RESUMO
The inflammatory process plays a critical role in the development of neurodegenerative diseases. Insulin is used in preclinical and clinical studies of neurological disorders. Its intranasal (IN) administration directly in the brain allows for its peripheral metabolic effects to be avoided. Swiss male mice were injected with lipopolysaccharide (LPS) (0.1â¯mg/kg) to induce low-grade inflammation. IN insulin treatment was initiated 4â¯h later at a dose of 1.7 IU once daily for 5 days. LPS induced cognitive deficits, which the IN insulin treatment reversed. LPS significantly decreased, whereas IN insulin significantly increased the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor-ß in the cortex. In the hippocampus, IN insulin significantly decreased the BDNF level. LPS significantly increased the interleukin (IL)-6 levels in the cortex, while IN Insulin significantly decreased its levels in the hippocampus. The tumor necrosis factor-α levels were significantly decreased by IN insulin both in the cortex and hippocampus. Moreover, IN insulin significantly increased the IL-10 levels in the cortex. The levels of oxidative and nitrosative stress were significantly higher in the LPS-treated mice; however, IN insulin had a modulatory effect on both. LPS significantly increased the antioxidant enzyme activity both in the cortex and hippocampus, whereas IN insulin significantly increased the activity of both superoxide dismutase and catalase in the hippocampus and that of catalase in the cortex. The hydrogen peroxide levels revealed that LPS significantly affected the electron transport chain. Therefore, IN insulin could be useful in the treatment of neuroinflammatory diseases.
Assuntos
Encefalopatias/tratamento farmacológico , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Insulina/farmacologia , Administração Intranasal , Animais , Encefalopatias/induzido quimicamente , Encefalopatias/metabolismo , Encefalopatias/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Fator de Crescimento Neural/metabolismoRESUMO
In the central nervous system, glial cells protect the brain against neuronal stress by inducing inflammatory responses; namely, intracellular signaling and cytokine production. However, chronic inflammation is often associated with degenerative diseases that can damage hormone signaling and mitochondrial function. Lipopolysaccharide (LPS) induces neuroinflammation by stimulating the production of interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α); moreover, it generates oxidative stress and impairs cognitive functions. The aim of the present study was to assess the therapeutic efficacy of intracerebroventricular (i.c.v.) injections of insulin against neuroinflammation. Inflammation was first induced in male Wistar rats (60 days old, n = 12/group) through an intraperitoneal injection of 0.1 mg/kg LPS. The i.c.v. insulin treatment at a 0.5 mU dose was initiated 4 h later and administered once a day for 5 days. Thereafter, the spatial memory of the rats was assessed, and the hippocampus and cortex were later dissected for biochemical analyses. Our results showed that LPS induced cognitive function impairments, but the insulin treatment reversed these effects. Whereas the levels of brain-derived neurotrophic factor and beta-nerve growth factor in the hippocampus were not altered by LPS, they were decreased in the cortex by insulin. The IL-1ß and TNF-α levels were increased in the cortex and hippocampus following exposure to LPS, but insulin reversed these effects. Evaluation of the H2O2levels and mitochondrial membrane potential revealed that LPS modulated mitochondrial function, an effect that was also reversed by insulin. Moreover, LPS induced oxidative stress by decreasing the superoxide dismutase and catalase activities and glutathione and sulfhydryl levels. Furthermore, the levels of oxidative stress probes/markers (i.e.,2',7'-dichlorodihydrofluoresceindiacetateand nitrite) were higher in the LPS-treated rats. These effects were all reversed in the cortex and hippocampus by insulin treatment. Our results suggest a potential role for insulin as a therapeutic drug against inflammatory diseases associated with mitochondrial dysfunction in the brain.
Assuntos
Insulina/farmacologia , Mitocôndrias/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Hipocampo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Infusões Intraventriculares , Insulina/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Aging is associated with impaired cognition and memory and increased susceptibility to neurodegenerative disorders. Physical exercise is neuroprotective; however, the major evidence of this effect involves studies of only aerobic training in young animals. The benefits of other exercise protocols such as strength training in aged animals remains unknown. Here, we investigated the effect of aerobic and strength training on spatial memory and hippocampal plasticity in aging rats. Aging Wistar rats performed aerobic or strength training for 50 min 3 to 4 days/week for 8 weeks. Spatial memory and neurotrophic and glutamatergic signaling in the hippocampus of aged rats were evaluated after aerobic or strength training. Both aerobic and strength training improved cognition during the performance of a spatial memory task. Remarkably, the improvement in spatial memory was accompanied by an increase in synaptic plasticity proteins within the hippocampus after exercise training, with some differences in the intracellular functions of those proteins between the two exercise protocols. Moreover, neurotrophic signaling (CREB, BDNF, and the P75NTR receptor) increased after training for both exercise protocols, and aerobic exercise specifically increased glutamatergic proteins (NMDA receptor and PSD-95). We also observed a decrease in DNA damage after aerobic training. In contrast, strength training increased levels of PKCα and the proinflammatory factors TNF-α and IL-1ß. Overall, our results show that both aerobic and strength training improved spatial memory in aging rats through inducing distinct molecular mechanisms of neuroplasticity. Our findings extend the idea that exercise protocols can be used to improve cognition during aging.