results Repertoire analysis revealed a dynamic, clonally expanded plasma cell population with features of an antigen-targeted response. Using multiple independent assays, 6 of 11 rAbs generated from CSF plasma cell clones specifically bound to AQP4. AQP4-specific rAbs recognized conformational epitopes and mediated both AQP4-directed antibody-dependent cellular cytotoxicity and complement-mediated lysis. When administered to rats with EAE, an AQP4-specific NMO CSF rAb induced NMO immunopathology: perivascular astrocyte depletion, myelinolysis, and complement and Ig deposition. Interpretation Molecular characterization of the CSF plasma cell repertoire in an early NMO patient demonstrates that AQP4-specfic Ig is synthesized intrathecally at disease onset and directly contributes to CNS pathology. AQP4 is now the first confirmed antigenic target in human demyelinating disease. Ann Neurol 2009;66:617,629 [source] Amelioration of brain pathology and behavioral dysfunction in mice with lupus following treatment with a tolerogenic peptideARTHRITIS & RHEUMATISM, Issue 12 2009Smadar Lapter Objective Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is manifested by neurologic deficits and psychiatric disorders. The aim of this study was to examine SLE-associated CNS pathology in lupus-prone (NZB × NZW)F1 (NZB/NZW) mice, and to evaluate the ameliorating effects of treatment with a tolerogenic peptide, hCDR1 (human first complementarity-determining region), on these manifestations. Methods Histopathologic analyses of brains from lupus-prone NZB/NZW mice treated with vehicle, hCDR1, or a control scrambled peptide were performed. The messenger RNA expression of SLE-associated cytokines and apoptosis-related molecules from the hippocampi was determined. Anxiety-like behavior was assessed by open-field tests and dark/light transfer tests, and memory deficit was assessed using a novel object recognition test. Results Infiltration was evident in the hippocampi of the lupus-afflicted mice, and the presence of CD3+ T cells as well as IgG and complement C3 complex deposition was observed. Furthermore, elevated levels of gliosis and loss of neuronal nuclei immunoreactivity were also observed in the hippocampi of the mice with lupus. Treatment with hCDR1 ameliorated the histopathologic changes. Treatment with hCDR1 down-regulated the high expression of interleukin-1, (IL-1,), IL-6, IL-10, interferon-,, transforming growth factor ,, and the proapoptotic molecule caspase 8 in the hippocampi of the mice with lupus, and up-regulated expression of the antiapoptotic bcl -xL gene. Diseased mice exhibited increased anxiety-like behavior and memory deficit. Treatment with hCDR1 improved these parameters, as assessed by behavior tests. Conclusion Treatment with hCDR1 ameliorated CNS pathology and improved the tested cognitive and mood-related behavior of the mice with lupus. Thus, hCDR1 is a novel candidate for the treatment of CNS lupus. [source] Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosingCANCER, Issue 6 2002A surrogate marker of brain penetration Abstract BACKGROUND Vincristine (VCR) is used widely in oncology practice, and regular dosing is commonly associated with the development of sensorimotor or autonomic neuropathies. However, the incidence of VCR-related central nervous system (CNS) toxicity is comparatively low, suggesting that the blood-brain barrier may limit drug penetration into the brain parenchyma. This study determined whether measurable concentrations of VCR could be detected in the cerebrospinal fluid (CSF), as a surrogate marker of brain parenchyma penetration, after bolus intravenous injection in children without primary CNS pathology. METHODS The authors studied 17 pediatric patients ages 2.5,14.1 years (median, 6.8 years) with acute lymphoblastic leukemia or non-Hodgkin lymphoma without evidence of leptomeningeal disease. Patients received VCR 1.5 mg/m2 by intravenous bolus injection followed at varying intervals by lumbar puncture for scheduled intrathecal methotrexate administration under general anesthesia. Paired VCR concentrations in both plasma and CSF were measured in each patient simultaneously at times ranging from 8 minutes to 146 minutes after the VCR injection. Three patients were studied twice. The paired samples were stored at ,40 °C until analysis using a high performance liquid chromatography assay with a sensitivity of 0.1 ,g/L in CSF and 0.4 ,g/L in plasma. RESULTS Plasma VCR concentrations ranged from 2.2 ,g/L to 91.2 ,g/L. No measurable VCR concentrations were detected in the CSF samples. CONCLUSIONS Measurable concentrations of VCR in CSF are not achieved after the administration of standard intravenous bolus doses of VCR. The current observations are consistent with the relative rarity of VCR-related CNS neurotoxicity compared with the commonly observed sensorimotor and autonomic neuropathies. These findings suggest that the penetration of VCR into the brain parenchyma of patients with a relatively intact blood-brain barrier is low and that VCR may have a limited role in the CNS-directed therapy of these patients. Cancer 2002;94:1815,20. © 2002 American Cancer Society. DOI 10.1002/cncr.10397 [source] | |||||||||||||