Papel do óxido nítrico no comportamento tipo-depressão induzido por LPS

Abstract

Psychiatric disorders, including depression, are among the leading causes of disability in the world. Thus, research on new pathways involved in the pathophysiology of this mental disorder that allows the discovery of new targets for the treatment of this disorder has been extensively studied. Nitric oxide (NO) and its enzymatic nitric oxide synthase (NOS) synthetase have been associated with depression and other affective disorders. In this context, the effect of pre-treatment of drugs that modulate the NO pathway in animals submitted to immunological challenge was determined by the systemic administration of LPS (0.5 mg / kg, ip). For both behaviors related to depression, pre-pulse inhibition (PPI) and locomotor activity, 24 h after endotoxin administration, respectively, were the key points for the development of depressive and neurochemical behaviors through evaluation of TBARS, nitrite and GSH in the cerebral areas (prefrontal cortex - CPF, hippocampus - HC and striatum - CE) were evaluated. LPS-treated animals, as well as those pretreated with L-ariginine prior to LPS, significantly increased the time of immobility in forced swimming compared to controls. A significant reduction in the immobility time of animals pretreated with aminoguanidine was observed when compared to the animals in the control and LPS groups. Remarkably, animals pretreated with sildenafil and L-NAME showed a significant decrease in immobility time when compared to the group receiving only LPS. The results showed that 24 hours after LPS administration, the locomotor activity assessed through the number of crosses in the open field, remained unchanged, with only a significant increase in animals treated with imipramine. A significant decrease in PPI levels was observed 24 h after administration of LPS at the pre-pulse intensities of 70, 75 and 80 dB relative to the control animals. Administration of all other drugs (imipramine, L-arginine, sildenafil, L-NAME and aminoguanidine) was able to prevent the reduction of PPI levels caused after systemic administration of LPS. GSH levels decreased in all brain areas studied, ie, prefrontal cortex, hippocampus and striatum, of LPS treated animals compared to controls. This reduction was maintained by pretreatment with L-arginine in the prefrontal cortex compared to LPS and controlled and prevented by pretreatment with imipramine, L-arginine, sildenafil, L-NAME, and aminoguanidine drugs. In the evaluation of lipid peroxidation after LPS administration, a significant increase in this parameter was evidenced. Administration of imipramine maintained increased levels of TBARS in the prefrontal cortex and striatum compared to control animals, but reduced this parameter when compared to LPS-treated animals. Administration of L-arginine, sildenafil, L-NAME and aminoguanidine reduced levels of lipid peroxidation when compared to LPS-treated animals in all brain areas studied. The pre-administration of imipramine, 1-arginine and aminoguanidine was able to prevent the increase of BDNF levels caused by the systemic administration of LPS. On the other hand, analyzes of BDNF levels 24 h after administration of LPS from animals pretreated with sildenafil and L-NAME did not demonstrate significant changes. An increase in IL-1β content was observed 24 h after administration of LPS in the prefrontal cortex, hippocampus and striatum, all drugs were able to prevent such changes in the hippocampus and striatum. Nitric oxide (NO) plays an important neuromodulatory role in the central nervous system. Any pharmacological manipulation of the NO pathway can be considered as a novel therapeutic approach for the treatment of CNS disorders, more so for mental depression (Heiberg et al., 2002) (1) (1) (1) (1).