Exposição sistêmica de camundongos adultos a lipopolissacarídeo de Escherichia coli: influência do sexo nas alterações comportamentais e neuroquímicase efeito do tratamento com escitalopram e doxiciclina

Abstract

Depression is one of the most prevalent psychiatric disorders, having the main clinical symptoms anorexia, reduced locomotor activity, anhedonia and lack of concentration. There is evidence that immunoinflammatory changes underlie depression. In addition, sex is a relevant factor for the manifestation of depression symptoms, although more recent evidence points to a similar severity of depression in both sexes. The treatment of depression is ineffective due to the fact that existing medications do not act on the different pathophysiological mechanisms of this disorder. In this context, the combination of antidepressants with different mechanisms of action is a common practice in non-responders or partial responders to antidepressants. It is worth mentioning that antidepressant and antimicrobial drugs have shown anti-inflammatory properties. The objectives of the present study were: i) to investigate the influence of sex on behavioral and neuroinflammatory/ oxidative changes in the animal model of depression-induced symptoms induced by single exposure to the lipopolysaccharide immune challenge (LPS) of Escherichia coli; and ii) to evaluate male animals under repeated exposure to LPS, the therapeutic effects of doxycycline and escitalopram alone and in combination. To reach the proposed objectives, the present study was divided into two protocols. In the first protocol, the depression model was induced by systemic and single exposure of male and female Swiss mice to E. coli lipopolysaccharide (LPS - 0.5 mg/kg) and evaluation after 24 hours. In the second protocol, only male animals were submitted to repeated exposure of LPS for 10 days and after 5 days of exposure to LPS the animals received doxycycline or escitalopram alone or in combination. Inflammatory/oxidative alterations were evaluated, as well as in protective signaling pathways. Protocol 1 showed that only male animals presented behavioral-type depressive changes, such as increased immobility of forced swimming and decrease in the preference for sucrose. The females presented anxiogenic behavior in the high cross labyrinth. Both males and females presented neuroinflammatory and oxidative alterations. In protocol 2, doxycycline (DOXI - 10 mg/kg) or escitalopram (ESCI - 4 mg/kg) alone or in combination reversed the increase in immobility induced by repeated exposure to LPS. Levels of IL-1β and TNF-α increased after LPS exposure, while DOXI and ESCI reversed these levels. DOXI and ESCI reversed the increase in nitrate levels induced by LPS. Protein expression levels of the nuclear factor kappa B (NF-B) and the marker of the ionized calcium binding adapter molecule-1 (IBA-1) expressed in the activated microglia were increased in the group exposed to LPS being reverted by DOXI and ESCI, whereas phosphorylated glycogen synthase kinase-3 (GSK3β) and phosphorylated extracellular regulated kinase (ERK 1/2) levels were decreased in the LPS group and reversed after the treatment protocol. DOXI also increased the protein levels of total ERK 1/2 and the transcriptional factor of the binding protein to the cAMP response element (CREB). Based on the results of the present study, DOXI when administered alone activated more neuroprotective mechanisms compared to ESCI, such as increased brain levels of GSH and phosphorylated CREB, in addition to the combination of the two drugs having reduced levels of NF-kB and increased GSK3β phosphorylated. Therefore, it is suggested that DOXI may act as an antidepressant, presenting higher effects than those observed with escitalopram.