Efeito da suplementação crônica com áxido graxo poliinsaturado ômega -3 e gordura vegetal hidrogenada em um modelo de comportamento doentio: influência da via da quinurenina nas alterações neurocomportamentais

Abstract

The sickness behavior has been well described experimentally and observationally in several animal species. In this context, lipopolysaccharide (LPS) is an endotoxin derived from gram-negative bacteria, which is used as a predictive model for the induction of sickness behavior in rodents. Thus, this study aimed to investigate the effect of chronic supplementation with omega-3 polyunsaturated fatty acid (n-3 PUFA) and hydrogenated vegetable fat (HVF) on the model of sickness behavior LPS-induced in aged mice. Aged animals received supplementation with n-3 PUFA and HVF for six months after administration of LPS for induction of sickness behavior. Twenty-four hours later, behavioral tests and biochemical determinations were performed. In general, LPS caused a severe body weight loss and alterations in behavioral tests. Chronic n-3 PUFA supplementation was able to prevent these LPS- generated alterations in behavioral tests in aged mice and HVF supplementation did not modulate these alterations. We investigated the involvement of the serotonergic system, LPS generated an increase in the levels of serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in the hippocampus, striatum and prefrontal cortex of the animals. Supplementation with n-3 PUFA protected against the increase in 5-HT and 5-HIAA levels generated by LPS, already HVF supplementation did not modulate these alterations and even potentiated the increase in 5-HT levels in the hippocampus. The administration of LPS generated a drastic increase in the levels of proinflammatory cytokines (IL-1β, IL-6, TNF-α and IFN-γ) in the three brain structures studied. In the presence of n-3 PUFA supplementation there was an attenuation in the increase of the levels of proinflammatory cytokines. HVF supplementation did not alter the increase in cytokine levels caused by LPS and also potentiated the increase of TNF-α levels in the brain structures studied. This increase in proinflammatory cytokines levels caused by LPS eventually activated the kynurenine pathway by the action of the indoleamine-2,3-dioxygenase (IDO) enzyme. Supplementation with n-3 PUFA modulated the activity of enzyme IDO, preventing the alteration in the enzymatic activity caused by LPS, already HVF supplementation did not modulate enzyme activity in the three brain structures. In view of the exacerbated activation in the kynurenine pathway caused by LPS, we investigated the branches neurotoxic and neuroprotective. In this context, LPS caused a decrease in the levels of kynurenic acid, which has neuroprotective properties. Supplementation with n-3 PUFA was able to prevent the decrease in levels of kynurenic acid caused by administration of LPS in hippocampus, striatum and prefrontal cortex. However, HVF supplementation did not influence alterations in levels of kynurenic acid caused by LPS and also contributed to the decrease in kynurenic acid/kynurenine ratio in brain structures studied. Investigating the pathway's neurotoxic branch, LPS generated an increase in levels of 3-hydroxykynurenine (3-HQ) and quinolinic acid (AQ) in hippocampus, striatum and prefrontal cortex of the aged animals. Supplementation with n-3 PUFA was able to prevent the increase in 3-HQ and AQ levels in all brain structures. On the other hand, supplementation with HVF aggravated the increase in 3-HQ and AQ levels exacerbated by LPS, increasing the neurotoxicity caused by sickness behavior. Thus, data from the present study showed that n-3 PUFA supplementation was able to protect against neurobehavioral and neurometabolic alterations caused by sickness behavior. We have also shown that HVF supplementation aggravated the alterations caused by sickness behavior. HVF supplementation, increased neuroinflammation via TNF-α which activated kynurenine pathway and further shifted the pathway balance towards the neurotoxic branch. Finally, we contributed to elucidate the pharmacological effects of n-3 PUFA and also demonstrated the deleterious effects of HVF in sickness behavior model. We hope that results of the present study may serve as a basis for epidemiological and public health studies in aged population that is severely affected by neurological diseases.