In the central nervous system (CNS), monocarboxylate transporter 1 (MCT1) is expressed in astrocytes and endothelial cells but also in oligodendroglia. Oligodendroglia support neurons and axons through lactate transportation by MCT1. Limited information is available on the MCT1 expression changes in candidate cells in the developing rat brain, especially in corpus callosum which is the most vulnerable area in demyelinating diseases. In the present study, we investigated the expression pattern of MCT1 during postnatal development in the rat corpus callosum using immunofluorescene staining, Western blotting analysis and RT-PCR. We reported that MCT1 gene and protein were consistently expressed in the rat corpus callosum from birth to adult. MCT1/CNPase and MCT1/GFAP immunofluorescence staining demonstrated that most of MCT1 positive cells were co-labeled with cyclic nucleotide 3´ phosphodiesterase (CNPase) in rat corpus callosum from P7 to adult, whereas MCT1(+)/GFAP(+) cells preserve the dominate position before P7. Moreover, there were significant associations between the expression of MCT1 protein and the expression of myelin basic protein (MBP) (correlation coefficient: r=0.962, P=0.009) from P7 to adult. Similarly, the MCT1 mRNA expression was also significantly associated with MBP mRNA expression (r=0.976, P=0.005). Our results are proposing that in the developing brain white matter, MCT1 is predominately expressed in oligodendrocyte though it mainly expressed in astrocyte in early postnatal, which indicate that MCT1 may involve in the oligodendrocyte development and myelination.

• MeSH
• bílá hmota metabolismus   MeSH
• corpus callosum metabolismus   MeSH
• krysa rodu rattus MeSH
• novorozená zvířata MeSH
• orgánová specificita MeSH
• potkani Sprague-Dawley MeSH
• přenašeče monokarboxylových kyselin metabolismus   MeSH
• regulace genové exprese fyziologie   MeSH
• stárnutí metabolismus   MeSH
• symportéry metabolismus   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)-specific Treg suppressor activity. RESULTS: We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)-10, IL-27, and transforming growth factor-β persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells. CONCLUSIONS: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function.

• Publikační typ
• časopisecké články MeSH

OBJECTIVES: The aim of the study was to determine changes of biomarkers of nervous tissue degradation in experimental model of osmotic blood-brain barrier opening or water intoxication and to find whether they correspond to changes in well defined clinical entities. METHODS: In the cerebro-spinal fluid taken via the suboccipital puncture, myelin basic protein (MBP ng/ml), neuron-specific enolase (NSE ng/ml) and TAU-protein (Tau pg/ml) were determined by ELISA in 19 controls and 29 experimental rats several hours or one week after the experimental intervention. RESULTS: Significant difference between the control and experimental groups was revealed only for the concentration of myelin basic protein. After the BBB opening, its level dramatically increased within hours and dropped back to control values within one week. Water intoxication induced only dilutional hypoproteinorachia. No significant changes were found in NSE and levels of TAU-protein were not detectable. CONCLUSION: 1. Increased permeability of cytoplasmic membranes induced by water intoxication does not alter any of monitored CSF biomarkers. 2. Osmotic opening of the BBB in vivo experiment without the presence of other pathological conditions leads to a damage of myelin, without impairment of neurons or their axons.

• MeSH
• axony MeSH
• biologické markery MeSH
• encefalitogenní základní proteiny MeSH
• hematoencefalická bariéra * metabolismus   MeSH
• intoxikace vodou * MeSH
• krysa rodu rattus MeSH
• myelinová pochva metabolismus   patologie   MeSH
• osmotický tlak MeSH
• proteiny tau MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A number of clinical neurological pathologies are associated with increased permeability of the blood brain barrier (BBB). Induced changes of the homeostatic mechanisms in the brain microenvironment lead among others to cellular changes in the CNS. The question was whether some of these changes can be induced by osmotic opening of BBB in an in vivo experiment and whether they can be detected in cerebrospinal fluid (CSF). CSF was taken via the suboccipital puncture from 10 healthy rats and six rats after the osmotic opening of the BBB. In all 16 animals, concentration of myelin basic protein (MBP ng/ml), Neuron-specific enolase (NSE ng/ml) and Tau-protein (Tau pg/ml) were determined in CSF by ELISA. Values in both groups were statistically evaluated. Significant difference between the control and experimental group was revealed only for the concentration of myelin basic protein (p<0.01). The presented results indicate that osmotic opening of the BBB in vivo experiment without the presence of other pathological conditions of the brain leads to a damage of myelin, without impairment of neurons or their axons.

• MeSH
• biologické markery MeSH
• encefalitogenní základní proteiny MeSH
• fosfopyruváthydratasa MeSH
• hematoencefalická bariéra účinky léků   metabolismus   patologie   MeSH
• mannitol toxicita   MeSH
• myelinová pochva účinky léků   metabolismus   patologie   MeSH
• nervová vlákna myelinizovaná účinky léků   metabolismus   patologie   MeSH
• osmotický tlak MeSH
• permeabilita MeSH
• potkani Wistar MeSH
• proteiny tau MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: TDP-43 proteinopathies represent a spectrum of neurodegenerative disorders. Variable clinical presentations including frontotemporal dementia, amyotrophic lateral sclerosis (ALS) and mixed forms are associated with the spatial heterogeneity of the TDP-43 pathology. Recent studies have emphasized the role of oligodendrocytes in the pathogenesis of ALS. OBJECTIVE: To evaluate whether TDP-43 proteinopathies are associated with an oligodendroglial response. METHODS: We performed a study on 7 controls and 10 diseased patients with spinal cord involvement. Using the oligodendroglia-specific antibody TPPP/p25, we assessed oligodendrocyte density in the lateral corticospinal tracts (LCSs) along with the presence of perineuronal oligodendrocytes (PNOGs) in the anterior horns. We performed a densitometry of myelin basic protein (MBP) immunoreactivity. The numbers of TDP-43 and p62 immunoreactive inclusions were counted in both the LCSs and the anterior horns. RESULTS: Double immunolabeling confirmed that oligodendrocytes harbor TDP-43 inclusions. In the LCSs, MBP density, but not the number of oligodendrocytes, was decreased in the diseased group. However, oligodendrocyte counts in the LCS correlated positively, and the density of MBP inversely, with the number of neuronal inclusions in the anterior horn, suggestive of a compensatory response of oligodendrocytes. The number of neurons with PNOGs correlated with the amount of inclusions. CONCLUSION: Our study further emphasizes the importance of oligodendroglia in the pathogenesis of TDP-43 proteinopathies with spinal cord involvement.

• MeSH
• buněčná inkluze metabolismus   patologie   MeSH
• buňky předních rohů míšních metabolismus   patologie   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• dospělí MeSH
• encefalitogenní základní proteiny metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mícha metabolismus   patologie   MeSH
• mladý dospělý MeSH
• motorické neurony metabolismus   patologie   MeSH
• oligodendroglie metabolismus   patologie   MeSH
• proteinopatie TDP-43 metabolismus   patologie   MeSH
• proteiny vázající RNA metabolismus   MeSH
• pyramidové dráhy metabolismus   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Glatiramer acetát (GA) je spolu s rekombinantními interferony beta prvním lékem, který byl úspěšně použit v léčbě nemocných s roztroušenou sklerózou mozkomíšní (RS). Chemicky se jedná o směs syntetických peptidů, které se svou strukturou podobají myelinovému bazickému proteinu považovanému za hlavní terč autoreaktivních T lymfocytů u nemocných s RS. Po subkutánní aplikaci je GA internalizován dendritickými buňkami, které jej ve formě antigenních peptidů předkládají v lymfatických uzlinách T lymfocytům. Rozpoznání těchto peptidů vede ke stimulaci regulačních subsetů T lymfocytů označovaných jako Treg a Th2, které prostřednictvím cytokinů tlumí aktivity základní složky poškozujícího zánětu u nemocných s RS, tj. subsetů Th17 a Th1. Zmnožené T lymfocyty specifické pro GA přecházejí přes hematoencefalickou bariéru a v CNS dále přispívají k tlumení poškozujícího zánětu. Tvorbou neurotrofních působků BDGF a NT-3,4 stimulují neuronální a oligodendrocytové progenitory k diferenciaci a migraci do demyelinizačních lézí. Vykazují tak i neuroprotektivní účinky. Snaha zavádět do klinické praxe nová léčiva určená pro pacienty s RS podnítila vývoj přípravků nazývaných glatiramoidy. S ohledem na charakteristiky jsou glatiramoidy řazeny do samostatné skupiny nebiologických komplexních léčiv. Pravidla pro jejich uvádění do klinické praxe zatím nebyla formulována. Výsledky experimentálních studií naznačují, že svým složením a účinkem nejsou nové glatiramoidy srovnatelné s glatiramer acetátem.

Glatiramer acetate (GA) is together with recombinant interferons beta the first disease modifying drugs in the treatment of patients with multiple sclerosis (MS). GA is undefined mixture of synthetic peptides which structures resemble myelin basic protein MBP, the principal target of auto reactive the cells in patients with MS. GA is after subcutaneous administration internalised by dendritic cells in which is further processed and presented in complex with HLAII molecules in lymph nodes to Tcells. Tcells recognizing GA fragments are stimulated to the differentiation to immunoregulatory subsets ofTreg and Th2. The harm immunopathological reactivity which hallmark is upregulated activity ofThUand Thl T cells is dampen by GA specific Treg and Th2 T cells. These cells are migrating to the brain displaying additional immunoregulatory effects. In addition, various neurotrophic cytokines such as BDGF and NT-3,4 are produced by these cells resulting in reparation of demyelinated lesions thus preventing neurodegeneration. New glatiramoids are now introduced to the clinical practice. Unique group of drugs called non-biological complex drugs is comprising glatiramoids. Results of experimental studies suggest that these new glatiramoids are different in their chemical nature and immunobiological activities compared to glatiramer acetate which seems currently irreplaceable in this regard.

• Klíčová slova
• glatiramoidy, komplexní nebiologická léčiva,
• MeSH
• centrální nervový systém imunologie   účinky léků   MeSH
• farmakoterapie trendy   MeSH
• glatiramer acetát MeSH
• lidé MeSH
• lymfocyty účinky léků   MeSH
• neuroprotektivní látky farmakologie   terapeutické užití   MeSH
• peptidy * farmakologie   terapeutické užití   MeSH
• polymery farmakologie   terapeutické užití   MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• zánět farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Skleróza multiplex je chronické zápalovo-demyelinizačné ochorenie centrálneho nervového systému s rozličnou klinickou prezentáciou. Hlavným cieľom liečby relaps-remitujúcej formy sklerózy multiplex (RR SM) je znížiť aktivitu ochorenia, čo znamená redukovať počet atakov, zmierniť progresiu zneschopnenia, ktoré má nepriaznivý vplyv na kvalitu života pacientov s SM. Okrem interferónu beta, ktorý sa používa v liečbe od r. 1993 je pre pacientov s relaps-remitujúcou (RR) formou sklerózy multiplex od r. l996 k dispozícii aj glatiramer acetát. Glatiramer acetát, imunomodulačný preparát na báze amínokyselinovej štruktúry myelín bázického proteínu (MBP), predstavuje jednu z prvých možností antigénne špecifickej liečby sklerózy multiplex. Od 1. apríla 2006 je dostupný aj pre pacientov v Slovenskej republike ako liek prvej voľby RR SM.

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with various clinical presentations. The main aim of treatment of the relapsing-remitting form of multiple sclerosis (RR MS) is to decrease the disease activity, i.e. to reduce the number of attacks, to slow the progression of disability adversely affecting patients' quality of life. Apart from interferon beta, which has been used in treatment since 1993, also glatiramer acetate has been available for patients with the relapsing-remitting (RR) form of multiple sclerosis since l996. Glatiramer acetate, an immuno-modulation product based upon amino acid structure of myelin basic protein (MBP), represents one of the first possibilities of antigen-specific therapy for multiple sclerosis. Since April 1st 2006 it has been available also for patients in the Slovak Republic as a first-choice drug for RR MS.

A single subcutaneous inoculation with 0.02 mg of heterologous myelin basic protein (MBP) in combination with Freund's complete adjuvant resulted in clinical and histological manifestations of experimental allergic encephalomyelitis (EAE) in 80-90% of treated guinea pigs. Daily parenteral administration of levamisole and etimisole during the latent period produced a suppressive effect on EAE development, reducing morbidity and mortality rates and preventing pathomorphological changes in the CNS. Animals receiving the drugs had decreased delayed hypersensitivity reactions to MBP in vitro. Etimisole brought about a moderate decline in the formation of circulating anti-MBP antibodies, while levamisole did not affect the strength of the humoral response, something which confirmed the primary role of cell-mediated immune reactions in the CNS demyelinization process. The reported findings may be significant in developing therapeutic strategies with respect to demyelinization diseases.

• MeSH
• encefalomyelitida autoimunitní experimentální imunologie   patologie   MeSH
• etimizol farmakologie   MeSH
• imidazoly farmakologie   MeSH
• levamisol farmakologie   MeSH
• makrofágy účinky léků   imunologie   MeSH
• mícha účinky léků   patologie   MeSH
• morčata MeSH
• tvorba protilátek MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• morčata MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH