Aside from the described immunological phenomenon, African sleeping sickness is characterized by a number of distinct neurological symptoms. They include disruption of sleep and extrapyramidal motor disturbances as well as neuropsychiatric changes (reviewed by Enanga et al. 2002). Although the histopathological reactions in the brain have been well described, the patho-genetic mechanisms behind the nervous system disease are still unclear. The blood-brain barrier (BBB), which separates circulating blood from the central nervous system, regulates the flow of materials to and from the brain. During the course of the disease, the integrity of the BBB becomes compromized and parasites cross the barrier. While the mechanism of this phenomenon is not understood, the following routes have been suggested: (1) entry of the parasite via the choroid plexus epithelium leading to the cerebrospinal fluid space; (2) entry via the cerebral capillary endothelium leading to the brain parenchyma and (3) penetration through disrupted tight junctions (Enanga et al. 2002; Londsdale-Eccles and Grab 2002). Morphologically, the BBB is constructed of apposed cerebral-endothelial capillary cells held together by so-called tight junctions. Tight junctions hold the brain microvascular endothelial cells closely together, thereby eliminating the gaps that usually occur between endothelial cells at other locations in the body. Central components of the tight junctions are transmembrane proteins such as occludin and claudins, and various membrane-associated guanylate kinases.
The picture is further complicated by the fact that trypanosomes react differently with different host species. When African trypanosomes gain access to the human brain, little or no damage to the barrier is observed. By contrast, chronic trypanosomiasis in rats is accompanied by extensive BBB damage. However, recent evidence demonstrated the direct translocation of T. brucei across the BBB in rats during the early stages of infections (Mulenga et al. 2001). Although extravascular trypanosomes were observed near capillaries, a generalized loss of proteins in the tight junction could not be identified.
Several chemotherapeutics are currently used to treat African sleeping sickness. Among them are compounds such as suramin, pentamidine, melarso-prol, eflornithine and, on an experimental basis, diminazene and nifurtimox (Stephenson and Wiselka 2000; Fairlamb 2003; Kioy et al. 2004). However, none of the therapeutic measures is very effective and no vaccination against trypanosome infections is available today. Therefore, new concepts and experimental strategies for developing novel drugs are required (Van Gompel and Vervoort 1997). Based on the described clinical evidence and based on the fact that most drugs, including many trypanocides, do not cross the BBB efficiently, it is important that new diagnostic and therapeutic approaches must address this problem as well.
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