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Dithiocarbamates, a class of compounds widely used in medicine and agriculture, have been reported to impair sleep structure. These effects have been attributed to the decrease in norepinephrine levels induced by these drugs. However, it has also been recently demonstrated that most of the mechanisms by which dithiocarbamates damage cell function involve changes in oxidative environment. To verify the potential relevance of the latter mechanism in the sleep impairment, we examined the sleep response of adult rats to an acute administration of diethyldithiocarbamate (DDTC). At the dose of 0.6 g/kg, DDTC induced fragmentation and a decrease in slow wave sleep (SWS), and a dramatic loss of paradoxical sleep (PS). These changes occurred soon after the treatment (day 0), persisted the following day (day 1), partially recovered on day 3, and regained near basal values on day 6. No sleep anomalies were observed with a lower dose of DDTC (0.06 mg/kg). On the other hand, when the higher dose of DDTC was given in association with either one of two antioxidants, alpha-tocopherol or melatonin, the amounts of SWS and PS significantly improved even on day 1, suggesting that the DDTC effects on sleep involved an impairment of the brain oxidative balance. Likewise, administration of the lower dose of DDTC 5 days before the higher dose induced a much earlier recovery of normal sleep, presumably due to the development of a tolerance to DDTC. On the whole, the data suggest that the brain oxidative environment may play a role in the mechanisms subserving sleep regulation.

An increasing body of evidence suggests a role for activated microglia in the pathogenesis of neurodegenerative disorders. Hence, it would be useful to have a better understanding of the significance of microglial activation for neuronal damage. Unfortunately, most models of microglial activation use invasive or long-lasting insults, which make it difficult to evaluate the role played by microglia. We have instead developed a model for microglial activation by using brief exposure to the widely available neurotoxin diethyl-dithiocarbamate (DDTC). Despite evidence for the neurotoxic nature of this substance, microglia involvement has not been hitherto investigated. After acute i.p. administration of DDTC at two different doses, microglia were already activated in selected areas of the rat brain (hippocampal dentate gyrus, entorhinal-pyriform cortex and hypothalamus) after 1 hour, reaching a peak at 3-6 hours and subsided within 6-48 hours, depending on the brain region. Microglia activation was associated with interleukin-1 beta immunopositivity between 3 and 6 hours and with up-regulation of major histocompatibility complex class II expression between 24 and 48 hours. No significant changes in astrocyte immunostaining were detected between 6 hours and 6 days. The TUNEL procedure revealed the death of a limited number of cells in the above-mentioned structures that peaked at 6h and then declined rapidly. Cell death was detected in sites with major, minor, or no microglial activation, indicating that these two events can occur concomitantly or independently. The study shows that the administration of DDTC provides a useful model for studying the implications of region-specific reactivity of microglia and its differential interaction with neuronal damage., (Copyright 2002 Wiley-Liss, Inc.)

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., (Copyright 1999 Elsevier Science B.V.)

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.