Microglia activation in a model of sleep disorder: an immunohistochemical study in the rat brain during Trypanosoma brucei infection.

Microglial cells play a key role in the events triggered by infection, injury or degeneration in the central nervous system not only as scavenger cells but also as immune effector elements. We analyzed the features and distribution of cells of the microglia/macrophage lineage with OX-42 and ED-1 immunohistochemistry in the brain of experimental rats infected with the extracellular parasite Trypanosoma brucei. Such experimental infection provides a rat model of sleeping sickness or African trypanosomiasis, and is hallmarked in its advanced stages by severe alterations of the animals' sleep structure. In infected rats a remarkable activation of microglia, revealed by OX-42 immunoreactivity, became evident in the 3rd week post-infection in periventricular and subpial brain regions, with a prevalence in the hypothalamus. These features were concomitant with the onset of sleep anomalies, monitored with electroencephalographic recordings. Microglia activation increased in the following weeks, paralleling the progressive alterations of sleep parameters, and was most marked in the terminal stages of the infection, corresponding to the 6th-7th weeks. In addition, ED-1-immunoreactive macrophages and ramified microglia, confined to hypothalamic periventricular and basal regions, were evident after 4 weeks of disease. Degeneration of neuronal perikarya was not detected histologically in the infected brains at any time point. These data provide evidence for a reaction of microglia and macrophages in the brain of trypanosome-infected rats, and point out a selective distribution of these activated cells. The findings are discussed in relation to the animals' sleep disorder during trypanosome infection.

Melatonin and its new agonist S-20098 restore synchronized sleep fragmented by experimental trypanosome infection in the rat.

The experimental infection with the parasite Trypanosoma brucei in the rat provides a unique model of dysfunction of the sleep regulatory mechanisms, because the length of synchronized sleep episodes is selectively and dramatically reduced in the advanced stages of the disease. In the present study, melatonin was acutely administered (3 mg/kg SC) to trypanosome-infected rats, before the sleep onset. This treatment resulted in a significant increase of the length of synchronized sleep episodes in respect to the infected animals and to those that had received only the vehicle. Thus, melatonin restored a normal sleep pattern during the infection. Similar findings were obtained with the new melatonin agonist S-20098. The sleep parameters were not significantly modified by either melatonin or S-20098 acute administration to noninfected animals. These findings indicate that exogenous melatonin and S-20098 exert a selective regulatory action on sleep fragmentation during experimental trypanosomiasis.