O papel do BDNF e da PRDX-1 na proteção contra o dano oxidativo central em ratos anedônicos submetidos a um protocolo de estresse crônico moderado

A ativação crônica do eixo hipotálamo-pituitária-adrenal (HPA) e o aumento sustentado de glicocorticoides têm sido associados à depressão maior (DM), e também a alterações envolvendo neurotrofinas e marcadores de estresse oxidativo em resposta à inflamação. O presente estudo teve como objetivo avaliar medidas centrais do fator neurotrófico derivado do cérebro (BDNF), de dano oxidativo, e da capacidade antioxidante total de ratos submetidos ao estresse crônico moderado e imprevisível (CUMS), além de investigar a relação entre os níveis de BDNF e proteínas diferencialmente expressas envolvidas em processos biológicos de estresse oxidativo e inflamação. Ratos Wistar machos foram submetidos ao CUMS por seis semanas. Conforme as taxas de preferência por sacarose, os animais foram classificados como anedônicos ou não-anedônicos. Após a coleta dos tecidos cerebrais, foram avaliados o dano oxidativo, a capacidade antioxidante total e os níveis de BDNF. A fim de estender a discussão sobre possíveis mecanismos envolvendo os achados experimentais, adicionalmente, foi realizada uma análise de bioinformática reunindo resultados de proteômica de outros estudos com protocolo experimental semelhante, visando identificar proteínas envolvidas com o estresse oxidativo e vias inflamatórias diferencialmente expressas em animais anedônicos. O CUMS esteve associado ao aumento das concentrações de BDNF e à diminuição da capacidade antioxidante total, além de não ter sido identificado dano oxidativo aos lipídios e proteínas nos animais estressados. Além disso, a abordagem proteômica de bioinformática indicou que animais anedônicos apresentam um aumento na expressão de peroxirredoxina-1 (PRDX-1) e uma diminuição na expressão de proteínas envolvidas com sinalização apoptótica e inflamatória (RELA, ASK-1 e TAK-1) no hipocampo. Essas evidências sugerem que o BDNF e a PRDX-1 podem representar uma resposta inicial contra o estresse, com papel compensatório, prevenindo o dano oxidativo a lipídios e proteínas através da modulação da defesa antioxidante, principalmente em animais anedônicos.Chronic activation of the HPA axis and sustained increase of glucocorticoids have been associated in major depression (MD), and also related to changes involving neurotrophins and oxidative stress markers in response to inflammation. This study aimed to evaluate central measures of brain-derived neurotrophic factor (BDNF), oxidative damage and total antioxidant capacity of rats submitted to chronic unpredictable mild stress (CUMS) and investigate the relationship between BDNF levels and differentially expressed proteins involved in oxidative stress and inflammatory biological processes. Wistar male rats were subjected to CUMS for six weeks. Based on the sucrose preference test, animals were divided into anhedonic and non-anhedonic clusters. After brain tissue collection, oxidative damage, total antioxidant capacity, and BDNF levels were evaluated. In order to extend discussion of possible mechanisms involving neurobiological findings, a bioinformatics approach was performed to identify proteins involved with oxidative stress and inflammation pathways that were differentially expressed in anhedonic animals from other studies with similar experimental protocol. CUMS was associated with an increase in BDNF concentrations accompanied by a decrease in total antioxidant capacity, besides the absence of oxidative damage to lipids and proteins in stressed animals. Withal, bioinformatics proteomic approach indicated that anhedonic animals showed a peroxiredoxin-1 (PRDX-1) up-regulation and a down-regulation of proteins involved with apoptotic and inflammation signaling (RELA, ASK-1 and TAK-1) in the hippocampus. These evidences suggest that BDNF and PRDX-1 may represent an initial response against stress, with a compensatory role, preventing oxidative damage to lipids and proteins through the modulation of antioxidant defense, mainly in anhedonic animals

Effects of lithium on inflammatory and neurotrophic factors after an immune challenge in a lisdexamfetamine animal model of mania

Objective: To evaluate whether an animal model of mania induced by lisdexamfetamine dimesylate (LDX) has an inflammatory profile and whether immune activation by lipopolysaccharides (LPS) has a cumulative effect on subsequent stimuli in this model. We also evaluated the action of lithium (Li) on inflammatory and neurotrophic factors. Methods: Adult male Wistar rats were subjected to an animal model of mania. After the open-field test, they were given LPS to induce systemic immune activation. Subsequently, the animals’ blood was collected, and their serum levels of brain-derived neurotrophic factor and inflammatory markers (tumor necrosis factor [TNF]-a, interleukin [IL]-6, IL-1b, IL-10, and inducible nitric oxide synthase [iNOS]) were measured. Results: LDX induced hyperactivity in the animals, but no inflammatory marker levels increased except brain-derived neurotrophic factor (BDNF). Li had no effect on serum BDNF levels but prevented iNOS levels from increasing in animals subjected to immune activation. Conclusion: Although Li prevented an LPS-induced increase in serum iNOS levels, its potential antiinflammatory effects in this animal model of mania were conflicting

Brain-derived neurotrophic factor serum levels and hippocampal volume in mild cognitive impairment and dementia due to Alzheimer disease

Background/Aims: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). Methods: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant ® . Results: MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. Discussion: The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction

Targeting inflammatory-mitochondrial response in major depression : current evidence and further challenges

The prevalence of psychiatric disorders has increased in recent years. Among existing mental disorders, major depressive disorder (MDD) has emerged as one of the leading causes of disability worldwide, affecting individuals throughout their lives. Currently, MDD affects 15% of adults in the Americas. Over the past 50 years, pharmacotherapy, psychotherapy, and brain stimulation have been used to treat MDD. The most common approach is still pharmacotherapy; however, studies show that about 40% of patients are refractory to existing treatments. Although the monoamine hypothesis has been widely accepted as a molecular mechanism to explain the etiology of depression, its relationship with other biochemical phenomena remains only partially understood. This is the case of the link between MDD and inflammation, mitochondrial dysfunction, and oxidative stress. Studies have found that depressive patients usually exhibit altered inflammatory markers, mitochondrial membrane depolarization, oxidized mitochondrial DNA, and thus high levels of both central and peripheral reactive oxygen species (ROS). The effect of antidepressants on these events remains unclear. Nevertheless, the effects of ROS on the brain are well known, including lipid peroxidation of neuronal membranes, accumulation of peroxidation products in neurons, protein and DNA damage, reduced antioxidant defenses, apoptosis induction, and neuroinflammation. Antioxidants such as ascorbic acid, tocopherols, and coenzyme Q have shown promise in some depressive patients, but without consensus on their efficacy. Hence, this paper provides a review of MDD and its association with inflammation, mitochondrial dysfunction, and oxidative stress and is aimed at thoroughly discussing the putative links between these events, which may contribute to the design and development of new therapeutic approaches for patients

O papel do BDNF e da PRDX-1 na proteção contra o dano oxidativo central em ratos anedônicos submetidos a um protocolo de estresse crônico moderado

A ativação crônica do eixo hipotálamo-pituitária-adrenal (HPA) e o aumento sustentado de glicocorticoides têm sido associados à depressão maior (DM), e também a alterações envolvendo neurotrofinas e marcadores de estresse oxidativo em resposta à inflamação. O presente estudo teve como objetivo avaliar medidas centrais do fator neurotrófico derivado do cérebro (BDNF), de dano oxidativo, e da capacidade antioxidante total de ratos submetidos ao estresse crônico moderado e imprevisível (CUMS), além de investigar a relação entre os níveis de BDNF e proteínas diferencialmente expressas envolvidas em processos biológicos de estresse oxidativo e inflamação. Ratos Wistar machos foram submetidos ao CUMS por seis semanas. Conforme as taxas de preferência por sacarose, os animais foram classificados como anedônicos ou não-anedônicos. Após a coleta dos tecidos cerebrais, foram avaliados o dano oxidativo, a capacidade antioxidante total e os níveis de BDNF. A fim de estender a discussão sobre possíveis mecanismos envolvendo os achados experimentais, adicionalmente, foi realizada uma análise de bioinformática reunindo resultados de proteômica de outros estudos com protocolo experimental semelhante, visando identificar proteínas envolvidas com o estresse oxidativo e vias inflamatórias diferencialmente expressas em animais anedônicos. O CUMS esteve associado ao aumento das concentrações de BDNF e à diminuição da capacidade antioxidante total, além de não ter sido identificado dano oxidativo aos lipídios e proteínas nos animais estressados. Além disso, a abordagem proteômica de bioinformática indicou que animais anedônicos apresentam um aumento na expressão de peroxirredoxina-1 (PRDX-1) e uma diminuição na expressão de proteínas envolvidas com sinalização apoptótica e inflamatória (RELA, ASK-1 e TAK-1) no hipocampo. Essas evidências sugerem que o BDNF e a PRDX-1 podem representar uma resposta inicial contra o estresse, com papel compensatório, prevenindo o dano oxidativo a lipídios e proteínas através da modulação da defesa antioxidante, principalmente em animais anedônicos.Chronic activation of the HPA axis and sustained increase of glucocorticoids have been associated in major depression (MD), and also related to changes involving neurotrophins and oxidative stress markers in response to inflammation. This study aimed to evaluate central measures of brain-derived neurotrophic factor (BDNF), oxidative damage and total antioxidant capacity of rats submitted to chronic unpredictable mild stress (CUMS) and investigate the relationship between BDNF levels and differentially expressed proteins involved in oxidative stress and inflammatory biological processes. Wistar male rats were subjected to CUMS for six weeks. Based on the sucrose preference test, animals were divided into anhedonic and non-anhedonic clusters. After brain tissue collection, oxidative damage, total antioxidant capacity, and BDNF levels were evaluated. In order to extend discussion of possible mechanisms involving neurobiological findings, a bioinformatics approach was performed to identify proteins involved with oxidative stress and inflammation pathways that were differentially expressed in anhedonic animals from other studies with similar experimental protocol. CUMS was associated with an increase in BDNF concentrations accompanied by a decrease in total antioxidant capacity, besides the absence of oxidative damage to lipids and proteins in stressed animals. Withal, bioinformatics proteomic approach indicated that anhedonic animals showed a peroxiredoxin-1 (PRDX-1) up-regulation and a down-regulation of proteins involved with apoptotic and inflammation signaling (RELA, ASK-1 and TAK-1) in the hippocampus. These evidences suggest that BDNF and PRDX-1 may represent an initial response against stress, with a compensatory role, preventing oxidative damage to lipids and proteins through the modulation of antioxidant defense, mainly in anhedonic animals

Effects of lithium on inflammatory and neurotrophic factors after an immune challenge in a lisdexamfetamine animal model of mania

Objective: To evaluate whether an animal model of mania induced by lisdexamfetamine dimesylate (LDX) has an inflammatory profile and whether immune activation by lipopolysaccharides (LPS) has a cumulative effect on subsequent stimuli in this model. We also evaluated the action of lithium (Li) on inflammatory and neurotrophic factors. Methods: Adult male Wistar rats were subjected to an animal model of mania. After the open-field test, they were given LPS to induce systemic immune activation. Subsequently, the animals’ blood was collected, and their serum levels of brain-derived neurotrophic factor and inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-1β, IL-10, and inducible nitric oxide synthase [iNOS]) were measured. Results: LDX induced hyperactivity in the animals, but no inflammatory marker levels increased except brain-derived neurotrophic factor (BDNF). Li had no effect on serum BDNF levels but prevented iNOS levels from increasing in animals subjected to immune activation. Conclusion: Although Li prevented an LPS-induced increase in serum iNOS levels, its potential anti-inflammatory effects in this animal model of mania were conflicting

Brain-derived neurotrophic factor serum levels and hippocampal volume in mild cognitive impairment and dementia due to Alzheimer disease

Background/Aims: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). Methods: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant ® . Results: MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. Discussion: The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction