RESUMO
Multiple sclerosis (MS) is an immune-mediated and degenerating disease in which myelin sheaths are damaged as a result of chronic progressive inflammation of the central nervous system. Tibolone [(7α,17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-in-3-one], a synthetic estrogenic compound with tissue-specific actions and used for menopausal hormone therapy, shows neuroprotective and antioxidant properties both in vivo and in vitro. In the present study, we analyzed whether tibolone plays a therapeutic role in experimental autoimmune encephalomyelitis (EAE) mice, a commonly used model of MS. Female C57BL/6 mice were induced with the myelin oligodendrocyte glycoprotein MOG35-55 and received s.c. tibolone (0.08 mg kg-1 ) injection every other day from the day of induction until death on the acute phase of the disease. Reactive gliosis, Toll like receptor 4 (TLR4), high mobility group box protein 1 (HMGB1), inflammasome parameters, activated Akt levels and myelin were assessed by a real-time polymerase chain reaction, immunohistochemistry, and western blot analysis. Our findings indicated that, in the EAE spinal cord, tibolone reversed the astrocytic and microglial reaction, and reduced the hyperexpression of TLR4 and HMGB1, as well as NLR family pyrin domain containing 3-caspase 1-interleukin-1ß inflammasome activation. At the same time, tibolone attenuated the Akt/nuclear factor kappa B pathway and limited the white matter demyelination area. Estrogen receptor expression was unaltered with tibolone treatment. Clinically, tibolone improved neurological symptoms without uterine compromise. Overall, our data suggest that tibolone may serve as a promising agent for the attenuation of MS-related inflammation.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Neurite (Inflamação)/prevenção & controle , Norpregnenos/uso terapêutico , Animais , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Feminino , Inflamação/patologia , Inflamação/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Neurite (Inflamação)/patologia , Fármacos Neuroprotetores/uso terapêutico , Indução de RemissãoRESUMO
Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.
Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Envelhecimento/imunologia , Animais , COVID-19/líquido cefalorraquidiano , COVID-19/complicações , COVID-19/imunologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/virologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Feminino , Humanos , Ativação Linfocitária , Macaca mulatta , Masculino , Neurite (Inflamação)/imunologia , Neurite (Inflamação)/prevenção & controle , Profilaxia Pré-Exposição , Linfócitos T/imunologia , Replicação Viral/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
Oxytocin (OXT) modulates social interactions, attenuates stressful responses and can decrease drug-seeking and taking behaviors. In previous studies, we observed that social defeat (SD) induced a long-lasting increase in ethanol intake and neuroinflammation in male mice. We also know that OXT blocks the increase in cocaine reward induced by SD. Therefore, in the present study we aimed to evaluate the effect of 1â¯mg/kg of OXT administered 30â¯min before each episode of SD on ethanol consumption and the neuroinflammatory response in adult male mice. Three weeks after the last SD, mice underwent oral ethanol self-administration (SA) procedure, and striatal levels of the two chemokines CX3CL1 and CXCL12 were measured after the last SD and at the end of the ethanol SA. OXT administration blocked the increase in voluntary ethanol consumption observed in defeated mice, although it did not affect motivation for ethanol. An increase in the striatal levels of CX3CL1 and CXCL12 was observed in defeated animals immediately after the last defeat and after the ethanol SA. However, defeated mice treated with OXT did not show this increase in the neuroinflammatory response. In conclusion, OXT treatment can be a powerful therapeutic target to reduce the negative effects of social stress on ethanol consumption and the neuroinflammatory process.
Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Neurite (Inflamação)/prevenção & controle , Ocitocina/farmacologia , Derrota Social , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Animais , Quimiocina CX3CL1/metabolismo , Quimiocina CXCL12/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Etanol/administração & dosagem , Etanol/farmacologia , Masculino , Camundongos , Motivação/efeitos dos fármacos , Neurite (Inflamação)/etiologia , Neurite (Inflamação)/metabolismo , Ocitocina/uso terapêutico , Recompensa , Autoadministração , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologiaRESUMO
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
BACKGROUND: Neuroinflammation is recognized as part of the pathological progression of Alzheimer's disease (AD), but the molecular mechanisms are still not entirely clear. Systemically, physical exercise has shown to have a positive modulating effect on markers of inflammation. It is not known if this general effect also takes place in the central nervous system in AD. The aim of this study was to investigate the effect of 16â¯weeks of moderate to high-intensity physical exercise on selected biomarkers of inflammation both systemically and in the CNS, in patients with AD. METHODS: Plasma and cerebrospinal fluid (CSF) from 198 patients with Alzheimer's disease participating in the Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study were analyzed for concentrations of 8isoprostane, soluble trigger receptor expressed on myeloid cells 2 (sTREM2), and the MSD v-plex proinflammation panel 1 human containing interferon gamma (IFNγ), Interleukin-10 (IL10), IL12p70, IL13, IL1ß, IL2, IL4, IL6, IL8, and tumor necrosis factor alpha (TNFα), before and after a 16-week intervention with physical exercise, and we studied whether changes were modulated by the patients' APOE genotype. RESULTS: Most inflammatory markers remained unchanged after exercise. We found an increasing effect of 16â¯weeks of physical exercise on sTREM2 measured in CSF. Further, IL6 in plasma increased in the exercise group after physical exercise (mean relative change 41.03, SD 76.7), compared to controls (-0.97, SD 49.4). In a sub-analysis according to APOE genotype, we found that in ε4 carriers, exercise had a stabilizing effect on IFNγ concentration with a mean relative change of 7.84 (SD 42.6), as compared to controls (114.7 (SD 188.3), pâ¯=â¯0.038. CONCLUSION: Our findings indicate an effect of physical exercise on markers of neuroinflammation in CSF measured by an increase in sTREM2 in patients with AD. Further, there may be a small inflammatory systemic effect related to physical exercise in patients with AD.
Assuntos
Doença de Alzheimer/reabilitação , Terapia por Exercício/métodos , Neurite (Inflamação)/prevenção & controle , Atividades Cotidianas , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Índice de Massa Corporal , Cognição , Transtornos Cognitivos/sangue , Transtornos Cognitivos/líquido cefalorraquidiano , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Células Musculares/metabolismo , Neurite (Inflamação)/sangue , Neurite (Inflamação)/líquido cefalorraquidiano , Neuroprostanos/metabolismo , Qualidade de Vida , Receptores Imunológicos/metabolismoRESUMO
OBJECTIVES: Postoperative cognitive dysfunction (POCD) is a common clinical complication, with an underlying pathophysiology linked to heightened levels of neuroinflammation. However, it requires clarification as to whether the depth of anesthesia modulates postoperative cognitive dysfunction. This study investigated the association between depth of anesthesia and POCD in elderly patients undergoing abdominal surgery. METHODS: A total of 120 patients aged 60 years or older who were planned for abdominal surgery under total intravenous anesthesia were included in this study. The depth of anesthesia was guided by monitoring Bispectral Index (BIS) data. All study participants completed a battery of nine neuropsychological tests before surgery and at 7 days and 3 months after surgery. POCD was calculated by using the reliable change index. Plasma concentration of C-reactive protein (CRP), interleukin (IL)-1ß, IL-10, S-100ß, and norepinephrine (NE) were measured. RESULTS: The incidence of POCD at 7 days after surgery in the deep anesthesia group was 19.2% (10/52), which was significantly lower (p = 0.032) than the light anesthesia group 39.6% (21/53). The depth of anesthesia had no effect on POCD at 3 months after surgery (10.3% vs 14.6%, respectively, p = 0.558). Similarly, plasma levels of CRP and IL-1ß in deep anesthesia group were lower than that in light anesthesia group at 7 days after surgery (p < 0.05), but not at 3 months after surgery (p > 0.05). There were no significant differences in the plasma concentration of IL-10, S-100ß, and NE between the groups (p > 0.05). CONCLUSIONS: Deep anesthesia under total intravenous anesthesia could decrease the occurrence of short-term POCD and inhibit postoperative peripheral inflammation in elderly patients undergoing abdominal surgery, compared with light anesthesia.
Assuntos
Abdome/cirurgia , Anestesia Geral/métodos , Neurite (Inflamação)/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Idoso , Anestésicos Combinados , Anestésicos Intravenosos , Proteína C-Reativa/metabolismo , Disfunção Cognitiva , Eletroencefalografia/métodos , Feminino , Humanos , Interleucina-10 , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Período Pós-Operatório , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismoRESUMO
BACKGROUND: Pain arising from the lumbar facet joints is a common cause of axial back pain in adults. Radiofrequency neurotomy (RFN) of the medial branches of the spinal dorsal rami has been used as a treatment option. The most common side effect is transient, localized, burning, neuritic-type pain, termed post-neurotomy neuritis (PNN). Corticosteroids have been administered through the radiofrequency cannula after neurotomy to prevent PNN, but no study has examined the effects of this on PNN. OBJECTIVES: We investigated the incidence of PNN in patients who received corticosteroids after RFN and in those patients who did not receive corticosteroids. STUDY DESIGN: Retrospective evaluation. SETTING: Single-site interventional pain management practice in an urban tertiary academic medical center. METHODS: One hundred and sixty-four patients were included in this study and were categorized into non-steroid (n = 87) and steroid (n = 77) groups. Patient's age, gender, body mass index (BMI), laterality of procedure, use of neuropathic pain medications, baseline pain, and duration of pain were all recorded. PNN was determined if the patient self-reported transient burning or neuropathic pain at the site prior to or at the 6-week routine follow-up encounter. RESULTS: There was no significant difference in demographic characteristics between the 2 groups in age, gender, baseline pain, and duration of pain. The proportion of patients in the steroid treated group with PNN was 5 out of 77 (6.4%) and the non-steroid group was 6 out of 87 (6.9%). There was no statistically significant difference between the groups. There was no statistically significant difference in the incidence in neuritis between individuals taking neuropathic agents and individuals not taking neuropathic agents. LIMITATIONS: This study has several limitations including small sample size, patients' self-reported neuropathic symptoms, and inability to draw strong conclusions due to the retrospective study design. A single interventionalist performed all the procedures in this retrospective study and variations in technique amongst others are inevitable. CONCLUSION: Administration of steroids after RFN does not reduce the incidence of post-neurotomy neuritis. Concurrently administering neuropathic medications does not protect against neuritis. KEY WORDS: Radiofrequency neurotomy, radiofrequency ablation, neuritis, corticosteroid, lumbar facet pain, post neurotomy neuritis.
Assuntos
Corticosteroides/uso terapêutico , Denervação/efeitos adversos , Neurite (Inflamação)/epidemiologia , Neurite (Inflamação)/prevenção & controle , Nervos Espinhais/cirurgia , Adulto , Idoso , Feminino , Humanos , Incidência , Dor Lombar/cirurgia , Região Lombossacral , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Articulação ZigapofisáriaAssuntos
Envelhecimento/efeitos dos fármacos , Inflamação/tratamento farmacológico , Neurite (Inflamação)/tratamento farmacológico , Animais , Citocinas , Humanos , Inflamação/prevenção & controle , Longevidade/efeitos dos fármacos , Longevidade/genética , Camundongos , Neurite (Inflamação)/prevenção & controleRESUMO
Regeneration failure after primary spinal cord injury (SCI) leads to diverse clinical complications in a severity- and level of SCI-dependent manner. The cost of treating both of them (initial regeneration failure and following complications) would be prohibitive, particularly in less developed nations. The well-recognized circumstances arose from primary SCI include excitotoxicity and inflammation. SCI increases concentrations of extracellular amino acids (EAAs) in the severity-dependent manner and the maximum level of EAAs at the injury site will be reduced by distance from the injury site. Increased concentrations of EAAs and their signaling result in energy and metabolic changes and eventually neurotoxicity. Therefore EAAs play a crucial role in moving towards secondary stage of SCI. There is a close correspondence between severity of SCI and intensity of acute inflammatory response, which includes proinflammatory cytokines (IL-1ß, TNF-α, and IL-6) and immune cells (neutrophils, microglia, and mast cells). The communication between microglia and astrocytes mediate formation of astroglial scar. The scar is thought to diminish the spread of inflammation and lesion volume, and on the other side poses an obstacle to achieving axon regeneration. Moreover, mast cells exert an anti-inflammatory role in the ground of injured spinal cord by degradation of proinflammatory mediators, while mast cells-derived histamine may cause excitotoxicity. Therefore research suggests a very double-sword remark about the work of inflammatory mediators in the injured spinal cord. Myelin associated inhibitors (MAIs) are among the growing list of extrinsic inhibitors of neuroregeneration in the injured-CNS. They function via NgR-dependent mechanisms. The time for intervention by NgR antagonists must be fixed according to the expression pattern of this receptor and its dependent MAIs after SCI. Altogether, experimental studies suggest potential benefits of combating EAAs, inflammatory mediators, and MAIs during the first minutes, hours and weeks after SCI, respectively. However, acute inflammation initially induced by SCI tends to be permanent, even at several years after SCI. This supports the notion that paying attention to inflammation must persist through time. The consideration of seconds-dependent state of spinal cord after primary injury is a very therapeutic and also preventive approach against future possible complications. It is thereby possible to propose "timing", which is perfectly practicable throughout the world, as an effective campaign against the final failure of SCI.
Assuntos
Medicina Baseada em Evidências , Regeneração Nervosa , Neurite (Inflamação)/prevenção & controle , Traumatismos da Medula Espinal/terapia , Nervos Espinhais/fisiologia , Tempo para o Tratamento , Animais , Anti-Inflamatórios/uso terapêutico , Terapia Combinada , Humanos , Escala de Gravidade do Ferimento , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Neurite (Inflamação)/etiologia , Receptores Nogo/agonistas , Receptores Nogo/antagonistas & inibidores , Receptores Nogo/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/imunologia , Nervos Espinhais/fisiopatologiaRESUMO
HIV-1 infection of the brain causes the neurodegenerative syndrome HIV-associated neurocognitive disorders (HAND), for which there is no specific treatment. Herein, we investigated the actions of insulin using ex vivo and in vivo models of HAND. Increased neuroinflammatory gene expression was observed in brains from patients with HIV/AIDS. The insulin receptor was detected on both neurons and glia, but its expression was unaffected by HIV-1 infection. Insulin treatment of HIV-infected primary human microglia suppressed supernatant HIV-1 p24 levels, reduced CXCL10 and IL-6 transcript levels, and induced peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. Insulin treatment of primary human neurons prevented HIV-1 Vpr-mediated cell process retraction and death. In feline immunodeficiency virus (FIV) infected cats, daily intranasal insulin treatment (20.0 IU/200 µl for 6 weeks) reduced CXCL10, IL-6, and FIV RNA detection in brain, although PPAR-γ in glia was increased compared with PBS-treated FIV+ control animals. These molecular changes were accompanied by diminished glial activation in cerebral cortex and white matter of insulin-treated FIV+ animals, with associated preservation of cortical neurons. Neuronal counts in parietal cortex, striatum, and hippocampus were higher in the FIV+/insulin-treated group compared with the FIV+/PBS-treated group. Moreover, intranasal insulin treatment improved neurobehavioral performance, including both memory and motor functions, in FIV+ animals. Therefore, insulin exerted ex vivo and in vivo antiviral, anti-inflammatory, and neuroprotective effects in models of HAND, representing a new therapeutic option for patients with inflammatory or infectious neurodegenerative disorders including HAND. SIGNIFICANCE STATEMENT: HIV-associated neurocognitive disorders (HAND) represent a spectrum disorder of neurocognitive dysfunctions resulting from HIV-1 infection. Although the exact mechanisms causing HAND are unknown, productive HIV-1 infection in the brain with associated neuroinflammation is a potential pathogenic mechanism resulting in neuronal damage and death. We report that, in HIV-infected microglia cultures, insulin treatment led to reduced viral replication and inflammatory gene expression. In addition, intranasal insulin treatment of experimentally feline immunodeficiency virus-infected animals resulted in improved motor and memory performances. We show that insulin restored expression of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), which is suppressed by HIV-1 replication. Our findings indicate a unique function for insulin in improving neurological outcomes in lentiviral infections, implicating insulin as a therapeutic intervention for HAND.
Assuntos
Complexo AIDS Demência/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Neurite (Inflamação)/prevenção & controle , Doenças Neurodegenerativas/prevenção & controle , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Administração Intranasal , Animais , Gatos , Morte Celular/efeitos dos fármacos , Feminino , HIV-1 , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Vírus da Imunodeficiência Felina , Insulina/administração & dosagem , Infecções por Lentivirus/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Gravidez , Receptor de Insulina/efeitos dos fármacosRESUMO
High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/day in HF diet) for a further 6 weeks. Chronic rhein treatment prevented the HF diet-induced recognition memory impairment assessed by the novel object recognition test, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits in the perirhinal cortex. Furthermore, rhein inhibited the HF diet-induced increased plasma LPS level and the proinflammatory macrophage accumulation in the colon and alteration of microbiota, including decreasing Bacteroides-Prevotella spp. and Desulfovibrios spp. DNA and increasing Bifidobacterium spp. and Lactobacillus spp. DNA. Moreover, rhein also reduced body weight and improved glucose tolerance in HF diet-induced obese mice. In conclusion, rhein improved recognition memory and prevented obesity in mice on a chronic HF diet. These beneficial effects occur via the modulation of microbiota, hypoendotoxinemia, inhibition of macrophage accumulation, anti-neuroinflammation and the improvement of BDNF expression. Therefore, supplementation with rhein-enriched food or herbal medicine could be beneficial as a preventive strategy for chronic HF diet-induced cognitive decline, microbiota alteration and neuroinflammation.
Assuntos
Antraquinonas/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Suplementos Nutricionais , Disbiose/prevenção & controle , Transtornos da Memória/prevenção & controle , Nootrópicos/uso terapêutico , Obesidade/dietoterapia , Animais , Fármacos Antiobesidade/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colo/imunologia , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Dieta Hiperlipídica/efeitos adversos , Disbiose/etiologia , Disbiose/microbiologia , Endotoxemia/etiologia , Endotoxemia/prevenção & controle , Fármacos Gastrointestinais/uso terapêutico , Intolerância à Glucose/etiologia , Intolerância à Glucose/prevenção & controle , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Transtornos da Memória/etiologia , Camundongos Endogâmicos C57BL , Neurite (Inflamação)/etiologia , Neurite (Inflamação)/prevenção & controle , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Obesidade/imunologia , Obesidade/patologia , Obesidade/fisiopatologia , Córtex Perirrinal/imunologia , Córtex Perirrinal/metabolismo , Córtex Perirrinal/patologia , Reconhecimento PsicológicoRESUMO
AIMS/INTRODUCTION: Dental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves. MATERIALS AND METHODS: DPSCs were isolated from the dental pulp of Sprague-Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68-positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC-conditioned media on lipopolysaccharide-stimulated murine macrophage RAW264.7 cells were investigated. RESULTS: Diabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68-positive monocytes/macrophages and the gene expressions of M1 macrophage-expressed cytokines, tumor necrosis factor-α and interleukin-1ß, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor-α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC-conditioned media significantly increased the gene expressions of interleukin-10 and CD206 in lipopolysaccharide-stimulated RAW264.7 cells. CONCLUSIONS: These results suggest that DPSC transplantation promoted macrophages polarization towards anti-inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy.
Assuntos
Polpa Dentária/transplante , Neuropatias Diabéticas/complicações , Macrófagos/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Neurite (Inflamação)/cirurgia , Nervo Isquiático/fisiopatologia , Animais , Polaridade Celular , Proliferação de Células , Sobrevivência Celular , Polpa Dentária/citologia , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Masculino , Condução Nervosa , Neurite (Inflamação)/etiologia , Neurite (Inflamação)/prevenção & controle , Fenótipo , Ratos , Ratos Sprague-DawleyRESUMO
Background: Clinical data on pure-neuritic leprosy (PNL) is limited. Objective: To study the clinical and epidemiological features of PNL in the leprosy post-elimination era. Methods: This was a retrospective analysis of the clinic records of leprosy patients from January 2006 to June 2013. Data regarding age, sex, disease duration, presenting complaints, nerves affected, complications and treatment received were extracted from PNL cases. Results: Among 906 registered leprosy cases, 48 (5·3%) were found to have PNL. The mean age was 36·9 ± 16·2 years and predominantly males were affected (85·4%). The mean delay between onset of symptoms and diagnosis was 2·1 ± 2·2 years. Multiple nerves were affected in 36 patients (75%) and 12 (25%) had only one nerve involved. Visible deformities at presentation were noted in 32 (66·7%) patients. Forty patients (83·3%) were treated with multi drug therapy-multibacillary (MDTMB) regimen and three (6·25%) were treated with MDT-paucibacillary regimen. Twenty-one patients (43·8%) were considered positive responders to treatment. There was no correlation between the duration of NFI and treatment outcome. Conclusion: PNL continues to occur in the post-elimination era. Grade 2 deformities are common in PNL compared to other leprosy patients because of delayed diagnosis and treatment. Distinct diagnosis and treatment guidelines and sensitisation of health care workers and physicians to the occurrence of PNL is the need of the day.
Assuntos
Erradicação de Doenças/métodos , Hanseníase/prevenção & controle , Mycobacterium leprae/fisiologia , Neurite (Inflamação)/prevenção & controle , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Índia , Hanseníase/epidemiologia , Hanseníase/microbiologia , Pessoa de Meia-Idade , Mycobacterium leprae/genética , Mycobacterium leprae/isolamento & purificação , Neurite (Inflamação)/epidemiologia , Neurite (Inflamação)/microbiologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Neurite (Inflamação)/prevenção & controle , Vacina Antirrábica/uso terapêutico , Doenças do Nervo Vestibulococlear/complicações , Doenças do Nervo Vestibulococlear/prevenção & controle , Feminino , Humanos , Pessoa de Meia-Idade , Neurite (Inflamação)/complicações , Profilaxia Pós-ExposiçãoRESUMO
BACKGROUND AIMS: After ischemic or hemorrhagic stroke, neurons in the penumbra surrounding regions of irreversible injury are vulnerable to delayed but progressive damage as a result of ischemia and hemin-induced neurotoxicity. There is no effective treatment to rescue such dying neurons. Mesenchymal stem cells (MSCs) hold promise for rescue of these damaged neurons. In this study, we evaluated the efficacy and mechanism of MSC-induced neuro-regeneration and immune modulation. METHODS: Oxygen-glucose deprivation (OGD) was used in our study. M17 neuronal cells were subjected to OGD stress then followed by co-culture with MSCs. Rescue effects were evaluated using proliferation and apoptosis assays. Cytokine assay and quantitative polymerase chain reaction were used to explore the underlying mechanism. Antibody and small molecule blocking experiments were also performed to further understand the mechanism. RESULTS: We showed that M17 proliferation was significantly decreased and the rate of apoptosis increased after exposure to OGD. These effects could be alleviated via co-culture with MSCs. Tumor necrosis factor-α was found elevated after OGD stress and was back to normal levels after co-culture with MSCs. We believe these effects involve interleukin-6 and vascular endothelial growth factor signaling pathways. DISCUSSION: Our studies have shown that MSCs have anti-inflammatory properties and the capacity to rescue injured neurons.
Assuntos
Comunicação Celular , Inflamação/prevenção & controle , Células-Tronco Mesenquimais/fisiologia , Neurite (Inflamação)/prevenção & controle , Neurônios/fisiologia , Acidente Vascular Cerebral/terapia , Apoptose/fisiologia , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glucose/deficiência , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Interleucina-6/farmacologia , Células-Tronco Mesenquimais/metabolismo , Neurite (Inflamação)/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Acidente Vascular Cerebral/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Impaired neuronal mitochondrial bioenergetics contributes to the pathophysiologic progression of diabetic peripheral neuropathy (DPN) and may be a focal point for disease management. We have demonstrated that modulating heat shock protein (Hsp) 90 and Hsp70 with the small-molecule drug KU-32 ameliorates psychosensory, electrophysiologic, morphologic, and bioenergetic deficits of DPN in animal models of type 1 diabetes. The current study used mouse models of type 1 and type 2 diabetes to determine the relationship of changes in sensory neuron mitochondrial bioenergetics to the onset of and recovery from DPN. The onset of DPN showed a tight temporal correlation with a decrease in mitochondrial bioenergetics in a genetic model of type 2 diabetes. In contrast, sensory hypoalgesia developed 10 weeks before the occurrence of significant declines in sensory neuron mitochondrial bioenergetics in the type 1 model. KU-32 therapy improved mitochondrial bioenergetics in both the type 1 and type 2 models, and this tightly correlated with a decrease in DPN. Mechanistically, improved mitochondrial function following KU-32 therapy required Hsp70, since the drug was ineffective in diabetic Hsp70 knockout mice. Our data indicate that changes in mitochondrial bioenergetics may rapidly contribute to nerve dysfunction in type 2 diabetes, but not type 1 diabetes, and that modulating Hsp70 offers an effective approach toward correcting sensory neuron bioenergetic deficits and DPN in both type 1 and type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Proteínas de Choque Térmico HSP70/metabolismo , Hipoglicemiantes/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Novobiocina/análogos & derivados , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Relação Dose-Resposta a Droga , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Proteínas de Choque Térmico HSP70/genética , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Neurite (Inflamação)/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Novobiocina/administração & dosagem , Novobiocina/sangue , Novobiocina/farmacocinética , Novobiocina/uso terapêutico , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismoRESUMO
The green tea component epigallocatechin-3-gallate (EGCG) may be beneficial in autoimmune diseases; however, the underlying mechanisms are not well understood. In this study, we determined the effect of EGCG on the development of experimental autoimmune encephalomyelitis, an animal model for human multiple sclerosis, and the underlying mechanisms. Female C57BL/6 mice were fed EGCG (0%, 0.15%, 0.3%, and 0.6% in diet) for 30 days and then immunized with specific antigen myelin oligodendrocyte glycoprotein 35-55. EGCG dose dependently attenuated clinical symptoms and pathological features (leukocyte infiltration and demyelination) in the central nervous system and inhibited antigen-specific T-cell proliferation and delayed-type hypersensitivity skin response. We further showed that EGCG reduced production of interferon-γ, IL-17, IL-6, IL-1ß, and tumor necrosis factor-α; decreased types 1 and 17 helper T cells (Th1 and Th17, respectively); and increased regulatory T-cell populations in lymph nodes, the spleen, and the central nervous system. Moreover, EGCG inhibited expression of transcription factors T-box expressed in T cells and retinoid-related orphan receptor-γt, the specific transcription factor for Th1 and Th17 differentiation, respectively; the plasma levels of intercellular adhesion molecule 1; and CCR6 expression in CD4(+) T cells. These results indicate that EGCG may attenuate experimental autoimmune encephalomyelitis autoimmune response by inhibiting immune cell infiltration and modulating the balance among pro- and anti-autoimmune CD4(+) T-cell subsets. Thus, we identified a novel mechanism that underlies EGCG's beneficial effect in autoimmune disease.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Catequina/análogos & derivados , Encefalomielite Autoimune Experimental/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/imunologia , Catequina/farmacologia , Proliferação de Células , Citocinas/metabolismo , Doenças Desmielinizantes/prevenção & controle , Suplementos Nutricionais , Regulação para Baixo , Encefalomielite Autoimune Experimental/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/prevenção & controle , Proteínas da Mielina/antagonistas & inibidores , Glicoproteína Mielina-Oligodendrócito , Neurite (Inflamação)/prevenção & controle , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Distribuição Aleatória , Proteínas com Domínio T/antagonistas & inibidores , Subpopulações de Linfócitos T/imunologiaRESUMO
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Increased expression of 5-lipoxygenase (5-LO), a key enzyme in the biosynthesis of leukotrienes (LTs), has been reported in MS lesions and LT levels are elevated in the cerebrospinal fluid of MS patients. To determine whether pharmacological inhibition of 5-LO attenuates demyelination, MK886, a 5-LO inhibitor, was given to mice fed with cuprizone. Gene and protein expression of 5-LO were increased at the peak of cuprizone-induced demyelination. Although MK886 did not attenuate cuprizone-induced demyelination in the corpus callosum or in the cortex, it attenuated cuprizone-induced axonal damage and motor deficits and reduced microglial activation and IL-6 production. These data suggest that during cuprizone-induced demyelination, the 5-LO pathway contributes to microglial activation and neuroinflammation and to axonal damage resulting in motor dysfunction. Thus, 5-LO inhibition may be a useful therapeutic treatment in demyelinating diseases of the CNS.