Determinação de alterações comportamentais e neuroquimicas do aprepitante no modelo crônico de depressão induzido pela administração repetida de lipopolissacarídeo em camundongos

Abstract

Depression is a multifactorial disease characterized by a set of psychological and physical symptoms associated with high rates of comorbidities, disability, and mortality. The drugs available for the treatment of depression act by controlling the levels of monoamines and require at least 3 weeks of administration for the initiation of antidepressant action. Recent evidence has showed the involvement of cytokines through activation of central and peripheral immunological pathways as well as the microbial translocation due to increased intestinal permeability (leaky gut) in the pathophysiology of depression. Based on the hypothesis of the cytokines in the depression it was developed the animal model of depression induced by the repeated administration of lipopolysaccharide (LPS). Through this model it is possible to determine new therapeutic targets for depression via regulation of immuno-inflammatory mediators. The system Substance P and its NK1 receptor is involved in the physiological regulation of inflammation and mood and its antagonism showed antidepressant phenotype in clinical and preclinical studies. Our study evaluated the behavioural and neurochemical effects of an antagonist of NK1, Aprepitant (Apr), in mice subjected to the model of depression induced by the intermittent administration of LPS. For the induction of depression, swiss female mice were injected with LPS intraperitoneally at the doses 750, 1000 and 1250 mg / kg 5 days a month for 4 months. Treatment with NK1 receptor (NK1R) antagonist, aprepitant (APR) at doses 4, 8 and 24 mg / kg, started 28 days after the last LPS challenge and lasted 14 days. Pharmacological validation was obtained with fluoxetine (FLU) 10 mg / kg. The control animals were treated with saline (SAL) 0.9% for 14 days. On the fourteenth day, one hour after the last treatment, the depression like behaviors was evaluated. Twenty-four hours later, anhedonia was evaluated using the sucrose preference test. After the last behavioral test the animals were euthanized and the prefrontal cortex, hippocampus and striatum were dissected for the neurochemical tests. The results showed that LPS induced depressive behavior. Treatment with APR and FLU showed antidepressant effect (reversing anhedonia and reducing the time of immobility in forced swimming) and anxiolytic activity evidenced in the open field test. Doses of APR 8 and 24 mg / kg showed better antidepressant activity. In the molecular parameters, we observed an increase in Iba1, NFκB and IL1β levels in the hippocampus. The increase in hippocampal IL1β levels was related to the reduction of SAT1 mRNA transcription, BDNF levels and increased IDO transcript expression related to decrease in tryptophan, kynurenine, and quinolinic acid levels. APR, at 24 mg / kg, reversed the behavioral changes induced by LPS through mechanisms related to the reduction of microglial activation and NFκB expression, with consequent reduction of inflammatory cytokines such as IFN-γ and TNF-α, reduction of IDO transcripts and increase of TDO and SAT1 mRNA, accompanied by the reduction of the levels of kynurenine and quinolinic acid levels in the hippocampus of mice. The FLU used as the standard antidepressant did not reverse the microglial activation, neuroinflammation and the amount of SAT1 transcripts triggered by LPS. In this context, the results show that blockade of the tachykinin pathway attenuates neuro-inflammatory, neurotrophic and genetic alterations triggered by repeated administration of LPS demonstrating a relevant therapeutic target for the treatment of depression.