RESUMO
BACKGROUND: In over 300 million clinical cases, antidepressant drugs seem to provide only symptomatic relief and limited protection in life-threatening depressive events. OBJECTIVES: To compare neuronal-signaling mechanism and neuroprotective roles of Thymoquinone (TQ) suspension and its SLN (TQSLN) against standard antidepressant drug fluoxetine. METHODS: This research investigated in-silico docking at NF-KB p50 active site, CLSM based gut permeation, screening of antidepressant activities and neurosignaling pathways involved. RESULTS: As compared to fluoxetine, TQ reporteda significantly better docking score (-6.83 v/s -6.22) and a better lower free binding energy of (-34.715 Kcal/mol v/s -28.537 Kcal/mol). While poorly oral bioavailable and P-gp substrate TQ reported approximately 250% higher gut permeation if delivered as TQSLN formulation. In locomotor studies, as compared to TQS, TQSLN favored more prominent (p< 0.010) elevation in average time, horizontalactivity, average-velocity, and total-movement with reduced rest time LPS treated groups. However, in the tail suspension test, TQSLN significantly reduced immobility time (p<0.010). Similarly, In the modified force swimming test, TQSLN also significantly reduced immobility time (p<0.010), but swimming time (p<0.010) and climbing time (p<0.050) were significantly elevated. Subsequently, TQSLN reported significantly elevated neuroprotective BDNF (p<0.010) as well as hippocampal 5HT/TRP; accompanied with reduced levels of hippocampal inflammatory markers TNF-α (p<0.001) and IL-6 (p<0.010) as well as lower kynurenine and tryptophan ratio (KYN/TRP). Similarly, the hippocampal CA1 region further revealed TQSL more predominantly attenuated NF-kB nuclear translocation in the brain. CONCLUSION: Despite the poor bioavailability of TQ, TQSLN potentially attenuates neuroinflammatory transmitters and favors BDNF to modulate depressive neurobehavioral states.
Assuntos
Comportamento Animal/efeitos dos fármacos , Benzoquinonas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lipossomos/farmacologia , NF-kappa B/metabolismo , Neuroproteção/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Disponibilidade Biológica , Depressão/tratamento farmacológico , Depressão/metabolismo , Sistemas de Liberação de Medicamentos , Simulação de Acoplamento Molecular , Nanopartículas , Neuroimunomodulação/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Preparações de Plantas/farmacologia , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.
Assuntos
Dopamina/imunologia , Esclerose Múltipla/tratamento farmacológico , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Dopamina/fisiologia , Dopaminérgicos/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/fisiopatologia , Humanos , Camundongos , Modelos Imunológicos , Modelos Neurológicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Receptores Dopaminérgicos/imunologia , Receptores Dopaminérgicos/fisiologia , Células Th17/efeitos dos fármacos , Células Th17/imunologiaRESUMO
We have previously reported that phytochemicals from Abies holophylla exhibit anti-inflammatory and neuroprotective effects by decreasing nitrite production and increasing nerve growth factor production. However, the exact mechanism underscoring these effects has not been revealed. In the present study, we aimed to explore the underlying anti-inflammatory mechanisms of A. holophylla and its phytochemicals. We studied various solvent fractions of A. holophylla and found the chloroform and hexane sub-fractions showed the most significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-activated murine microglia. Concomitantly, the terpenoids isolated from chloroform and hexane fractions showed similar anti-neuroinflammatory effects with significant inhibition of NO and reactive oxygen species production, and decreased protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase. Interestingly, these terpenoids inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), which further inhibited the production of pro-inflammatory mediators, including prostaglandin E2, tumor necrosis factor, and interleukins (IL-6 and IL-1ß), with a potency greater than that of the well-known iNOS inhibitor NG-mono-methyl-L-arginine (L-NMMA). These results suggest that the chloroform- and hexane-soluble fraction mediated the mitogen-activated protein kinase (MAPK) inhibition, in particular the JNK pathway, thereby lowering the inflammatory cascades in LPS-activated murine microglia. Thus, our study suggests that the chloroform and hexane fractions of A. holophylla and their terpenoids may be potential drug candidates for drug discovery against LPS-induced neuroinflammation and neuroinflammatory-related neurodegeneration.
Assuntos
Abies/química , Inflamação/prevenção & controle , Microglia/efeitos dos fármacos , Terpenos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Microglia/fisiologia , Neurite (Inflamação)/induzido quimicamente , Neurite (Inflamação)/metabolismo , Neurite (Inflamação)/prevenção & controle , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Terpenos/isolamento & purificação , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.
Assuntos
Ácidos Graxos Insaturados/farmacologia , Dor/tratamento farmacológico , Prurido/tratamento farmacológico , Psoríase/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Biópsia , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/toxicidade , Células Cultivadas , Modelos Animais de Doenças , Ácidos Graxos Insaturados/uso terapêutico , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/imunologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor/induzido quimicamente , Dor/imunologia , Dor/patologia , Técnicas de Patch-Clamp , Cultura Primária de Células , Prurido/induzido quimicamente , Prurido/imunologia , Prurido/patologia , Psoríase/complicações , Psoríase/imunologia , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/inervação , Canais de Cátion TRPV/metabolismoRESUMO
Alzheimer's disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.
Assuntos
Envelhecimento/genética , Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Canabinoides/uso terapêutico , Hipoglicemiantes/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/fisiopatologia , Ensaios Clínicos como Assunto , Disfunção Cognitiva/genética , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Depressão/genética , Depressão/imunologia , Depressão/fisiopatologia , Depressão/prevenção & controle , Suplementos Nutricionais , Microbioma Gastrointestinal/imunologia , Humanos , Inflamação , Resistência à Insulina , Síndrome Metabólica/genética , Síndrome Metabólica/imunologia , Síndrome Metabólica/fisiopatologia , Síndrome Metabólica/prevenção & controle , Neuroimunomodulação/efeitos dos fármacos , Estresse Psicológico/genética , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/prevenção & controleRESUMO
Neurotoxicity is a common side effect of chemotherapeutics that often leads to the development of chemotherapy-induced peripheral neuropathy (CIPN). The peptide Prokineticin 2 (PK2) has a key role in experimental models of CIPN and can be considered an insult-inducible endangering mediator. Since primary afferent sensory neurons are highly sensitive to anticancer drugs, giving rise to dysesthesias, the aim of our study was to evaluate the alterations induced by vincristine (VCR) and bortezomib (BTZ) exposure in sensory neuron cultures and the possible preventive effect of blocking PK2 signaling. Both VCR and BTZ induced a concentration-dependent reduction of total neurite length that was prevented by the PK receptor antagonist PC1. Antagonizing the PK system also reduced the upregulation of PK2, PK-R1, TLR4, IL-6, and IL-10 expression induced by chemotherapeutic drugs. In conclusion, inhibition of PK signaling with PC1 prevented the neurotoxic effects of chemotherapeutics, suggesting a promising strategy for neuroprotective therapies against the sensory neuron damage induced by exposure to these drugs.
Assuntos
Antineoplásicos/toxicidade , Bortezomib/toxicidade , Hormônios Gastrointestinais/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuropeptídeos/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Células Receptoras Sensoriais/efeitos dos fármacos , Triazinas/farmacologia , Vincristina/toxicidade , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação para Baixo , Avaliação Pré-Clínica de Medicamentos , Hormônios Gastrointestinais/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Neuritos/efeitos dos fármacos , Neuritos/ultraestrutura , Neuroimunomodulação/efeitos dos fármacos , Neuropeptídeos/fisiologia , Fármacos Neuroprotetores/uso terapêutico , RNA Mensageiro/biossíntese , Células Receptoras Sensoriais/fisiologia , Células Receptoras Sensoriais/ultraestrutura , Triazinas/uso terapêuticoAssuntos
COVID-19 , Curcumina/farmacologia , Depressão , Transtornos Psicofisiológicos , Anti-Inflamatórios não Esteroides/farmacologia , COVID-19/complicações , COVID-19/imunologia , COVID-19/psicologia , Depressão/tratamento farmacológico , Depressão/imunologia , Depressão/virologia , Humanos , Medicina Tradicional do Leste Asiático/métodos , Neuroimunomodulação/efeitos dos fármacos , Transtornos Psicofisiológicos/tratamento farmacológico , Transtornos Psicofisiológicos/etiologia , Transtornos Psicofisiológicos/imunologia , Transtornos Psicofisiológicos/psicologia , SARS-CoV-2RESUMO
BACKGROUND: Western pattern diets induce neuroinflammation and impair cognitive behavior in humans and animals. Neuroinflammation and cognitive impairment have been associated with microbiota dysbiosis, through the gut-brain axis. Furthermore, microbiota-accessible carbohydrates (MACs) found in dietary fiber are important in shaping the microbial ecosystem and have the potential to improve the gut-brain-axis. However, the effects of MACs on neuroinflammation and cognition in an obese condition have not yet been investigated. The present study aimed to evaluate the effect of MACs on the microbiota-gut-brain axis and cognitive function in obese mice induced by a high-fat and fiber deficient (HF-FD) diet. METHODS: C57Bl/6 J male mice were fed with either a control HF-FD or a HF-MAC diet for 15 weeks. Moreover, an additional group was fed with the HF-MAC diet in combination with an antibiotic cocktail (HF-MAC + AB). Following the 15-week treatment, cognitive behavior was investigated; blood, cecum content, colon, and brain samples were collected to determine metabolic parameters, endotoxin, gut microbiota, colon, and brain pathology. RESULTS: We report MACs supplementation prevented HF-FD-induced cognitive impairment in nesting building and temporal order memory tests. MACs prevented gut microbiota dysbiosis, including increasing richness, α-diversity and composition shift, especially in Bacteroidetes and its lower taxa. Furthermore, MACs increased colonic mucus thickness, tight junction protein expression, reduced endotoxemia, and decreased colonic and systemic inflammation. In the hippocampus, MACs suppressed HF-FD-induced neuroglia activation and inflammation, improved insulin IRS-pAKT-pGSK3ß-pTau synapse signaling, in addition to the synaptic ultrastructure and associated proteins. Furthermore, MACs' effects on improving colon-cognitive parameters were eliminated by wide spectrum antibiotic microbiota ablation. CONCLUSIONS: These results suggest that MACs improve cognitive impairments via the gut microbiota-brain axis induced by the consumption of an HF-FD. Supplemental MACs to combat obesity-related gut and brain dysfunction offer a promising approach to prevent neurodegenerative diseases associated with Westernized dietary patterns and obesity.
Assuntos
Disfunção Cognitiva/etiologia , Dieta Hiperlipídica/efeitos adversos , Fibras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/complicações , Animais , Metabolismo dos Carboidratos , Carboidratos , Suplementos Nutricionais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroimunomodulação/efeitos dos fármacosRESUMO
BACKGROUND: Yokukansan is a traditional Japanese herbal medicine that has an antiallodynic effect in patients with chronic pain. However, the mechanisms by which yokukansan inhibits neuropathic pain are unclear. OBJECTIVE: This study aimed to investigate the molecular effects of yokukansan on neuroinflammation in U373 MG glioblastoma astrocytoma cells, which express a functional high-affinity neurokinin 1 receptor (substance P receptor), and produce interleukin (IL)-6 and IL-8 in response to stimulation by substance P (SP). METHODS: We assessed the effect of yokukansan on the expression of ERK1/2, P38 MAPK, nuclear factor (NF)-κB, and cyclooxygenase-2 (COX-2) in U373 cells by western blot assay. Levels of IL-6 and IL-8 in conditioned medium obtained after stimulation of cells with SP for 24 h were measured by enzyme-linked immunosorbent assay. All experiments were conducted in triplicate. Results were analyzed by one-way ANOVA, and significance was accepted at p < 0.05. RESULTS: Yokukansan suppressed SP-induced production of IL-6 and IL-8 by U373 MG cells, and downregulated SP-induced COX-2 expression. Yokukansan also inhibited phosphorylation of ERK1/2 and p38 MAPK, as well as nuclear translocation of NF-κB, induced by SP stimulation of U373 MG cells. CONCLUSION: Yokukansan exhibits anti-inflammatory activity by suppressing SP-induced production of IL-6 and IL-8 and downregulating COX-2 expression in U373 MG cells, possibly via inhibition of the activation of signaling molecules, such as ERK1/2, p38 MAPK, and NF-κB.
Assuntos
Neoplasias Encefálicas/patologia , Medicamentos de Ervas Chinesas/farmacologia , Glioblastoma/patologia , Neurite (Inflamação)/prevenção & controle , Substância P/farmacologia , Anti-Inflamatórios/farmacologia , Astrocitoma/imunologia , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioblastoma/imunologia , Glioblastoma/metabolismo , Interações Ervas-Drogas , Medicina Herbária , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Japão , Neurite (Inflamação)/induzido quimicamente , Neurite (Inflamação)/imunologia , Neurite (Inflamação)/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The brain renin-angiotensin system plays a vital role in the modulation of the neuroinflammatory responses and the progression of dopaminergic (DA) degeneration. Angiotensin II (Ang II) induces microglia activation via angiotensin II type 1 receptor (AT1R), which in turn affects the function of DA neurons. Endophilin A2 (EPA2) is involved in fast endophilin-mediated endocytosis and quickly endocytoses several G-protein-coupled receptor (GPCR), while AT1R belongs to GPCR family. Therefore, we speculated that EPA2 may modulate microglia activation via endocytosing AT1R. Biochanin A is an O-methylated isoflavone, classified as a kind of phytoestrogen due to its chemical structure that is similar to mammalian estrogens. In this study, we investigated the protective effects of biochanin A on Ang II-induced DA neurons damage in vivo, and molecular mechanisms. The results showed that biochanin A treatment for 7 days attenuated the behavioral dysfunction, inhibited the microglial activation, and prevented DA neuron damage in Ang II-induced rats. Furthermore, biochanin A increased EPA2 expression and decreased the expression of AT1R, gp91phox, p22 phox, NLRP3, ASC, Caspase-1, IL-1ß, IL-6, IL-18, and TNF-α. In summary, these results suggest that biochanin A exerts protective effects in Ang II-induced model rats, and the mechanisms may involve inhibition of inflammatory responses, an increase in EPA2 expression and a decrease in AT1R expression.
Assuntos
Aciltransferases/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Genisteína/farmacologia , Aciltransferases/genética , Angiotensina II/farmacologia , Animais , Neurônios Dopaminérgicos/fisiologia , Genisteína/metabolismo , Inflamação , Lipopolissacarídeos , Masculino , Microglia/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Óxido Nítrico/metabolismo , Fitoestrógenos/farmacologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas GRESUMO
Alzheimer's disease (AD), the most common cause of dementia remains of unclear etiology with current pharmacological therapies failing to halt disease progression. Several pathophysiological mechanisms have been implicated in AD pathogenesis including amyloid-ß protein (Aß) accumulation, tau hyperphosphorylation, neuroinflammation and alterations in bioactive lipid metabolism. Sphingolipids, such as sphingosine-1-phosphate (S1P) and intracellular ceramide/S1P balance are highly implicated in central nervous system physiology as well as in AD pathogenesis. FTY720/Fingolimod, a structural sphingosine analog and S1P receptor (S1PR) modulator that is currently used in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been shown to exert beneficial effects on AD progression. Recent in vitro and in vivo evidence indicate that fingolimod may suppress Aß secretion and deposition, inhibit apoptosis and enhance brain-derived neurotrophic factor (BDNF) production. Furthermore, it regulates neuroinflammation, protects against N-methyl-D-aspartate (NMDA)-excitotoxicity and modulates receptor for advanced glycation end products signaling axis that is highly implicated in AD pathogenesis. This review discusses the underlying molecular mechanisms of the emerging neuroprotective role of fingolimod in AD and its therapeutic potential, aiming to shed more light on AD pathogenesis as well as direct future treatment strategies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Cloridrato de Fingolimode/uso terapêutico , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Antígenos de Neoplasias/fisiologia , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Fingolimode/farmacologia , Humanos , Fatores Imunológicos/farmacologia , Inflamação , Camundongos , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Modelos Biológicos , N-Metilaspartato/antagonistas & inibidores , Proteínas do Tecido Nervoso/fisiologia , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Especificidade da Espécie , Esfingolipídeos/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/fisiologiaRESUMO
BACKGROUND: Western-style diets arouse neuroinflammation and impair emotional and cognitive behavior in humans and animals. Our previous study showed that a high-fructose diet caused the hippocampal neuroinflammatory response and neuronal loss in animals, but the underlying mechanisms remained elusive. Here, alterations in the gut microbiota and intestinal epithelial barrier were investigated as the causes of hippocampal neuroinflammation induced by high-fructose diet. RESULTS: A high-fructose diet caused the hippocampal neuroinflammatory response, reactive gliosis, and neuronal loss in C57BL/6N mice. Depletion of the gut microbiota using broad-spectrum antibiotics suppressed the hippocampal neuroinflammatory response in fructose-fed mice, but these animals still exhibited neuronal loss. Gut microbiota compositional alteration, short-chain fatty acids (SCFAs) reduction, intestinal epithelial barrier impairment, NOD-like receptor family pyrin domain-containing 6 (NLRP6) inflammasome dysfunction, high levels of serum endotoxin, and FITC-dextran were observed in fructose-fed mice. Of note, SCFAs, as well as pioglitazone (a selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist), shaped the gut microbiota and ameliorated intestinal epithelial barrier impairment and NLRP6 inflammasome dysfunction in fructose-fed mice. Moreover, SCFAs-mediated NLRP6 inflammasome activation was inhibited by histamine (a bacterial metabolite) in ex vivo colonic explants and suppressed in murine CT26 colon carcinoma cells transfected with NLRP6 siRNA. However, pioglitazone and GW9662 (a PPAR-γ antagonist) exerted no impact on SCFAs-mediated NLRP6 inflammasome activation in ex vivo colonic explants, suggesting that SCFAs may stimulate NLRP6 inflammasome independently of PPAR-γ activation. SCFAs and pioglitazone prevented fructose-induced hippocampal neuroinflammatory response and neuronal loss in mice. Additionally, SCFAs activated colonic NLRP6 inflammasome and increased DCX+ newborn neurons in the hippocampal DG of control mice. CONCLUSIONS: Our findings reveal that gut dysbiosis is a critical factor for a high-fructose diet-induced hippocampal neuroinflammation in C57BL/6N mice possibly mediated by impairing intestinal epithelial barrier. Mechanistically, the defective colonic NLRP6 inflammasome is responsible for intestinal epithelial barrier impairment. SCFAs can stimulate NLRP6 inflammasome and ameliorate the impairment of intestinal epithelial barrier, resulting in the protection against a high-fructose diet-induced hippocampal neuroinflammation and neuronal loss. This study addresses a gap in the understanding of neuronal injury associated with Western-style diets. A new intervention strategy for reducing the risk of neurodegenerative diseases through SCFAs supplementation or dietary fiber consumption is emphasized.
Assuntos
Disbiose/induzido quimicamente , Ácidos Graxos Voláteis/administração & dosagem , Frutose/efeitos adversos , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Animais , Proteína Duplacortina , Microbioma Gastrointestinal , Hipocampo/patologia , Inflamassomos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroimunomodulação/efeitos dos fármacos , Pioglitazona/administração & dosagemRESUMO
Objective: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. Methods: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. Results: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. Conclusion: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.
Assuntos
Humanos , Animais , Transtornos de Ansiedade/tratamento farmacológico , Acetilcisteína/farmacologia , Ansiolíticos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Hipnóticos e Sedativos/farmacologia , Acetamidas/farmacologia , Neuroimunomodulação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Glutamina/efeitos dos fármacosRESUMO
Daily supplementation of blueberries (BBs) reverses age-related deficits in behavior in aged rats. However, it is unknown whether BB is more beneficial to one subset of the population dependent on baseline cognitive performance and inflammatory status. To examine the effect of individual differences on the efficacy of BB, aged rats (17 months old) were assessed for cognition in the radial arm water maze (RAWM) and divided into good, average, and poor performers based on navigation errors. Half of the rats in each cognitive group were then fed a control or a 2% BB diet for 8 weeks before retesting. Serum samples were collected, pre-diet and post-diet, to assess inflammation. Latency in the radial arm water maze was significantly reduced in the BB-fed poor performers (p < .05) and preserved in the BB-fed good performers. The control-fed good performers committed more working and reference memory errors in the post-test than pretest (p < .05), whereas the BB-fed good performers showed no change. An in vitro study using the serum showed that BB supplementation attenuated lipopolysaccharide (LPS)-induced nitrite and tumor necrosis factor-alpha, and cognitive performance was associated with innate anti-inflammatory capability. Therefore, consumption of BB may reverse some age-related deficits in cognition, as well as preserve function among those with intact cognitive ability.
Assuntos
Envelhecimento , Anti-Inflamatórios , Antioxidantes , Mirtilos Azuis (Planta) , Cognição , Dietoterapia/métodos , Envelhecimento/imunologia , Envelhecimento/psicologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Comportamento Animal , Cognição/efeitos dos fármacos , Cognição/fisiologia , Aprendizagem em Labirinto , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Plantas Medicinais , Ratos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangueRESUMO
Liu-Wei-Di-Huang (LW) is a Yin nourishing and kidney tonifying prescription in traditional Chinese medicine with promising pharmacological characteristics that can be further exploited and developed in modern medicine. We provide a comprehensive and detailed literature report on the clinical and experimental pharmacology of LW, including its quality control parameters, phytochemistry, pharmacokinetics, and toxicology. Our literature review indicates that the LW prescription possesses a unique combination of pharmacological characteristics that can be safely used for treating very different diseases. Quality control and pharmacokinetic parameters of LW are mostly based on its major bioactive phytochemical constituents. We postulate that modulating or rebalancing the neuroendocrine immunomodulation network in the body is the underlying mechanism of the multiple pharmacological activities displayed by LW.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Rim/efeitos dos fármacos , Medicina Tradicional Chinesa , Neuroimunomodulação/efeitos dos fármacos , Deficiência da Energia Yin/tratamento farmacológico , Animais , Medicamentos de Ervas Chinesas/química , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Controle de QualidadeRESUMO
This study was aimed to evaluate the effects of near-infrared (NIR) photobiomodulation (PBM) combined with coenzyme Q10 (CoQ10) on depressive-like behavior, cerebral oxidative stress, inflammation, and apoptosis markers in mice. To induce a depressive-like model, mice were subjected to sub-chronic restraint stress for 5 consecutive days. NIR PBM (810 nm laser, 33.3 J/cm2) and/or CoQ10 (500 mg/kg/day, gavage) were administered for five days concomitantly with immobilization. Behavior was evaluated by the forced swim test (FST), tail suspension test (TST), and open field test (OFT). Mitochondrial membrane potential as well as oxidative stress, neuroinflammatory, and markers of apoptosis were evaluated in the prefrontal cortex (PFC) and hippocampus (HIP). The serum levels of pro-inflammatory cytokines, cortisol, and corticosterone were also measured. PBM or CoQ10, or the combination, ameliorated depressive-like behaviors induced by restraint stress as indicated by decreased immobility time in both the FST and TST. PBM and/or CoQ10 treatments decreased lipid peroxidation and enhanced total antioxidant capacity (TAC), GSH levels, GPx and SOD activities in both brain areas. The neuroinflammatory response in the HIP and PFC was suppressed, as indicated by decreased NF-kB, p38, and JNK levels in PBM and/or CoQ10 groups. Intrinsic apoptosis biomarkers, BAX, Bcl-2, cytochrome c release, and caspase-3 and -9, were also significantly down-regulated by both treatments. Furthermore, both treatments decreased the elevated serum levels of cortisol, corticosterone, TNF-α, and IL-6 induced by restraint stress. Transcranial NIR PBM and CoQ10 therapies may be effective antidepressant strategies for the prevention of psychopathological and behavioral symptoms induced by stress.
Assuntos
Depressão/terapia , Estresse Psicológico/terapia , Ubiquinona/análogos & derivados , Animais , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Depressão/induzido quimicamente , Transtorno Depressivo/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Terapia com Luz de Baixa Intensidade/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuroimunomodulação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ubiquinona/metabolismo , Ubiquinona/farmacologiaRESUMO
OBJECTIVE: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. METHODS: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. RESULTS: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. CONCLUSION: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.
Assuntos
Acetamidas/farmacologia , Acetilcisteína/farmacologia , Ansiolíticos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Ácidos Graxos Ômega-3/farmacologia , Hipnóticos e Sedativos/farmacologia , Animais , Modelos Animais de Doenças , Glutamina/efeitos dos fármacos , Humanos , Neuroimunomodulação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Stress is thought to impair immune function through emotional or behavioral manifestations thus the present study was done to assessed the effect of ethanolic extract of Butea frondosa (BF) leaves on behaviour, immunomodulatory activity and brain acetyl cholinesterase activity in normal and stress induced male rats. Neuroprotective effects of BF, doses (100,200,400mg/kg p.o) were measured by assessing the changes in the behaviour and the immunity of the rats. In stress control, the results indicated that the retention transfer latency, time spent in a closed arm, agglutination, total leukocytes counts (TLC), total paw edema ,size of spleen , decreased significantly (p<0.01) while glucose level, size of the kidney and the liver, AChE activity increased significantly (p<0.01) in comparison with normal control. In BF (200mg/kg) treated rats, the results indicated that the time spent in a closed arm (p<0.01), agglutination (p<0.01), TLC (p<0.01), total paw edema (p<0.05), size of spleen(p<0.01), increased significantly while glucose level (p<0.01), size of the kidney and the liver (p<0.01), AChE activity (p<0.01) decreased significantly in comparison with stress control. This study therefore concluded that the ethanolic extract of BF (200mg/kg) showed a protective effect against the stress induced impaired immune system and the psychological disorders.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Butea , Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Neuroimunomodulação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta , Estresse Psicológico/tratamento farmacológico , Acetilcolinesterase/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Butea/química , Inibidores da Colinesterase/farmacologia , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Fatores Imunológicos/isolamento & purificação , Masculino , Fármacos Neuroprotetores/farmacologia , Fitoterapia , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Ratos Sprague-Dawley , Estresse Psicológico/enzimologia , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologiaRESUMO
Epigenetic modifications of DNA and histone proteins are emerging as fundamental mechanisms by which neural cells adapt their transcriptional response to environmental cues, such as, immune stimuli or stress. In particular, histone H3 phospho(Ser10)-acetylation(Lys14) (H3S10phK14ac) has been linked to activation of specific gene expression. The purpose of this study was to investigate the role of H3S10phK14ac in a neuroinflammatory condition. Adult male rats received a intraperitoneal injection of lipopolysaccharide (LPS) (830⯵g/Kg/i.p., nâ¯=â¯6) or vehicle (saline 1â¯mL/kg/i.p., nâ¯=â¯6) and were sacrificed 2 or 6â¯h later. We showed marked region- and time-specific increases in H3S10phK14ac in the hypothalamus and hippocampus, two principal target regions of LPS. These changes were accompanied by a marked transcriptional activation of interleukin (IL) 1ß, IL-6, Tumour Necrosis Factor (TNF) α, the inducible nitric oxide synthase (iNOS) and the immediate early gene c-Fos. By means of chromatin immunoprecipitation, we demonstrated an increased region- and time-specific association of H3S10phK14ac with the promoters of IL-6, c-Fos and iNOS genes, suggesting that part of the LPS-induced transcriptional activation of these genes is regulated by H3S10phK14ac. Finally, by means of multiple immunofluorescence approach, we showed that increased H3S10phK14ac is cell type-specific, being neurons and reactive microglia, the principal histological types involved in this response. Present data point to H3S10phK14ac as a principal epigenetic regulator of neural cell response to systemic LPS and underline the importance of distinct time-, region- and cell-specific epigenetic mechanisms that regulate gene transcription to understand the mechanistic complexity of neuroinflammatory response to immune challenges.
Assuntos
Histonas/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Epigênese Genética/fisiologia , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipotálamo/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Microglia/metabolismo , Microglia/fisiologia , Neuroimunomodulação/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Ativação Transcricional/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Polychlorinated biphenyls (PCBs) are ubiquitous in the environment and exposure to them is associated with immune, endocrine and neural dysfunction. Effects of PCBs on inflammation and immunity are best described in spleen and blood, with fewer studies on neural tissues. This is an important gap in knowledge, as molecules typically associated with neuroinflammation also serve neuromodulatory roles and interact with hormones in normal brain development. The current study used Sprague-Dawley rats to assess whether gestational PCB exposure altered hypothalamic gene expression and serum cytokine concentration in neonatal animals given an immune challenge. Dams were fed wafers containing a mixture of PCBs at an environmentally relevant dose and composition (20⯵g/kg, 1:1:1 Aroclor 1242:1248:1254) or oil vehicle control throughout their pregnancy. One day old male and female offspring were treated with an inflammatory challenge (lipopolysaccharide, LPS, 50⯵g/kg, sc) or saline vehicle control approximately 3.5â¯h prior to tissue collection. Across both basal and activated inflammatory states, PCB exposure caused greater expression of a subset of inflammatory genes in the hypothalamus and lower expression of genes involved in dopamine, serotonin, and opioid systems compared to oil controls. PCB exposure also altered reactions to inflammatory challenge: it reversed the normal decrease in Esr2 hypothalamic expression and induced an abnormal increase in IL-1b and IL-6 serum concentration in response to LPS. Many of these effects were sex specific. Given the potential long-term consequences of neuroimmune disruption, our findings demonstrate the need for further research.