Mahamane Keita

Centre Hospitalier Universitaire de Limoges, Limages, Limousin, France

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Publications (16)25.27 Total impact

  • J-M Vallat · L Magy · M Keita
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    ABSTRACT: Immunoglobulins have a variety of actions in dysimmune disorders. In neurological conditions such as the dysimmune neuropathies and multiple sclerosis, immunoglobulins are thought to exert a twofold effect: an immunomodulating action and a positive action on remyelination. We outline well recognized immunomodulator actions including the suppression of antibody production and neutralization of pathogenic antibodies, action on T lymphocytes and endothelial cells, modulation of complement proteins, and modulation of the expression of Fc gamma receptors on the surface of macrophages. Along with these actions in dysimmune disorders of the central and peripheral nervous systems, recent studies have provided evidence for an action on remyelination. In cultures of oligodendrocytes or myelinating cocultures of rat embryo brains, we have noted a direct action of immunoglobulins (tégéline) on myelination of the central nervous system. Our investigations have also indicated that immunoglobulins have an action on myelination of the peripheral nervous system. We employed the experimental acute neuritis model as well as in vitro models such as cultures of embryonic dorsal root ganglia and isolated Schwann cells. Interestingly the typical IgM immunoglobulins seemed more active than typical IgG ones. This observation may prompt new therapeutic options.
    No preview · Article · Jul 2006 · Revue Neurologique
  • J.-M. Vallat · L. Magy · M. Keita
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    ABSTRACT: Immunoglobulins have a variety of actions in dysimmune disorders. In neurological conditions such as the dysimmune neuropathies and multiple sclerosis, immunoglobulins are thought to exert a twofold effect: an immunomodulating action and a positive action on remyelination.We outline well recognized immunomodulator actions including the suppression of antibody production and neutralization of pathogenic antibodies, action on T lymphocytes and endothelial cells, modulation of complement proteins, and modulation of the expression of Fcγ receptors on the surface of macrophages.Along with these actions in dysimmune disorders of the central and peripheral nervous systems, recent studies have provided evidence for an action on remyelination. In cultures of oligodendrocytes or myelinating cocultures of rat embryo brains, we have noted a direct action of immunoglobulins (tégéline) on myelination of the central nervous system. Our investigations have also indicated that immunoglobulins have an action on myelination of the peripheral nervous system. We employed the experimental acute neuritis model as well as in vitro models such as cultures of embryonic dorsal toot ganglia and isolated Schwann cells. Interestingly the typical IgM immunoglobulins seemed more active than typical IgG ones. This observation may prompt new therapeutic options.
    No preview · Article · Jun 2006 · Revue Neurologique

  • No preview · Article · Mar 2005 · Revue Neurologique
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    Full-text · Article · Sep 2004 · Revue Neurologique
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    ABSTRACT: Animal models of Human African Trypanosomiasis (HAT) have been developed to understand the pathogenic mechanisms leading to the passage into the neurological phase, most of them referring to histological aspects but not clinical or behavioral data. Our study aimed at defining simple clinical and/or behavioral markers of the passage between the hemolymphatic phase and the meningo-encephalitic stage of the disease. Sprague-Dawley rats (n=24) were infected with Trypanosoma brucei brucei AnTat 1.1E. Food intake and body weight were measured daily from the day of infection until death. Hematocrit was measured twice a week. Behavioral disturbances were evaluated through an Open-field test. A sudden weight loss occurred on the twelfth day after infection, due to a significant drop of food intake starting two days before. The rats developed an anemic state shown by the hematocrit measurements. The Open-field test showed them to be less active and reactive as soon as the second week after infestation. A complementary histological study observed trypanosomes and inflammatory cells in the choroid plexus at the same period. These results are in favor of central nervous system functional disturbances. The observed weight loss is discussed as being a parameter of the entry in the meningo-encephalitic phase. The rat model reproduces neurological symptoms observed in the human disease and may prove to be useful for further neurohistological and therapeutic studies.
    Full-text · Article · Jan 2004 · Experimental Biology and Medicine
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    ABSTRACT: Transplantation of glial cells into the central nervous system (CNS) may be a promising approach for the treatment of myelin disorders such as multiple sclerosis (MS). Myelination by transplantation of oligodendrocyte precursors has been obtained in different animal models of demyelination. A strategy to favor CNS remyelination is to enrich the lesioned areas in growth factors to stimulate the quiescent population of oligodendrocyte precursors. In this context, we have developed a genetically modified CG4 cell line (CG4-FGF2), which are able to release significant amounts of fibroblast growth factor 2 (FGF2) in a controlable fashion in vitro. The data presented here demonstrate that upon induction with Dox, CG4-FGF2 cells retain their capacity to differentiate in vitro. Additionally, we provide evidence that FGF2 release by engineered cells enhance proliferation and migration of cells of the oligodendrocyte lineage without preventing them to differentiate and myelinate axons in vitro.
    No preview · Article · Jan 2004 · Experimental Neurology
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    ABSTRACT: The amount of myelination in vivo and in vitro depends on the number of oligodendrocyte progenitors, their differentiation, and on the neuron function. It has been shown that continuous administration of FGF2, a mitotic and neuroprotective factor, allows oligodendrocyte progenitors to proliferate, but prevents them from differentiating and myelinating. This study was designed to test the effect of transient exposure to FGF2 on myelination in an oligodendrocyte/neuron coculture system. At 2 days in vitro, cultures were treated with a single dose of 20 ng/ml FGF2. Cell proliferation was determined by BrdU uptake. The number of cells of the oligodendrocyte lineage was determined by immunocytology of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). The maturation of oligodendrocytes and myelination was followed by immunocytological analysis of MBP (myelin basic protein). Electron microscopy was used to study the ultrastructure of myelin. BrdU uptake procedure showed an increase in cell proliferation in FGF2-treated cultures after 48 h of treatment. At 15-18 days in vitro, CNPase(+) and MBP(+) cells were much more abundant in cultures treated with FGF2 than in control cultures. We observed differentiation and maturation of oligodendrocytes and a higher degree of myelination in FGF2-treated cultures compared to controls. Electron microscopy showed the presence of myelin structures in FGF2-treated cultures that did not differ morphologically from those observed in control cultures. Transient exposure of cultured brain cells to FGF2 increased myelination in vitro. Administration of FGF2 over a short period might thus enhance remyelination in demyelinating diseases in vivo.
    No preview · Article · Jun 2003 · Experimental Neurology
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    ABSTRACT: A variety of immunocytochemical techniques are now widely used for the electron and light microscopic examination of biological samples. They are employed routinely for investigating the role of certain proteins in nervous tissue. Immunoelectron microscopic studies require the tissue to be fixed and embedded in a solid support, which may disrupt cellular structures and destroy crucial antigens. A technique of post-embedding with LR white resin has been developed, and it has been shown that certain antigens tolerate fixation with glutaraldehyde. In this study, we optimized a previous post-embedding method using low-water-miscible low-temperature embedding resin (LR white) to immunostain MBP, P0, NF and S100 proteins in peripheral nerves fixed with a relatively high concentration of glutaraldehyde found to be compatible with the morphology of normally compacted nerve fibers from humans and adult animals. The main difference in the procedures described here from previous ones is the elimination of vibratome sectioning, rendering this immunostaining technique more accessible to neuropathological laboratories using standard equipment for the ultrastructural study of peripheral nerves. It may prove of value for localization and quantification of these proteins in normal and pathological conditions.
    No preview · Article · Jul 2002 · Journal of the Peripheral Nervous System
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    ABSTRACT: The myelin-associated glycoprotein (MAG) possesses two isoforms, known as S-MAG and L-MAG. We followed the expression and localization of L-MAG in comparison to myelin basic protein (MBP) during myelination in dissociated embryonic rat brain cell cocultures. Using immunofluorescence microscopy, we observed L-MAG and MBP in oligodendrocyte (OL) cell bodies and processes before and at the onset of myelination. At advanced stages of myelination, L-MAG immunostaining decreased, and subsequently disappeared from OL soma and myelinated internodes, whereas MBP immunoreactivity decreased only in the OL soma. These results are consistent with biochemical studies and provide the first clear demonstration of a transient expression of L-MAG during the early stages of myelination in vitro, providing further evidence that L-MAG plays a role during this period.
    No preview · Article · Feb 2002 · Developmental Neuroscience
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    ABSTRACT: Human African trypanosomiasis, or sleeping sickness, evolves toward a meningoencephalitic stage, with a breakage in the blood-brain barrier, perivascular infiltrates, and astrocytosis. The involvement of nitric oxide (NO) has been evoked in the pathogenic development of the illness, since NO was found to be increased in the brain of animals infected with Trypanosoma brucei (T. b.) brucei. An excessive NO production can lead to alterations of neuronal signaling and to cell damage through the cytotoxicity of NO and its derivatives, especially peroxynitrites. In African trypanosomiasis, the sites of NO production and its role in the pathogenicity of lesions in the central nervous system (CNS) are unknown. In a chronic model of African trypanosomiasis (mice infected with T. b. brucei surviving with episodic suramin administration), NADPH-diaphorase staining of brain slides revealed that NO synthase (NOS) activity is located not only in endothelial cells, choroid plexus ependymal cells, and neurons as in control mice but also in mononuclear inflammatory cells located in perivascular and parenchyma infiltrates. An immunohistochemical study showed that the mononuclear inflammatory cells expressed an inducible NOS activity. Furthermore, the presence of nitrotyrosine in inflammatory lesions demonstrated an increased NO production and the intermediate formation of peroxynitrites. The detection of extensive formation of nitrotyrosine in the CNS parenchyma was observed in mice having shown neurological disorders, suggesting the role of peroxynitrites in the appearance of neurological troubles. In conclusion, this study confirmed the increased NO synthesis in the CNS of mice infected with T. b. brucei and suggests a deleterious role for NO, through the formation of peroxynitrites, in the pathogenesis of African CNS trypanosomiasis.
    Full-text · Article · Jun 2000 · Experimental Parasitology
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    ABSTRACT: Diminazene aceturate (Berenyl®) has not been commercialized for therapeutic human usage; difluromethylornithine or DFMO (Ornidyl®) has only been made available very recently, and nifurtimox (Lampit®) has had limited usage. Thus presently, there are only three available drug products, all known for over half a century, for treating patients with human African trypanosomiasis (HAT): pentamidine (Lomidine® which is no longer commercially available and has been replaced by the more expensive Pentacarinat®) and suramin (Moranyl®) for cases in early stages which do not yet have CNS involvement, and only melarsoprol (Arsobal®) for the later meningoencephalitic stage. Furthermore, melarsoprol is a very toxic medication which itself causes an often fatal encephalopathy in 5 to 10% of treated patients [1,2].
    No preview · Chapter · Jan 1999
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    ABSTRACT: Chemotherapy for human African trypanosomiasis (HAT), or sleeping sickness, is unreliable because of resistance, refraction and toxic and adverse side-effects. Using a long-term experimental model of HAT with involvement of the central nervous system (CNS), we tested the ability of a megazol and suramin combination treatment to eliminate CNS trypanosomes. This consisted of 20 mg suramin per kg body weight administered intraperitoneally (i.p.), followed 24 h later by 4 daily doses (80 mg/kg) of megazol given either i.p. or per os. One week post-treatment, neurological disorders had disappeared. One of 15 mice relapsed in each application group at 81 and 98 days after treatment, respectively. At six months, no signs of relapse were seen in remaining mice, indicating that this chemotherapy regimen was curative. Immunohistochemical (astrocytosis) and histological (inflammatory lesions) examinations of brain tissues showed that animals returned to normal from 2 months post-treatment. These results suggest that the megazol-suramin combination reversed the CNS pathology in this model.
    Preview · Article · Oct 1998 · Tropical Medicine & International Health

  • No preview · Article · Sep 1998
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    ABSTRACT: Melarsoprol has remained the chosen drug for the late-stage treatment of human African trypanosomiasis (HAT) due both to Trypanosoma brucei (T.b.) gambiense and T.b. rhodesiense; however, arsenical encephalopathies, which are often fatal, occur in 5-10% of the treated cases. To date, two major problems have not been solved. The first one is the precise diagnosis of early involvement of the central nervous system (CNS) which determines the therapeutics to be administered. The second one is linked to the lack of data on in vivo efficacy of products which are effective in vitro against trypanosomes. Answers have to be provided by experimental animal models of HAT. Such models would allow for better studies of the pathology and pathogenesis of the disease, as well as therapeutic trials of potentially effective new drugs or combinations. We have developed acute and chronic murine and sheep experimental animal models of HAT infected by T. b. brucei. Meningoencephalitis and neurological signs are relatively difficult to obtain in murine models and require artificial means, such as suramin treatment on day 21 after-infection. The chronic murine model has demonstrated CNS involvement with meningitis, followed by meningoencephalitis with progressive astrocytosis. The sheep model develops a disease with CNS complications and cerebrospinal fluid can be collected. In the sheep model, we have described anti-galactocerebrosides antibodies, which represent major components of myelin, which may indicate an autoimmune process in the CNS. We then described these antibodies in the cerebrospinal fluids and sera from patients at a late-stage of the disease. From a therapeutic point of view, we have cured mice or sheep with low doses of melarsoprol, or with the nitroimidazole derivatives Ro 15-0216 and megazol, alone or combined with suramin. Further studies of these nitroimidazole compounds, which could be proposed for human use, have to be carried out on a-primate model infected by T.b. gambiense. To our knowledge, this primate model is not available. This is why we have recently developed a T. b. gambiense primate model of HAT on Cercopithecus aethiops.
    No preview · Article · Feb 1998 · Bulletin de la Société de pathologie exotique
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    ABSTRACT: A simple and sensitive high-performance liquid chromatographic method has been developed to measure megazol in human plasma. The method was optimized and validated according to the Washington Concensus Conference on the Validation of Analytical Methods (V.P. Shah et al., Eur. J. Drug Metab. Pharmacokinet., 15 (1991) 249). The criteria of complete validation were specificity, linearity, precision, analytical recovery, dilution and stability. It involved extraction of the plasma with dichloromethane, followed by reversed-phase high-performance liquid chromatography using a Kromasil C8 column and UV detection at 360 nm. The retention times of the internal standard (tinidazol) and megazol were 6.10 and 9.60 min, respectively. The standard curve was linear from 2 ng ml-1 (limit of quantification) to 2000 ng ml-1. The coefficients of variation for all the criteria of validation were less than 6%; 85 to 92% extraction efficiencies were obtained. Megazol was stable during the storage period (one month at -20 degrees C) in plasma and for two months at 25 degrees C in standard solution. The method was tested by measuring the plasma concentration following oral administration to rat and was shown to be suitable for pharmacokinetic studies.
    No preview · Article · Sep 1997 · Journal of chromatography. B, Biomedical sciences and applications
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    ABSTRACT: The search for a chronic experimental model for human African trypanosomiasis (HAT) in animals with cerebral lesions and neurological disorders has been difficult. Models with meningo-encephalitis have been proposed using Trypanosoma brucei gambiense or T. b. rhodesiense. Meningo-encephalitis is rare in infection with T. b. brucei. It has been shown that the treatment of mice infected with T. b. brucei with diminazene aceturate (Berenyl) led to development of a rapid meningo-encephalitis. In this study, we report the development of a chronic experimental model of HAT in mice infected with T. b. brucei AnTat 1.1E. To obtain a chronic evolution of the infection, on Day 21 postinfection, mice were treated with a dose of suramin (Moranyl) at 20 mg x kg(-1) body weight, a dose which failed to eliminate trypanosomes in the central nervous system (CNS). This treatment, repeated after each parasitemic relapse in the blood, allowed animals to survive more than 300 days postinfection. After a few weeks of infection, mice displayed neurological signs. Histological studies showed the appearance of increasing inflammatory lesions, from meningitis to meningo-encephalitis, with progression of lesions throughout the perivascular spaces in cerebral and cerebellum parenchyma. No demyelination or neuronal alteration were observed except in the necrotic spaces. Trypanosomes were observed in different structures in CNS. An immunohistochemical study of glial fibrillary acidic protein (GFAP) showed an increasing astrocytosis according to the duration of the infection. This model reproduces neurological and histological pathology observed in the human disease and can be useful for further immunopathological, neurohistological and therapeutic studies on this condition.
    No preview · Article · Mar 1997 · Experimental Parasitology