RESUMEN
Ischemic stroke occurs due a blockage in the blood flow to the brain, leading to damage to the nervous system. The prevalent morbidities resulting from stroke include post-stroke infection, as sepsis. Additionally, oxidative stress is recognized for inducing functional deficits in peripheral organs during sepsis. Therefore, sex differences in stroke exist and we aimed to investigate the peripheral oxidative stress caused by sepsis after stroke in male and female rats. Wistar rats (male and female) were divided into sham+sham, middle cerebral artery occlusion (MCAO) + sham, sham+ cecal ligation and perforation (CLP) and MCAO+CLP groups to males and female rats. Animals were subjected to MCAO or sham and after 7 days, were subjected to sepsis by CLP or sham. After 24 h, serum, total brain, lung, liver, heart, and spleen were collected. Brain edema, myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) concentration, oxidative damage to lipids and proteins, and catalase activity were evaluated. Brain edema was observed only in male rats in MCAO+CLP group compared to MCAO+sham. Regarding MPO activity, an increase was verified in male in different organs and serum in MCAO+CLP group. For N/N levels, the increase was more pronounced in females submitted to MCAO+CLP. In general, to oxidative stress, an increase was only observed in animals exposed to MCAO+CLP, or with a greater increase in this group compared to the others. The findings provided the first indication that animals exposed to MCAO exhibit a heightened vulnerability to the harmful impacts of sepsis, as evidenced by brain edema and peripheral oxidative stress, and this susceptibility is dependent of sex.
Asunto(s)
Edema Encefálico , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media , Estrés Oxidativo , Peroxidasa , Ratas Wistar , Sepsis , Animales , Femenino , Masculino , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/fisiopatología , Infarto de la Arteria Cerebral Media/sangre , Sepsis/metabolismo , Sepsis/fisiopatología , Sepsis/complicaciones , Sepsis/sangre , Factores Sexuales , Peroxidasa/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/patología , Edema Encefálico/fisiopatología , Nitratos/sangre , Nitratos/metabolismo , Nitritos/sangre , Nitritos/metabolismo , Ratas , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/irrigación sanguínea , Catalasa/metabolismoRESUMEN
Excessive fructose consumption is associated with the incidence of obesity and systemic inflammation, resulting in increased oxidative damage and failure to the function of brain structures. Thus, we hypothesized that fructose consumption will significantly increase inflammation, oxidative damage, and mitochondrial dysfunction in the mouse brain and, consequently, memory damage. The effects of different fructose concentrations on inflammatory and biochemical parameters in the mouse brain were evaluated. Male Swiss mice were randomized into four groups: control, with exclusive water intake, 5%, 10%, and 20% fructose group. The 10% and 20% fructose groups showed an increase in epididymal fat, in addition to higher food consumption. Inflammatory markers were increased in epididymal fat and in some brain structures. In the evaluation of oxidative damage, it was possible to observe significant increases in the hypothalamus, prefrontal cortex, and hippocampus. In the epididymal fat and in the prefrontal cortex, there was a decrease in the activity of the mitochondrial respiratory chain complexes and an increase in the striatum. Furthermore, short memory was impaired in the 10% and 20% groups but not long memory. In conclusion, excess fructose consumption can cause fat accumulation, inflammation, oxidative damage, and mitochondrial dysfunction, which can damage brain structures and consequently memory.
Asunto(s)
Fructosa , Obesidad , Ratones , Masculino , Animales , Fructosa/efectos adversos , Estrés Oxidativo , Inflamación , EncéfaloRESUMEN
Propose/aim of study: Modafinil (MD) is a psychostimulant drug used off-label and cognitive dysfunction may be a significant emerging treatment target for this drug. The objective of this study was to evaluate the effect of MD on the neurochemical parameters and memory impairment of rats submitted to sepsis by cecal ligation and perforation (CLP).Material and method: Male Wistar rats (250-350g) were submitted to CLP, or sham as control, and divided into the sham + water, sham + MD (300 mg/kg), CLP + water, and CLP + MD (300 mg/kg) groups. Ten days after the administration of MD and CLP, the rats were submitted to a memory test by passive avoidance apparatus being sacrificed. The nitrite and nitrate (N/N) concentration, myeloperoxidase (MPO) and catalase (CAT) activity, lipid and protein oxidative damage, and brain-derived neurotrophic factor (BDNF) levels were measured in the prefrontal cortex and hippocampus.Results: The passive avoidance test verified an increase in the latency time compared training and test section in the groups sham + water and CLP + MD. Decreased N/N concentration and MPO activity were verified in the prefrontal cortex of rats submitted to CLP and MD treatment, as well as reduced protein and lipid oxidative damage in the hippocampus, which was accompanied by increased CAT activity and BDNF levels.Conclusion: Our data indicate the role of MD in attenuating oxidative stress parameters, the alteration of BDNF, and an improvement in memory impairment in rats ten days after induction of sepsis.
RESUMEN
OBJECTIVE: 6-Shogaol, bioactive compound of Zingiber officinale Roscoe, has anti-inflammatory, antioxidant, and neuroprotective properties. The objective of the present study was to verify the effect of 6-shogaol on behavioral parameters in a preclinical model based on a maternal immune activation (MIA) by lipopolysaccharide (LPS). METHODOLOGY: Twelve pregnant Wistar rats received 100-µg/kg LPS or saline solution on gestational day (GD) 9.5. Male offspring participated in the study and in the postnatal day (PND) 30 and 55 were supplemented with 6-shogaol or saline solution, by gavage at a dose of 10 mg/kg/day, orally for 5 days. In the PND 35 and 60 was performed the behavioral tests: grooming, crossing, and rearing that evaluated repetitive movements, anxiety, and interest in the new, respectively, and the inhibitory avoidance test that evaluated short-term (STM) and long-term memory (LTM). RESULT: Prenatal exposure to LPS increased the grooming and crossing episodes at different ages and reduced rearing episodes in PND 37. Treatment with 6-shogaol reversed these parameters. In the inhibitory avoidance test, an improvement of memory was identified with 6-shogaol in the STM and LTM at both ages comparing training and test session of treated groups and between groups. CONCLUSION: Administration of 6-shogaol reverses the stereotypy, exploratory behavior, and memory impairment in prenatal LPS-exposed offspring, acting as a promising therapeutic component against brain disorders associated with the process of MIA.
Asunto(s)
Lipopolisacáridos , Efectos Tardíos de la Exposición Prenatal , Animales , Conducta Animal , Catecoles/farmacología , Femenino , Lipopolisacáridos/toxicidad , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas WistarRESUMEN
6-Shogaol is one of the main active phenolic components of ginger and has neuroprotective effects by protecting brain against the oxidative stress and regulate the levels of neurotrophic factors. The objective of the present study was to verify the effect of 6-shogaol on neurochemical parameters in offspring after maternal immune activation by lipopolysaccharide (LPS) in rats. Twelve pregnant Wistar rats received 100 µg/kg of LPS or saline solution on the gestational day 9.5. Male offspring participated in the study and from the postnatal days (PND) 30 and 55, respectively, they were supplemented with 6-shogaol or saline solution, by gavage at a dose of 10 mg/kg/day, orally for 5 days. In PND 37 and 62, analysis of kinase signaling regulated by extracellular signal 1/2 (ERK 1/2), levels of neurotrophic factor derived from the brain (BDNF), and neuron-specific enolase (NSE), lipid and protein oxidative damage was evaluated by 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine (3-NT), respectively, and myeloperoxidase (MPO) activity was performed in the hippocampus. Prenatal exposure to LPS significantly decreased ERK and BDNF levels in PND 37 and 62, increased NSE levels and lipid damage in rats in PND 37, and increased 3-NT level in rats in PND 62. With treatment using 6-shogaol, an increase in ERK and BDNF levels was identified in PND 37 and 62 and a reduction in HNE and MPO activity in rats in PND 37 and 62, respectively. 6-Shogaol positively increased markers of neuronal growth, plasticity and synaptic activity and reduced oxidative damage in the hippocampus in an animal model of autism by maternal immune activation.
Asunto(s)
Lipopolisacáridos , Efectos Tardíos de la Exposición Prenatal , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Catecoles , Femenino , Hipocampo/metabolismo , Humanos , Lipopolisacáridos/toxicidad , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas , Ratas Wistar , Solución SalinaRESUMEN
Sepsis is a complication of an infection which imbalance the normal regulation of several organ systems, including the central nervous system (CNS). Evidence points towards inflammation and oxidative stress as major steps associated with brain dysfunction in sepsis. Thus, we investigated the folic acid (FA) effect as an important antioxidant compound on acute brain dysfunction in rats and long term cognitive impairment and survival. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with FA (10 mg/kg after CLP) or vehicle (veh). Animals were divided into sham + veh, sham + FA, CLP + veh and CLP + FA groups. Twenty-four hours after surgery, the hippocampus and prefrontal cortex were obtained and assayed for levels of blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. Survival was performed during 10 days after surgery and memory was evaluated. FA reduced BBB permeability, MPO activity in hippocampus and pre frontal cortex in 24 h and lipid peroxidation in hippocampus and improves the survival rate after sepsis. Long term cognitive improvement was verified with FA in septic rats compared with CLP + veh. Our data demonstrates that FA reduces the memory impairment in 10 days after sepsis and mortality in part by decreasing BBB permeability and oxidative stress parameters in the brain.
Asunto(s)
Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Cognición/efectos de los fármacos , Disfunción Cognitiva/prevención & control , Ácido Fólico/farmacología , Estrés Oxidativo/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiopatología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Modelos Animales de Enfermedad , Peroxidación de Lípido/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Carbonilación Proteica/efectos de los fármacos , Ratas Wistar , Sepsis/metabolismo , Sepsis/fisiopatología , Sepsis/psicologíaRESUMEN
Sepsis-associated encephalopathy is a serious consequence of sepsis, triggered by the host response against an infectious agent, that can lead to brain damage and cognitive impairment. Several mechanisms have been proposed in this bidirectional communication between the immune system and the brain after sepsis as neuroinflammation, oxidative stress, and mitochondrial dysfunction. Stanniocalcin-1 (STC-1), an endogen neuroprotective protein, acts as an anti-inflammatory and suppresses superoxide generation through induction of uncoupling proteins (UCPs) in the mitochondria. Here, we demonstrated a protective role of STC-1 on inflammatory responses in vitro, in activated microglia stimulated with LPS, and on neuroinflammation, oxidative stress, and mitochondrial function in the hippocampus of rats subjected to an animal model of sepsis by cecal ligation and puncture (CLP), as well the consequences on long-term memory. Recombinant human STC-1 (rhSTC1) suppressed the pro-inflammatory cytokine production in LPS-stimulated microglia without changing the UCP-2 expression. Besides, rhSTC1 injected into the cisterna magna decreased acute hippocampal inflammation and oxidative stress and increased the activity of complex I and II activity of mitochondrial respiratory chain and creatine kinase at 24 h after sepsis. rhSTC1 was effective in preventing long-term cognitive impairment after CLP. In conclusion, rhSTC1 confers significant neuroprotection by inhibiting the inflammatory response in microglia and protecting against sepsis-associated encephalopathy in rats.
Asunto(s)
Encefalitis/prevención & control , Glicoproteínas/administración & dosificación , Microglía/efectos de los fármacos , Microglía/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Encefalopatía Asociada a la Sepsis/prevención & control , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas WistarRESUMEN
Sepsis survivors present acute and long-term cognitive impairment and the pathophysiology of neurological dysfunction in sepsis involves microglial activation. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes have been demonstrated to perpetuate neuroinflammation. Thus, we investigated the involvement of the NLRP3 inflammasome activation on early and late brain changes in experimental sepsis. Two-month-old male Wistar rats were submitted to the sepsis model by cecal ligation and perforation (CLP group) or laparotomy only (sham group). Immediately after surgery, the animals received saline or NLRP3 inflammasome formation inhibitor (MCC950, 140 ng/kg) intracerebroventricularly. Prefrontal cortex and hippocampus were isolated for cytokine analysis, microglial and astrocyte activation, oxidative stress measurements, nitric oxide formation, and mitochondrial respiratory chain activity at 24 h after CLP. A subset of animals was followed for 10 days for survival assessment, and then behavioral tests were performed. The administration of MCC950 restored the elevation of IL-1ß, TNF-α, IL-6, and IL-10 cytokine levels in the hippocampus. NLRP3 receptor levels increased in the prefrontal cortex and hippocampus at 24 h after sepsis, associated with microglial, but not astrocyte, activation. MCC950 reduced oxidative damage to lipids and proteins as well as preserved the activity of the enzyme SOD in the hippocampus. Mitochondrial respiratory chain activity presented variations in both structures studied. MCC950 reduced microglial activation, decreased acute neurochemical and behavioral alteration, and increased survival after experimental sepsis.
Asunto(s)
Encéfalo/patología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sepsis/complicaciones , Enfermedad Aguda , Animales , Astrocitos/metabolismo , Encéfalo/metabolismo , Catalasa/metabolismo , Citocinas/metabolismo , Transporte de Electrón , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/metabolismo , Mediadores de Inflamación/metabolismo , Estimación de Kaplan-Meier , Peroxidación de Lípido , Masculino , Memoria , Trastornos de la Memoria/fisiopatología , Microglía/metabolismo , Mitocondrias/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Estrés Oxidativo , Corteza Prefrontal/metabolismo , Carbonilación Proteica , Ratas Wistar , Superóxido Dismutasa/metabolismo , Análisis de SupervivenciaRESUMEN
Sepsis causes organ dysfunction due to an infection, and it may impact the central nervous system. Neuroinflammation and oxidative stress are related to brain dysfunction after sepsis. Both processes affect microglia activation, neurotrophin production, and long-term cognition. Fish oil (FO) is an anti-inflammatory compound, and lipoic acid (LA) is a universal antioxidant substance. They exert neuroprotective roles when administered alone. We aimed at determining the effect of FO+LA combination on microglia activation and brain dysfunction after sepsis. Microglia cells from neonatal pups were co-treated with lipopolysaccharide (LPS) and FO or LA, alone or combined, for 24 h. Cytokine levels were measured. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) and treated orally with FO, LA, or FO+LA. At 24 h after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of cytokines, myeloperoxidase (MPO) activity, protein carbonyls, superoxide dismutase (SOD), and catalase (CAT) activity. At 10 days after surgery, brain-derived neurotrophic factor (BDNF) levels were determined and behavioral tests were performed. The combination diminished in vitro levels of pro-inflammatory cytokines. The combination reduced TNF-α in the cortex, IL-1ß in the prefrontal cortex, as well as MPO activity, and decreased protein carbonyls formation in all structures. The combination enhanced catalase activity in the prefrontal cortex and hippocampus, elevated BDNF levels in all structures, and prevented behavioral impairment. In summary, the combination was effective in preventing cognitive damage by reducing neuroinflammation and oxidative stress and increasing BDNF levels.
Asunto(s)
Encéfalo/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/prevención & control , Aceites de Pescado/farmacología , Inflamación/patología , Estrés Oxidativo/efectos de los fármacos , Sepsis/complicaciones , Ácido Tióctico/farmacología , Animales , Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Catalasa/metabolismo , Células Cultivadas , Citocinas/metabolismo , Femenino , Inflamación/complicaciones , Estimación de Kaplan-Meier , Trastornos de la Memoria/complicaciones , Microglía/efectos de los fármacos , Microglía/metabolismo , Prueba de Campo Abierto , Peroxidasa/metabolismo , Carbonilación Proteica/efectos de los fármacos , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Obesity is characterized by chronic inflammation of low grade. The cholinergic anti-inflammatory pathway favors the reduction of the inflammatory response. In this work the effect of stimulation of the cholinergic anti-inflammatory pathway on SHIRPA behavioral test and mitochondrial respiratory chain activity in obese mice was evaluated. The animals were paired in four groups: saline + control diet; donepezil + control diet; saline + high-fat diet and donepezil + high-fat diet. 5 mg/kg/day orally of donepezil or saline were given 7 days before the beginning of the diet until completing 11 weeks of the experiment. Food intake and body weight were measured. At the end of the experiment the animals were submitted to the SHIRPA behavioral test, soon after they were killed by decapitation, the open abdominal cavity and the mesenteric fat were removed. The hypothalamus, hippocampus, prefrontal cortex, and striatum were removed for evaluation of the mitochondrial respiratory chain. It can be observed that donepezil prevented weight gain and food consumption, as well as a tendency to prevent the accumulation of mesenteric fat in obese animals. There was no behavioral change in obese animals, nor did the influence of donepezil on these parameters. On the other hand, donepezil did not prevent inhibition of complex I activity, prevented the inhibition of complex II, and showed a tendency to prevent IV complex activity inhibited in obesity. With these results it can be concluded that the activation of the cholinergic anti-inflammatory pathway is promising for the alterations found in obesity.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Encéfalo/metabolismo , Donepezilo/uso terapéutico , Metabolismo Energético/efectos de los fármacos , Obesidad/prevención & control , Animales , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/antagonistas & inhibidores , Complejo II de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/antagonistas & inhibidores , Complejo IV de Transporte de Electrones/metabolismo , Masculino , Ratones , Obesidad/metabolismoRESUMEN
Evidences has suggested that in the early life the innate immune system presents plasticity and the time and dose-adequate stimuli in this phase may program long-lasting immunological responses that persist until adulthood. We aimed to evaluate whether LPS challenge in early childhood period may modulate brain alterations after sepsis in adult life. Experiments were performed to evaluate the LPS challenge in early childhood or adult period on acute and long-term brain alterations after model of sepsis by cecal ligation and perforation (CLP) in adult life. Wistar rats were divided in saline+sham, LPS+sham, saline+CLP and LPS+CLP groups to determine cytokine levels and nitrite/nitrate concentration in cerebrospinal fluid (CSF); oxidative damage, activity of antioxidant enzymes (superoxide dismutase-SOD and catalase-CAT); blood brain barrier (BBB) permeability; myeloperoxidase (MPO) and epigenetic enzymes activities in the hippocampus and prefrontal cortex (at 24 h after CLP) and cognitive function, survival and brain-derived neurotrophic factor (BDNF) level (at ten days after CLP). LPS-preconditioning in early life could lead to decreased levels of TNF-α and IL-6 and oxidative damage parameters in the brain after CLP in adult rats. In addition, LPS-preconditioning in early life increase CAT activity, attenuates the BBB permeability and epigenetic enzymes alterations and in long term, improves the memory, BDNF levels and survival. In conclusion, rats submitted to CLP in adulthood displayed acute neuroinflammation, neurochemical and epigenetic alteration improvement accompanied in long term by an increase in survival, neurotrophin level and memory performance when preconditioned with LPS in the early life.
Asunto(s)
Encéfalo/inmunología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Neuroinmunomodulación/inmunología , Neuroprotección/inmunología , Sepsis/inmunología , Factores de Edad , Animales , Encéfalo/efectos de los fármacos , Masculino , Neuroinmunomodulación/efectos de los fármacos , Neuroprotección/efectos de los fármacos , Ratas , Ratas Wistar , Sepsis/inducido químicamenteRESUMEN
OBJECTIVES: Sepsis is a severe organic dysfunction caused by an infection that affects the normal regulation of several organ systems, including the central nervous system. Inflammation and oxidative stress play crucial roles in the development of brain dysfunction in sepsis. The aim of this study was to determine the effect of a fish oil (FO)-55-enriched lipid emulsion as an important anti-inflammatory compound on brain dysfunction in septic rats. METHODS: Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with FO (600 µL/kg after CLP) or vehicle (saline; sal). Animals were divided into sham+sal, sham+FO, CLP+sal and CLP+FO groups. At 24 h and 10 d after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of interleukin (IL)-1ß and IL-10, blood-brain barrier permeability, nitrite/nitrate concentration, myeloperoxidase activity, thiobarbituric acid reactive species formation, protein carbonyls, superoxide dismutase and catalase activity, and brain-derived neurotrophic factor levels. Behavioral tasks were performed 10 d after surgery. RESULTS: FO reduced BBB permeability in the prefrontal cortex and total cortex of septic rats, decreased IL-1ß levels and protein carbonylation in all brain structures, and diminished myeloperoxidase activity in the hippocampus and prefrontal cortex. FO enhanced brain-derived neurotrophic factor levels in the hippocampus and prefrontal cortex and prevented cognitive impairment. CONCLUSIONS: FO diminishes the negative effect of polymicrobial sepsis in the rat brain by reducing inflammatory and oxidative stress markers.
Asunto(s)
Antiinflamatorios/farmacología , Disfunción Cognitiva/prevención & control , Aceites de Pescado/farmacocinética , Estrés Oxidativo/efectos de los fármacos , Sepsis/psicología , Animales , Biomarcadores/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Enfermedades del Ciego/complicaciones , Enfermedades del Ciego/microbiología , Ciego/irrigación sanguínea , Ciego/microbiología , Disfunción Cognitiva/microbiología , Modelos Animales de Enfermedad , Emulsiones , Lóbulo Frontal/efectos de los fármacos , Interleucina-1beta/metabolismo , Perforación Intestinal/complicaciones , Perforación Intestinal/microbiología , Ligadura/efectos adversos , Masculino , Permeabilidad , Carbonilación Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Sepsis/etiología , Sepsis/microbiologíaRESUMEN
Postoperative cognitive dysfunction (POCD) is defined by cognitive impairment determined by neuropsychological tests from before to after surgery. Several mechanisms have been proposed in this bidirectional communication between the immune system and the brain after surgery. We aimed at understanding the mechanisms underlying POCD elderly rats in an experimental tibial fracture model. Elderly male Wistar rats were subjected to tibial fracture (TF) model. Control (sham) and fracture (TF) groups were followed to determine nitrite/nitrate concentration; oxidative damage to lipids and proteins; the activity of antioxidant enzymes (superoxide dismutase-SOD and catalase-CAT), mitochondrial respiratory chain enzymes, and creatine kinase (CK); and BDNF levels in the hippocampus and prefrontal cortex (at 24â¯h and at seven days) and cognitive function through habituation to the open field task and novel object recognition task (only at seven days). TF group presented increased concentration of nitrite/nitrate, hippocampal lipid peroxidation at seven days, protein oxidative damage in the prefrontal cortex and hippocampus at 24â¯h, decreased antioxidant activity in both structures on the first postoperative day and compromised function of the mitochondrial respiratory chain complexes as well as the CK enzyme. In addition, the levels of BDNF were reduced and memory function was impaired in the TF group. In conclusion, elderly rats submitted to an experimental model of tibial fracture displayed memory impairment accompanied by an increase in oxidative stress, mitochondrial dysfunction and reduced neurotrophin level.
Asunto(s)
Disfunción Cognitiva/fisiopatología , Mitocondrias/fisiología , Estrés Oxidativo/fisiología , Factores de Edad , Animales , Antioxidantes/metabolismo , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición/fisiología , Trastornos del Conocimiento/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Peroxidación de Lípido , Masculino , Trastornos de la Memoria/metabolismo , Complicaciones Posoperatorias/fisiopatología , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Sepsis is caused by a dysregulated host response to infection, often associated with acute central nervous system (CNS) dysfunction, which results in long-term cognitive impairment. Dimethyl fumarate (DMF) is an important agent against inflammatory response and reactive species in CNS disorders. Evaluate the effect of DMF on acute and long-term brain dysfunction after experimental sepsis in rats. Male Wistar rats were submitted to the cecal ligation and puncture (CLP) model. The groups were divided into sham (control) + vehicle, sham + NAC, sham + DMF, CLP + vehicle, CLP + NAC, and CLP + DMF. The animals were treated with DMF (15 mg/kg at 0 and 12 h after CLP, per gavage) and the administration of n-acetylcysteine (NAC) (20 mg/kg; 3, 6, and 12 h after CLP, subcutaneously) was used as positive control. Twenty-four hours after CLP, cytokines, myeloperoxidase (MPO), nitrite/nitrate (N/N), oxidative damage to lipids and proteins, and antioxidant enzymes were evaluated in the hippocampus, total cortex, and prefrontal cortex. At 10 days after sepsis induction, behavioral tests were performed to assess cognitive damage. We observed an increase in cytokine levels, MPO activity, N/N concentration, and oxidative damage, a reduction in SOD and GPx activity in the brain structures, and cognitive damage in CLP rats. DMF treatment was effective in reversing these parameters. DMF reduces sepsis-induced neuroinflammation, oxidative stress, and cognitive impairment in rats subjected to the CLP model.
Asunto(s)
Trastornos del Conocimiento , Dimetilfumarato/uso terapéutico , Inmunosupresores/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/etiología , Estrés Oxidativo/efectos de los fármacos , Sepsis/complicaciones , Animales , Catalasa/metabolismo , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Citocinas/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Infiltración Neutrófila/efectos de los fármacos , Nitratos/metabolismo , Nitritos/metabolismo , Carbonilación Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
Neurological dysfunction as a result of neuroinflammation has been reported in sepsis and cause high mortality. High levels of cytokines stimulate the formation of neurotoxic metabolites by kynurenine (KYN) pathway. Vitamin B6 (vit B6) has anti-inflammatory and antioxidant properties and also acts as a cofactor for enzymes of the KYN pathway. Thus, by using a relevant animal model of polymicrobial sepsis, we studied the effect of vit B6 on the KYN pathway, acute neurochemical and neuroinflammatory parameters, and cognitive dysfunction in rats. Male Wistar rats (250-300 g) were submitted to cecal ligation and perforation (CLP) and divided into sham + saline, sham + vit B6, CLP + saline, and CLP + vit B6 (600 mg/kg, s.c.) groups. Twenty-four hours later, the prefrontal cortex and hippocampus were removed for neurochemical and neuroinflammatory analyses. Animals were followed for 10 days to determine survival rate, when cognitive function was assessed by behavioral tests. Vitamin B6 interfered in the activation of kynurenine pathway, which led to an improvement in neurochemical and neuroinflammatory parameters and, consequently, in the cognitive functions of septic animals. Thus, the results indicate that vit B6 exerts neuroprotective effects in acute and late consequences after sepsis.
Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Quinurenina/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Vitamina B 6/uso terapéutico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Disfunción Cognitiva/patología , Citocinas/metabolismo , Metabolismo Energético/efectos de los fármacos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Estimación de Kaplan-Meier , Peroxidación de Lípido/efectos de los fármacos , Masculino , Nitratos/metabolismo , Nitritos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Permeabilidad , Peroxidasa/metabolismo , Carbonilación Proteica/efectos de los fármacos , Ratas Wistar , Triptófano/metabolismo , Vitamina B 6/farmacologíaRESUMEN
Sepsis is a complication of an infection which imbalance the normal regulation of several organ systems, including the central nervous system (CNS). Evidence points towards inflammation and oxidative stress as major steps associated with brain dysfunction in sepsis. Thus, we investigated the α-lipoic acid (ALA) effect as an important antioxidant compound on brain dysfunction in rats. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with ALA (200 mg/kg after CLP) or vehicle. Animals were divided into sham + saline, sham + ALA, CLP + saline and CLP + ALA groups. Twelve, 24 h and 10 days after surgery, the hippocampus, prefrontal cortex and cortex were obtained and assayed for levels of TNF-α and IL-1ß, blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, thiobarbituric acid reactive species (TBARS) formation, protein carbonyls, superoxide dismutase (SOD) and catalase (CAT) activity and neurotrophins levels. Behavioral tasks were performed 10 days after surgery. ALA reduced BBB permeability and TNF-α levels in hippocampus in 24 h and IL-1ß levels and MPO activity in hippocampus and prefrontal cortex in 24 h. ALA reduced nitrite/nitrate concentration and lipid peroxidation in 24 h in all structures and protein carbonylation in 12 and 24 h in hippocampus and cortex. CAT activity increased in the hippocampus and cortex in all times. ALA enhanced NGF levels in hippocampus and cortex and prevented cognitive impairment. Our data demonstrates that ALA reduces the consequences of polymicrobial sepsis in rats by decreasing inflammatory and oxidative stress parameters in the brain.
Asunto(s)
Antioxidantes/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Coinfección/tratamiento farmacológico , Mediadores de Inflamación/antagonistas & inhibidores , Sepsis/tratamiento farmacológico , Ácido Tióctico/uso terapéutico , Enfermedad Aguda , Animales , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Coinfección/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Sepsis/metabolismo , Ácido Tióctico/farmacología , Factores de TiempoRESUMEN
OBJECTIVE: Supplementation with ω-3 polyunsaturated fatty acids (PUFAs) can positively contribute to neurologic development, modulating inflammatory responses, promoting homeostasis, and having a positive effect on animal behaviors associated with mental disorders. The aim of this study was to evaluate behavioral and biochemical effects of ω-3 fatty acid supplementation in an animal model for mental disorders by prenatal maternal exposure to lipopolysaccardies (LPS) from the maternal immune activation. METHODS: Twelve pregnant Wistar rats were used. Each rat received 100 µg/kg of LPS or saline solution on gestational day (GD) 9.5. The offspring remained with mothers until weaning and from postnatal day (PND) 30 were supplemented with ω-3 PUFA or saline solution by gavage at a dose of 0.8 g/kg orally for 21 d. On PND 52, the animals underwent behavioral tests; then, they were sacrificed, and the brain structures were dissected and analyzed by levels: neuron-specific enolase (NSE), brain-derived neurotrophic factor, and transforming growth factor (TGF)-ß. RESULT: Prenatal exposure to LPS significantly increased the episodes of stereotyped movements and decreased social interaction in the offspring (P = 0.009 and P = 0.001, respectively), after ω-3 PUFA supplementation these parameters reversed (P = 0.005 and P = 0.013, respectively). Significant changes also were identified in the biochemical analysis in NSE and TGF-ß in the brain structures; these conditions were reversed after ω-3 PUFA supplementation. CONCLUSION: Supplementation with ω-3 PUFA reversed animal behaviors that often are observed in autism and other mental disorders in rats prenatally exposed to LPS, and also exerted neuroprotective effects in marker levels of neuronal damage and expression of TGF-ß.
Asunto(s)
Ácidos Grasos Omega-3/farmacología , Relaciones Interpersonales , Lipopolisacáridos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Conducta Estereotipada/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Suplementos Dietéticos , Femenino , Masculino , Embarazo , Ratas , Ratas Wistar , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , DesteteRESUMEN
Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue that was recently approved to treat obesity in some countries. Considering that liraglutide effects on brain energy metabolism are little known, we evaluated the effects of liraglutide on the energy metabolism. Animals received a single or daily injection of saline or liraglutide during 7 days (25, 50, 100, or 300 µg/kg i.p.). Twenty-four hours after the single or last injection, the rats were euthanized and the hypothalamus, prefrontal cortex, cerebellum, hippocampus, striatum, and posterior cortex were isolated. Our results demonstrated that a single dose of liraglutide in young rats increased the activity of complexes and inhibited creatine kinase activity. Repeated administrations of liraglutide in young rats reduced the activity of complexes and activated creatine kinase activity. In adult rats, a single dose of liraglutide reduced the activity of complex I and creatine kinase and increased the activity of complexes II and IV. Repeated administrations of liraglutide in adult rats increased the activity of complexes I and IV and reduced the activity of complex II and creatine kinase. We concluded that liraglutide may interfere in energy metabolism, because analysis of different times of administrations, concentrations, and level of brain development leads to divergent results.
Asunto(s)
Encéfalo/metabolismo , Metabolismo Energético/efectos de los fármacos , Hipoglucemiantes/farmacología , Liraglutida/farmacología , Envejecimiento , Animales , Encéfalo/efectos de los fármacos , Creatina Quinasa/metabolismo , Relación Dosis-Respuesta a Droga , Complejo I de Transporte de Electrón/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Complejo III de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Liraglutida/administración & dosificación , Masculino , Ratas , Ratas WistarRESUMEN
Sepsis is a severe clinical syndrome in which a system-wide inflammatory response follows initial attempts to eliminate pathogens. It is not novel that in sepsis the brain is one of the first organs affected which causes an increase in morbidity and mortality and its consequences may be exacerbated when associated with a diagnosis of chronic inflammation, such as in obesity. Thus, the aim of the present study is to evaluate the susceptibility to brain damage after sepsis in obese rats. During two months, Wistar rats, 60 days, 250-300g received hypercaloric nutrition to induce obesity. Sepsis was submitted to the cecal ligation and perforation (CLP) procedure and sham-operated rats was considered control group. The experimental groups were divided into Sham + Eutrophic, Sham + Obesity, CLP + Eutrophic and CLP + Obesity. Twelve and twenty four hours after surgery the blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, oxidative damage to lipids and proteins and superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in the hippocampus, cortex and prefrontal cortex. The data indicate that in obese rats subjected to sepsis occurs an increase of BBB permeability in different brain regions compared to eutrophic septic rats. This alteration reflected an increase of MPO activity, concentration of nitrite/nitrate, oxidative damage to lipids and proteins and an imbalance of SOD and CAT especially 24 hours after sepsis. It follows that obesity due to its pro-inflammatory phenotype can aggravate or accelerate the sepsis-induced damage in rat brain.