RESUMO
Increasing evidence has indicated that prebiotics as an alternative treatment for neuropsychiatric diseases. This study evaluated the prebiotics Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on the modulation of neuroinflammation and cognition in an experimental model of mice high-fat diet fed. Initially, mice were distributed in the following groups: (A) control standard diet (n = 15) and (B) HFD for 18 weeks (n = 30). In the 13th week, the mice were later divided into the following experimental groups: (A) Control (n = 15); (B) HFD (n = 14); and (C) HFD + Prebiotics (n = 14). From the 13th week, the HFD + Prebiotics group received a high-fat diet and a combination of FOS and GOS. In the 18th week, all animals performed the T-maze and Barnes Maze, and were later euthanized. Biochemical and molecular analyzes were performed to assess neuroinflammation, neurogenesis, synaptic plasticity, and intestinal inflammation. Mice fed HFD had higher blood glucose, triglyceridemia, cholesterolemia, and higher serum IL-1ß associated with impaired learning and memory. These obese mice also showed activation of microglia and astrocytes and significant immunoreactivity of neuroinflammatory and apoptosis markers, such as TNF-α, COX-2, and Caspase-3, in addition to lower expression of neurogenesis and synaptic plasticity markers, such as NeuN, KI-67, CREB-p, and BDNF. FOS and GOS treatment significantly improved the biochemistry profile and decreased serum IL-1ß levels. Treatment with FOS and GOS also reduced TNF-α, COX-2, Caspase-3, Iba-1, and GFAP-positive cells in the dentate gyrus, decreasing neuroinflammation and neuronal death caused by chronic HFD consumption. In addition, FOS and GOS promoted synaptic plasticity by increasing NeuN, p-CREB, BDNF, and KI-67, restoring spatial learning ability and memory. Moreover, FOS and GOS on HFD modulated the insulin pathway, which was proved by up-regulating IRS/PI3K/AKT signaling pathway, followed by a decreasing Aß plate and Tau phosphorylation. Furthermore, the prebiotic intervention reshaped the HFD-induced imbalanced gut microbiota by modulating the composition of the bacterial community, markedly increasing Bacteroidetes. In addition, prebiotics decreased intestinal inflammation and leaky gut. In conclusion, FOS and GOS significantly modulated the gut microbiota and IRS/PI3K/AKT signaling pathway, decreased neuroinflammation, and promoted neuroplasticity improving spatial learning and memory. Schematic summarizing of the pathways by FOS and GOS improves memory and learning through the gut-brain axis. FOS and GOS improve the microbial profile, reducing intestinal inflammation and leaky gut in the distal colon. Specifically, the administration of FOS and GOS decreases the expression of TLR4, TNF-α, IL-1ß, and MMP9 and increases the expression of occludin and IL-10. Prebiotics inhibit neuroinflammation, neuronal apoptosis, and reactive gliosis in the hippocampus but restore synaptic plasticity, neuronal proliferation, and neurogenesis.
RESUMO
Multiple sclerosis is a severe demyelinating disease mediated by cells of the innate and adaptive immune system, especially pathogenic T lymphocytes that produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). Although the factors and molecules that drive the genesis of these cells are not completely known, some were discovered and shown to promote the development of such cells, such as dietary factors. In this regard, iron, the most abundant chemical element on Earth, has been implicated in the development of pathogenic T lymphocytes and in MS development via its effects on neurons and glia. Therefore, the aim of this paper is to revise the state-of-art regarding the role of iron metabolism in cells of key importance to MS pathophysiology, such as pathogenic CD4+ T cells and CNS resident cells. Harnessing the knowledge of iron metabolism may aid in the discovery of new molecular targets and in the development of new drugs that tackle MS and other diseases that share similar pathophysiology.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Humanos , Esclerose Múltipla/etiologia , Esclerose Múltipla/terapia , Linfócitos T , CitocinasRESUMO
Parkinson's disease (PD) remains a disease of little known etiology. In addition to the motor symptoms, depression is present in about 40% of patients, contributing to the loss of quality of life. Recently, the involvement of the autophagy mechanism in the pathogenesis of depression has been studied, in addition to its involvement in PD as well. In this study, we tested the effects of metformin, an antidiabetic drug also with antidepressant effects, on depressive-like behavior in a rotenone-induced PD model and on the autophagy process. Mice 8-week-old male C57BL/6 were induced with rotenone for 20 consecutive days (2.5 mg/kg/day) and treated with metformin (200 mg/kg/day) from the 5th day of induction. All the animals were submitted to rotarod, sucrose preference and tail suspension tests. After euthanasia, the substantia nigra and hippocampus were removed for analysis by western blotting or fixed and analyzed by immunofluorescence. The results show that there was an impairment of autophagy in animals induced by rotenone both in nigral and extranigral regions as well as a depressive-like behavior. Metformin was able to inhibit depressive-like behavior and increase signaling pathway proteins, transcription factors and autophagosome-forming proteins, thus inducing autophagy in both the hippocampus and the substantia nigra. In conclusion, we show that metformin has an antidepressant effect in a rotenone-induced PD model, which may result, at least in part, from the induction of the autophagy process.
Assuntos
Metformina , Doença de Parkinson , Animais , Antidepressivos/farmacologia , Autofagia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Qualidade de Vida , Rotenona/farmacologia , Substância Negra , Sacarose/metabolismo , Sacarose/farmacologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/farmacologiaRESUMO
Multiple sclerosis (MS) is a highly disabling, progressive neurodegenerative disease with no curative treatment available. Although significant progress has been made in understanding how MS develops, there remain aspects of disease pathogenesis that are yet to be fully elucidated. In this regard, studies have shown that dysfunctional adenosinergic signaling plays a pivotal role, as patients with MS have altered levels adenosine (ADO), adenosine receptors and proteins involved in the generation and termination of ADO signaling, such as CD39 and adenosine deaminase (ADA). We have therefore performed a literature review regarding the involvement of the adenosinergic system in the development of MS and propose mechanisms by which the modulation of this system can support drug development and repurposing.
Assuntos
Esclerose Múltipla , Doenças Neurodegenerativas , Receptores Purinérgicos P1 , Adenosina/imunologia , Adenosina Desaminase/imunologia , Apirase/imunologia , Humanos , Esclerose Múltipla/etiologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/terapia , Receptores Purinérgicos P1/imunologia , Transdução de SinaisRESUMO
Metabolites produced by the gut microbiota have been shown to play an important role in numerous inflammatory, neuropsychiatric, and neurodegenerative diseases. Specifically, microbial metabolites have been implicated in the modulation of innate and adaptive immunity, especially in the generation of regulatory T cells (Tregs), which are key regulators of multiple sclerosis (MS) pathogenesis. Furthermore, they affect processes relevant to MS pathophysiology, such as inflammation and demyelination, which makes them attractive molecules to be explored as therapeutics in MS. In this review, we discuss the importance of these metabolites as factors contributing to disease pathogenesis and as therapeutic targets in MS. Establishing an improved understanding of these gut-microbiota derived metabolites may provide new avenues for the treatment of MS.
RESUMO
Insulin deficiency or resistance can promote dementia and hallmarks of Alzheimer's disease (AD). The formation of neurofibrillary tangles of p-TAU protein, extracellular Aß plaques, and neuronal loss is related to the switching off insulin signaling in cognition brain areas. Metformin is a biguanide antihyperglycemic drug used worldwide for the treatment of type 2 diabetes. Some studies have demonstrated that metformin exerts neuroprotective, anti-inflammatory, anti-oxidant, and nootropic effects. This study aimed to evaluate metformin's effects on long-term memory and p-Tau and amyloid ß modulation, which are hallmarks of AD in diabetic mice. Swiss Webster mice were distributed in the following experimental groups: control; treated with streptozotocin (STZ) that is an agent toxic to the insulin-producing beta cells; STZ + metformin 200 mg/kg (M200). STZ mice showed significant augmentation of time spent to reach the target box in the Barnes maze, while M200 mice showed a significant time reduction. Moreover, the M200 group showed reduced GFAP immunoreactivity in hippocampal dentate gyrus and CA1 compared with the STZ group. STZ mice showed high p-Tau levels, reduced p-CREB, and accumulation of ß-amyloid (Aß) plaque in hippocampal areas and corpus callosum. In contrast, all these changes were reversed in the M200 group. Protein expressions of p-Tau, p-ERK, pGSK3, iNOS, nNOS, PARP, Cytochrome c, caspase 3, and GluN2A were increased in the parietal cortex of STZ mice and significantly counteracted in M200 mice. Moreover, M200 mice also showed significantly high levels of eNOS, AMPK, and p-AKT expression. In conclusion, metformin improved spatial memory in diabetic mice, which can be associated with reducing p-Tau and ß-amyloid (Aß) plaque load and inhibition of neuronal death.
Assuntos
Doença de Alzheimer , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Metformina , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Metformina/farmacologia , Camundongos , Camundongos Transgênicos , Placa Amiloide , Proteínas tauRESUMO
Multiple Sclerosis (MS) is a neuroinflammatory and chronic Central Nervous System (CNS) disease that affects millions of people worldwide. The search for more promising drugs for the treatment of MS has led to studies on Sildenafil, a phosphodiesterase type 5 Inhibitor (PDE5I) that has been shown to possess neuroprotective effects in the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. We have previously shown that Sildenafil improves the clinical score of EAE mice via modulation of apoptotic pathways, but other signaling pathways were not previously covered. Therefore, the aim of the present study was to further investigate the effects of Sildenafil treatment on autophagy and nitrosative stress signaling pathways in EAE. 24 female C57BL/6 mice were divided into the following groups: (A) Control - received only water; (B) EAE - EAE untreated mice; (C) SILD - EAE mice treated with 25mg/kg of Sildenafil s.c. The results showed that EAE mice presented a pro-nitrosative profile characterized by high tissue nitrite levels, lowered levels of p-eNOS and high levels of iNOS. Furthermore, decreased levels of LC3, beclin-1 and ATG5, suggests impaired autophagy, and decreased levels of AMPK in the spinal cord were also detected in EAE mice. Surprisingly, treatment with Sildenafil inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK. In conclusion, we propose that Sildenafil alleviates EAE by activating autophagy via the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB-BDNF pathways in the spinal cord.
Assuntos
Autofagia/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Medula Espinal/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Estresse Nitrosativo/efeitos dos fármacosRESUMO
Major depressive disorder (MDD) is a chronic affective disorder that has a strong neuroinflammatory component underpinning its etiology. Recent studies indicate that MDD is also associated with changes in the gut microbiota and that the latter is mainly modulated by diet. Microbiota-based personalized nutrition aims to provide an individual-specific diet that will yield the maximum benefit from a given diet since the gut microbiota is accounted for the variations that individuals present in response to a given food. In this review, we present and discuss 5 possible outcomes of using microbiota-based personalized nutrition. Harnessing this approach is essential to design more accurate therapies to prevent and treat MDD or to even help in drug metabolism, especially in the case of antidepressants.
Assuntos
Transtorno Depressivo Maior , Microbioma Gastrointestinal , Antidepressivos , Depressão , Transtorno Depressivo Maior/terapia , Dieta , HumanosRESUMO
Chagas disease (CD) is a tropical and still neglected disease caused by Trypanosoma cruzi that affects >8 million of people worldwide. Although limited, emerging data suggest that gut microbiota dysfunction may be a new mechanism underlying CD pathogenesis. T. cruzi infection leads to changes in the gut microbiota composition of vector insects, mice, and humans. Alterations in insect and mice microbiota due to T. cruzi have been associated with a decreased immune response against the parasite, influencing the establishment and progression of infection. Further, changes in the gut microbiota are linked with inflammatory and neuropsychiatric disorders, comorbid conditions in CD. Therefore, this review article critically analyses the current data on CD and the gut microbiota of insects, mice, and humans and discusses its importance for CD pathogenesis. An enhanced understanding of host microbiota will be critical for the development of alternative therapeutic approaches to target CD, such as gut microbiota-directed interventions.
RESUMO
The cellular and molecular basis to understand the relationship between Chagas disease (CD), a infection caused by Trypanosoma cruzi, and depression, a common psychiatric comorbidity in CD patients, is largely unknown. Clinical studies show an association between CD and depression and preclinical evidence suggests that depressive-like behaviors in T. cruzi infected mice are due, at least partially, to immune dysregulation. However, mechanistic studies regarding this issue are still lacking. Herein, we present and discuss the state of art of data on CD and depression, and revise the mechanisms that may explain the development of depression in CD. We also discuss how the knowledge generated by current and future data may contribute to the discovery of new mechanisms underlying depressive symptoms associated with CD and, hence, to the identification of new therapeutic targets, which ultimately may change the way we see and treat CD and its psychiatric comorbidities.
Assuntos
Doença de Chagas , Transtorno Depressivo Maior , Trypanosoma cruzi , Animais , Humanos , Camundongos , Oxirredução , Estresse OxidativoRESUMO
Multiple sclerosis (MS) is a chronic immuno-inflammatory disease of the central nervous system characterized by demyelination and axonal damage. Cognitive changes are common in individuals with MS since inflammatory molecules secreted by microglia interfere with the physiological mechanisms of synaptic plasticity. According to previous data, inhibition of PDE5 promotes the accumulation of cGMP, which inhibits neuroinflammation and seems to improve synaptic plasticity and memory. The present study aimed to evaluate the effect of sildenafil on the signaling pathways of neuroinflammation and synaptic plasticity in experimental autoimmune encephalomyelitis (EAE). C57BL/6 mice were divided into three experimental groups (n = 10/group): (a) Control; (b) EAE; (c) EAE + sild (25 mg/kg/21 days). Sildenafil was able to delay the onset and attenuate the severity of the clinical symptoms of EAE. The drug also reduced the infiltration of CD4+ T lymphocytes and their respective IL-17 and TNF-α cytokines. Moreover, sildenafil reduced neuroinflammation in the hippocampus (assessed by the reduction of inflammatory markers IL-1ß, pIKBα and pNFkB and reactive gliosis, as well as elevating the inhibitory cytokines TGF-ß and IL-10). Moreover, sildenafil induced increased levels of NeuN, BDNF and pCREB, protein kinases (PKA, PKG, and pERK) and synaptophysin, and modulated the expression of the glutamate receptors AMPA and NMDA. The present findings demonstrated that sildenafil has therapeutic potential for cognitive deficit associated with multiple sclerosis.
Assuntos
Anti-Inflamatórios/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/patologia , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Citrato de Sildenafila/farmacologiaRESUMO
The disruption of the gut microbial composition, defined as dysbiosis, has been associated with many neurological disorders with inflammatory components. The alteration of the gut microbiota leads to an increase in pro-inflammatory cytokines that are associated with metabolic diseases (such as obesity and type 2 diabetes), autoimmune arthritis, and neuropsychiatric diseases. Prebiotics are defined as non-digestible carbohydrates and promote the growth of beneficial bacteria such as bifidobacteria and lactobacillus, exert beneficial effects on improving dysbiosis and its associated inflammatory state. Preclinical and clinical data indicated that some prebiotics also have positive impacts on the central nervous system (CNS) due to the modulation of neuroinflammation and thus may have a key role in the modulation of cognitive impairment, anxiety, and depression. The present manuscript reviews the state-of-art of the effects of prebiotics in cognitive impairment, anxiety, and depressive disorders. Data from clinical studies are still scarce, and further clinical trials are needed to corroborate the potential therapeutic cognitive, antidepressant, and anxiolytic of prebiotics. Prebiotics may provide patients suffering from cognitive deficits, depression, and anxiety with a new tool to minimize disease symptoms and increase the quality of life.
Assuntos
Ansiedade/dietoterapia , Disfunção Cognitiva/dietoterapia , Depressão/dietoterapia , Prebióticos/administração & dosagem , Animais , Ansiedade/metabolismo , Ansiedade/psicologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Depressão/metabolismo , Depressão/psicologia , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismoRESUMO
Phosphodiesterase-5 inhibitors (PDE5Is) have been shown to modulate cell death/cell survival in different in vivo and in vitro models of disease by activating many signaling pathways. This review aimed at elucidating how PDE5Is can inhibit apoptosis. In this study, we describe many signaling pathways involved with the mechanism of action of PDE5Is that ultimately inhibit apoptosis and thus promote cell survival.
Assuntos
Apoptose/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Encefalomielite Autoimune Experimental/tratamento farmacológico , Neurônios/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Animais , Apoptose/genética , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , GMP Cíclico/agonistas , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Camundongos , Neurônios/enzimologia , Neurônios/patologia , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Medula Espinal/patologiaRESUMO
Apoptosis is one form of cell death that is intimately related to health and pathological conditions. In most neuroinflammatory and/or neurodegenerative diseases, apoptosis is associated with disease development and pathology and inhibition of this process leads to considerable amelioration. It is becoming evident that apoptosis also participates in the pathogenesis of Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). Drugs such as Sildenafil, a Phosphodiesterase type 5 Inhibitor (PDE5I), have proven to be neuroprotective in MS models. However, it is not known whether Sildenafil is able to modulate cell death, specifically apoptosis, in EAE mice. Therefore, the aim of this study was to determine the effects of Sildenafil on extrinsic and intrinsic apoptosis pathways in the spinal cord of C57BL/6 mice with EAE. TUNEL analysis showed that EAE mice had elevated number of TUNEL+ cells and that treatment with Sildenafil led to reduced number of dying cells, indicating that Sildenafil was able to inhibit cell death. We observed that both extrinsic and intrinsic pathways of apoptosis were governing the dynamics of EAE progression. We showed that in EAE mice there were increased levels of extrinsic (Caspase-8, -3, TNF-α, FADD) and intrinsic (Caspase-9, Bax and Cytochrome C) apoptosis markers. Bcl-2, an anti-apoptotic protein, was downregulated in EAE mice. We also demonstrated that EAE mice had increased levels of non-caspase mediators of cell survival/cell death (p-IκBα and p-MAPK-p38). Besides, EAE mice presented augmented demyelination. Nevertheless, this is the first research to demonstrate that Sildenafil, when administered concomitant to disease induction, modulated the expression of pro- and anti-apoptotic proteins of the extrinsic and intrinsic pathways, as well as diminished the expression of non-caspase mediators and promoted remyelination in the spinal cord, indicating neuroprotective effects. Thus, the present study demonstrated that Sildenafil inhibits apoptosis by two distinct, although interconnected, mechanisms: directly by modulating caspase expression (through extrinsic and intrinsic pathways) and indirectly by modulating the expression of molecules involved in cell death and/or cell survival.