Search

O comportamento-doente e outros efeitos associados a intoxicação pelo lipopolissacarídeo (LPS) tem sido amplamente investigado por diversos campos da ciência contemporânea. Essa macromolécula bacteriana é capaz de ativar o sistema imunitário (SI) inato e gerar mecanismos adaptativos inflamatórios. Os mecanismos inflamatórios humorais e teciduais, tanto periféricos quanto centrais, estão envolvidos com diversas condições neuropsiquiátricas e representam uma importante condição para etiologia e patogênese destas desordens. O trabalho a seguir aborda alguns aspectos comportamentais e bioquímicos de ratos ou camundongos, quando injetados com LPS sistemicamente. Utilizou-se administrações agudas ou múltiplas e tarefas de avaliações comportamentais de memórias aversivas e espaciais, bem como sensibilização locomotora. Os resultados obtidos mostraram que o LPS induziu aumento das latências de teste da esquiva inibitória, que não foram observados nos grupos controle. Em outro experimento utilizando LPS e exercício físico forçado, no labirinto aquático de Morris os animais tratados somente com LPS apresentaram melhor desempenho após reativação de memória remota. Posteriormente não foi observado ansiedade ou déficit de memória. Foram observadas alterações significativas da S100B no líquido cefalorraquidiano de animais tratados com LPS. No soro essas diferenças foram sutis e não puderam discriminar os grupos. A corticosterona plasmática estava alterada nos animais com melhores desempenhos cognitivos. Noutro experimento, utilizando a sensibilização locomotora o LPS foi capaz de promover a expressão desse comportamento quando administrado com uma dose não sensibilizatória de cocaína. As conclusões apontam para o papel facilitador do LPS em tarefas de memória e sensibilização locomotora. Os possíveis mecanismos envolvidos devem estar relacionados com a ativação do eixo-HPA e outros mecanismos neuroimunológicos. Os paralelos traçados vão nas direções da comorbidade existente entre depressão e dependência química. E o autor busca discutir uma possível relação da bases neuroimunobiológicas com pensamentos cognitivistas. Sickness behavior and other effects induced by lipopolysaccharide (LPS) have been widely used in contemporary neuroscience. This molecule triggers innate immune responses as inflammation, that has been reported to be involved with depression and others neuropsychiatric conditions. The main question of this thesis is about behavioral aspects of rats and mice treated with LPS, and possible relations between depression and addiction. In rats, a single LPS administration facilitated inhibitory avoidance (IA) memory retention but it did not changed serum or cerebrospinal fluid (CSF) S100B levels. The multiple LPS administration improved memory in the Morris water maze task (MWM) during the second testing, which occurred 24 hours after retraining. They also equally increased plasma corticosterone levels. CSF but not serum levels of S100B were increased by both LPS doses. In other experiment, LPS and cocaine were administered intraperitonealy in young-adult male C57bl/6 mice during a 5-day acquisition phase. After a 48-h withdrawal period all groups were challenged with cocaine to evaluate locomotor expression. During the acquisition phase, the LPS-treated groups displayed characteristic hypolocomotion related to sickness behavior. The low dose of cocaine did not increase the distance travelled, characterizing a nonsensitization dose. Groups that received both LPS and cocaine did not display hypolocomotion, indicating that cocaine might counteract hypolocomotion sickness behavior. Moreover, during challenge, only these animals expressed locomotor sensitization. Thus, LPS can induce memory retention and locomotor sensitization. The mechanisms involved in this data may be stress system and other neuroimmunological interactions.

Background: Inflammatory responses in brain are primarily mediated by microglia, but growing evidence suggests a crucial importance of astrocytes. S100B, a calcium-binding protein secreted by astrocytes, has properties of a neurotrophic or an inflammatory cytokine. However, it is not known whether primary signals occurring during induction of an inflammatory response (e.g. lipopolysaccharide, LPS) directly modulate S100B. Methods: In this work, we evaluated whether S100B levels in cerebrospinal fluid (CSF) and serum of Wistar rats are affected by LPS administered by intraperitoneal (IP) or intracerebroventricular (ICV) injection, as well as whether primary astrocyte cultures respond directly to lipopolysaccharide. Results: Our data suggest that S100B secretion in brain tissue is stimulated rapidly and persistently (for at least 24 h) by ICV LPS administration. This increase in CSF S100B was transient when LPS was IP administered. In contrast to these S100B results, we observed an increase in in TNFa levels in serum, but not in CSF, after IP administration of LPS. In isolated astrocytes and in acute hippocampal slices, we observed a direct stimulation of S100B secretion by LPS at a concentration of 10 μg/mL. An involvement of TLR4 was confirmed by use of specific inhibitors. However, lower levels of LPS in astrocyte cultures were able to induce a decrease in S100B secretion after 24 h, without significant change in intracellular content of S100B. In addition, after 24 h exposure to LPS, we observed a decrease in astrocytic glutathione and an increase in astrocytic glial fibrillary acidic protein. Conclusions: Together, these data contribute to the understanding of the effects of LPS on astrocytes, particularly on S100B secretion, and help us to interpret cerebrospinal fluid and serum changes for this protein in neuroinflammatory diseases. Moreover, non-brain S100B-expressing tissues may be differentially regulated, since LPS administration did not lead to increased serum levels of S100B.