RESUMO
Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis.
Assuntos
Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Transtornos Cognitivos/etiologia , Sepse/complicações , Sepse/metabolismo , Transdução de Sinais , Animais , Anticorpos Monoclonais/farmacologia , Biomarcadores , Barreira Hematoencefálica/metabolismo , Antígenos CD40/antagonistas & inibidores , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Encefalite/etiologia , Encefalite/metabolismo , Humanos , Estimativa de Kaplan-Meier , Microglia/metabolismo , Sepse/mortalidade , Regulação para CimaRESUMO
PURPOSE: Some studies have shown the role of gastrin-releasing peptide (GRP) on the production and release of cytokines both in animal models and in humans with inflammatory diseases, but there are no reports on the effects of GRP in ocular inflammatory disease, mainly uveitis. The authors report on the effects of the GRP receptor (GRPR) antagonist RC-3095 in a well-established model for uveitis induced by the administration of lipopolysaccharide (LPS), comparing its effects with those of glucocorticoids. METHODS: Adult male Wistar rats (weight range, 250-300 g; n = 6 per group) were randomly divided into four groups: saline, LPS + saline, LPS + dexamethasone, LPS + RC-3095. Two hours after LPS administration, RC-3095 (0.3 mg/kg, single dose, subcutaneously) or dexamethasone (1 mg/kg, each 6 hours, subcutaneously) was administered. After 24 and 48 hours, rats were anesthetized, aqueous humor was sampled, and the irides were removed. Aqueous humor tumor necrosis factor-alpha, monocyte chemoattractant protein-1 concentration, myeloperoxidase activity were determined. In addition, oxidative damage to the irides was determined by the measure of thiobarbituric acid reactive substances and protein carbonyl content. RESULTS: The acute administration of RC-3095 exhibited anti-inflammatory actions, characterized by a reduction of myeloperoxidase activity and a decrease in tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels, to a greater extent than dexamethasone. In addition, RC-3095 elicits important action against irides oxidative damage. CONCLUSIONS: These findings suggest that GRP participates in the inflammatory response in an animal model of uveitis, making GRPR a target for new therapeutic options in the treatment of uveitis.
Assuntos
Anticarcinógenos/uso terapêutico , Bombesina/análogos & derivados , Modelos Animais de Doenças , Fragmentos de Peptídeos/uso terapêutico , Receptores da Bombesina/antagonistas & inibidores , Uveíte/tratamento farmacológico , Animais , Humor Aquoso/metabolismo , Bombesina/uso terapêutico , Quimiocina CCL2/metabolismo , Dexametasona/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Escherichia coli , Peptídeo Liberador de Gastrina/fisiologia , Glucocorticoides/uso terapêutico , Iris/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Peroxidase/metabolismo , Carbonilação Proteica , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Uveíte/induzido quimicamente , Uveíte/metabolismoRESUMO
Schizophrenia is a complex neuropsychiatric disorder in which symptoms can be classified as either positive, such as delusions and hallucinations, or negative, such as blunted affect and social withdrawal. However, the mechanisms underlying this disease are poorly understood. There is evidence that reactive oxygen species (ROS) play an important role in the pathogenesis of many diseases, particularly those which are neurological and psychiatric in nature. Ketamine has been used to induce a schizophrenia-like condition as an animal model in which to study this condition. In the present study we tested the effects of sub-anesthetic doses of ketamine on various parameters of oxidative stress in the brain of rats. Our results indicate that lipid peroxidation and tissue protein oxidation were affected by varying sub-anesthetic doses of ketamine in multiple cerebral structures. Additionally, the activity of the antioxidant enzymes CAT and SOD was measured and was also found to be altered in most of the structures tested. In conclusion, we observe an increase in oxidative damage marked by an increase in lipid peroxidation, oxidative protein damage and a decrease in enzymatic defenses, in an animal model of schizophrenia. Given that oxidative stress could be related to schizophrenia, these findings may explain, at least in part, the mechanisms underlying in this disease.