Alterations of orexinergic and melanin-concentrating hormone neurons in experimental sleeping sickness.

Human African trypanosomiasis or sleeping sickness is a severe, neglected tropical disease caused by the extracellular parasite Trypanosoma brucei. The disease, which leads to chronic neuroinflammation, is characterized by sleep and wake disturbances, documented also in rodent models. In rats and mice infected with Trypanosoma brucei brucei, we here tested the hypothesis that the disease could target neurons of the lateral hypothalamus (LH) containing orexin (OX)-A or melanin-concentrating hormone (MCH), implicated in sleep/wake regulation. In the cerebrospinal fluid of infected rats, the OX-A level was significantly decreased early after parasite neuroinvasion, and returned to the control level at an advanced disease stage. The number of immunohistochemically characterized OX-A and MCH neurons decreased significantly in infected rats during disease progression and in infected mice at an advanced disease stage. A marked reduction of the complexity of dendritic arborizations of OX-A neurons was documented in infected mice. The evaluation of NeuN-immunoreactive neurons did not reveal significant neuronal loss in the LH of infected mice, thus suggesting a potential selective vulnerability of OX-A and MCH neurons. Immunophenotyping and quantitative analysis showed in infected mice marked activation of microglial cells surrounding OX-A neurons. Day/night oscillation of c-Fos baseline expression was used as marker of OX-A neuron activity in mice. In control animals Fos was expressed in a higher proportion of OX-A neurons in the night (activity) phase than in the day (rest) phase. Interestingly, in infected mice the diurnal spontaneous Fos oscillation was reversed, with a proportion of OX-A/Fos neurons significantly higher at daytime than at nighttime. Altogether the findings reveal a progressive decrease of OX-A and MCH neurons and dysregulation of OX-A neuron diurnal activity in rodent models of sleeping sickness. The data point to the involvement of these peptidergic neurons in the pathogenesis of sleep/wake alterations in the disease and to their vulnerability to inflammatory signaling.

Signaling pathways in chronic myeloid leukemia and leukemic stem cell maintenance: key role of stromal microenvironment.

Chronic myeloid leukemia (CML) is caused by the malignant transformation of hematopoietic stem cells in leukemic stem cells. From the introduction of the anti-cancer drug imatinib, the therapy of CML has been positively transformed. However, following treatment most patients display a residual CML disease attributed to the presence of quiescent leukemic stem cells intrinsically resistant to imatinib. Considering that the later cancer cells lose their chemoresistance in vitro, it appears that the stromal microenvironment plays a crucial role in CML-affected cell chemoresistance. In the present review, we summarize and discuss the recent findings on signaling pathways through which stromal cells sustain CML leukemogenesis, as well as leukemic stem cell maintenance and chemoresistance.

Validation of anticonvulsant and sedative activity of six medicinal plants.

Acanthus montanus, Alchornea laxiflora, Hyptis spicigera, Microglossa pyrifolia, Piliostigma reticulatum, and Voacanga africana were evaluated with respect to anticonvulsant and sedative activity in mice using animal models (maximal electroshock (MES), N-methyl-D-aspartate (NMDA), pentylenetetrazol (PTZ), isonicotinic hydrazide acid (INH), picrotoxin (PIC), and strychnine (STR)-induced convulsions or turning behavior and diazepam-induced sleep). Acanthus montanus protected 66.6% of mice against MES-, PIC-, and STR-induced convulsions and 83.3% of mice from PTZ-induced convulsions. Alchornea laxiflora protected 75% and 87.5% of mice in the STR and NMDA tests, respectively, at a dose of 120 mg/kg. Hyptis spicigera protected 100 and 87.5% of mice against STR- and PTZ-induced convulsions, respectively, at a dose of 160 mg/kg. Microglossa pyrifolia protected 50% to 100% of mice against convulsions. Piliostigma reticulatum protected 62.5% to 100% of mice against convulsions and turning behavior. Voacanga africana protected 62.5% to 87.5% of mice against convulsions and turning behavior. All of the plants except A. laxiflora also exerted sedative activity by strongly increasing the total duration of sleep induced by diazepam.