Trypanosoma brucei brucei:A Long-Term Model of Human African Trypanosomiasis in Mice, Meningo-Encephalitis, Astrocytosis, and Neurological Disorders

Keita, M.; Bouteille, Bernard; Enanga, Bertin; Vallat, J. M.; Dumas, Michel

doi:10.1006/expr.1996.4136

Cited by 59 publications

(62 citation statements)

References 32 publications

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“…Therefore, the results should be interpreted with caution. The increase of CSF GFAP found in some of the patients with second-stage HAT is consistent with the astrogliosis observed in HAT and experimental models of HAT, 2,4,6,[20][21][22]24,25 but in the present study, no conclusions regarding the use of CSF GFAP as a second-stage disease marker can be made. Increased CSF GFAP occurs only when astrogliosis is very pronounced, such as in Alzheimer's disease, vascular dementia, and multiple sclerosis.…”

Section: Discussionsupporting

confidence: 86%

“…19 Immunohistochemical studies of GFAP in experimental and in vitro models of HAT show extensive astrogliosis accompanied by production of prostaglandin, interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1, tumor necrosis factor-␣, and interferon-␥, which contribute to CNS pathology. 6,[20][21][22][23][24][25] The observed astrocyte activation and associated cytokine production may be a key element in CNS inflammatory processes.The neurofilament is a major structural element of neurons. Its principal role is to maintain axon caliber and neuronal size and shape.…”

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confidence: 99%

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Detection of light subunit neurofilament and glial fibrillary acidic protein in cerebrospinal fluid of Trypanosoma brucei gambiense-infected patients.

Lejon¹,

Rosengren²,

Büscher³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Light subunit neurofilament (NFL) and glial fibrillary acidic protein (GFAP) concentrations were determined in cerebrospinal fluid (CSF) of 34 patients with human African trypanosomiasis (HAT), five serologically positive but parasitologically unconfirmed individuals, and four healthy controls without evidence of HAT. In patients with second stage HAT (n ϭ 30), NFL levels were abnormally elevated in 10 cases and GFAP levels in five. The astrogliosis observed in HAT and experimental models of HAT is confirmed in our study by the presence of increased GFAP levels in the CSF. The abnormal NFL CSF levels reflect structural damage of nerve cells in 33 % of the second-stage patients studied. To our knowledge, this is the first time neuronal damage in HAT patients is demonstrated by using biochemical markers of brain damage in the CSF.Human African trypanosomiasis (HAT) or sleeping sickness is a tropical disease caused by Trypanosoma brucei gambiense. Two consecutive disease stages can be discerned: 1 the first, a hemolymphatic phase, is followed by a second, meningoencephalitic phase, which is associated with the spread of trypanosomes into the central nervous system (CNS). The meningoencephalitis observed in African trypanosomiasis is characterized by parasite invasion of the meninges and choroid plexus, infiltration of the leptomeninges and perivascular areas by IgM producing plasma cells, Mott cells, and T helper/inducer cells, diffuse microglial hyperplasia, astrogliosis in the white matter, and demyelination of neurons. 2-6 A correct stage determination is indispensable since it is directly related to the choice of an optimal treatment with minimal risk for the patient. This is currently carried out by examining the cerebrospinal fluid (CSF) for cell number, protein concentration, and presence of trypanosomes.Other CSF parameters associated with second-stage HAT, such as the occurrence of IgM, 7,8 trypanosome-specific antibodies, [8][9][10] and autoantibodies against CNS components such as myelin, 11 galactocerebroside, 12,13 and the 200-kD and 160-kD neurofilament proteins, 14 have been described. These autoantibodies may be induced by cerebrospecific antigens leaking from injured nervous tissue, or otherwise may be actively involved in the pathogenesis of the nervous system damage in HAT by initiating or maintaining demyelination and nerve cell injury. 2,15,16 The glial fibrillary acidic protein (GFAP) is a major structural protein of astrocytes. It composes the glial intermediate filament, 17,18 which forms the morphologic basis of astrogliosis. 19 Immunohistochemical studies of GFAP in experimental and in vitro models of HAT show extensive astrogliosis accompanied by production of prostaglandin, interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1, tumor necrosis factor-␣, and interferon-␥, which contribute to CNS pathology. 6,[20][21][22][23][24][25] The observed astrocyte activation and associated cytokine production may be a key element in CNS inflammatory processes.The neurofilament is ...

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Detection of light subunit neurofilament and glial fibrillary acidic protein in cerebrospinal fluid of Trypanosoma brucei gambiense-infected patients.

Lejon¹,

Rosengren²,

Büscher³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…For histological studies, sections were stained with haematoxylin and eosin. Immunohistochemistry was performed as described by Keita et al (1997) to identify the glial fibrillary acidic protein (GFAP), a major protein of differentiated intermediate filament. Thus with this group, it was possible to evaluate the regression of histological alterations.…”

Section: Combination Chemotherapymentioning

confidence: 99%

Megazol combined with suramin: a chemotherapy regimen which reversed the CNS pathology in a model of human African trypanosomiasis in mice

Enanga

Keita

Chauvière

et al. 1998

Tropical Med Int Health

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SummaryChemotherapy 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 (IP), followed 24 h later by 4 daily doses (80 mg/kg) of megazol given either IP 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. keywords megazol, suramin, CNS-trypanosomiasis correspondence B. Bouteille,

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“…In mice infected by T. brucei, immunohistochemical studies with GFAP demonstrated the occurrence of astrocytosis directly related to time of infection: in its initial phase it occurred in the white matter, and posteriorly, in the neuropil, in a diffuse form 24 . Binucleate cells, reactive to GFAP, near or associated to neurons suggest that astrocytes are capable of splitting and that these alterations represent the final result of neuronal destruction 6 , in an attempt to restore neuronal volume 28 .…”

Section: Discussionmentioning

confidence: 98%

Astrocytic and microglial response and histopathological changes in the brain of horses with experimental chronic Trypanosoma evansi infection

Lemos

Marques

Aquino

et al. 2008

Rev. Inst. Med. trop. S. Paulo

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SUMMARYThis study aimed to characterize astrocytic and microglial response in the central nervous system (CNS) of equines experimentally infected with T. evansi. The experimental group comprised males and females with various degrees of crossbreeding, ages between four and seven years. The animals were inoculated intravenously with 10 6 trypomastigotes of T. evansi originally isolated from a naturally infected dog. All equines inoculated with T. evansi were observed until they presented symptoms of CNS disturbance, characterized by motor incoordination of the pelvic limbs, which occurred 67 days after inoculation (DAI) and 124 DAI. The animals in the control group did not present any clinical symptom and were observed up to the 125 th DAI. For this purpose the HE histochemical stain and the avidin biotin peroxidase method was used. Lesions in the CNS of experimentally infected horses were those of a wide spread non suppurative meningoencephalomyelitis.The severity of lesions varied in different parts of the nervous system, reflecting an irregular distribution of inflammatory vascular changes. The infiltration of mononuclear cells was associated with anisomorphic gliosis and reactive microglia was identified. The intensity of the astrocytic response in the CNS of the equines infected by T. evansi characterizes the importance of the performance of these cells in this trypanosomiasis. The characteristic gliosis observed in the animals in this experiment suggests the ability of these cells as mediators of immune response. The parasite, T. evansi, was not identified in the nervous tissues.

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Trypanosoma brucei brucei:A Long-Term Model of Human African Trypanosomiasis in Mice, Meningo-Encephalitis, Astrocytosis, and Neurological Disorders

Cited by 59 publications

References 32 publications

Detection of light subunit neurofilament and glial fibrillary acidic protein in cerebrospinal fluid of Trypanosoma brucei gambiense-infected patients.

Detection of light subunit neurofilament and glial fibrillary acidic protein in cerebrospinal fluid of Trypanosoma brucei gambiense-infected patients.

Megazol combined with suramin: a chemotherapy regimen which reversed the CNS pathology in a model of human African trypanosomiasis in mice

Astrocytic and microglial response and histopathological changes in the brain of horses with experimental chronic Trypanosoma evansi infection

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