RESUMEN
Depression is a prevalent psychiatric disorder with elusive pathogenesis. Studies have proposed that enhancement and persistence of aseptic inflammation in the central nervous system (CNS) may be closely associated with the development of depressive disorder. High mobility group box 1 (HMGB1) has obtained significant attention as an evoking and regulating factor in various inflammation-related diseases. It is a non-histone DNA-binding protein that can be released as a pro-inflammatory cytokine by glial cells and neurons in the CNS. Microglia, as the immune cell of the brain, interacts with HMGB1 and induces neuroinflammation and neurodegeneration in the CNS. Therefore, in the current review, we aim to investigate the role of microglial HMGB1 in the pathogenetic process of depression.
RESUMEN
Our previous study reported that fully reduced high mobility group box 1 (frHMGB1) and disulfide HMGB1 (dsHMGB1) induce depressivelike behavior; however, the underlying mechanisms remain unclear. In the present study, the induction of depression via the kynurenine pathway by different redox states of HMGB1 was investigated in vivo and in vitro. To evaluate the expression of enzymes of the kynurenine pathway, reverse transcriptionquantitative PCR and western blot analyses were conducted. Additionally, cytokine levels were measured by ELISAs. Following intracerebroventricular injection of ds and frHMGB1, behavioral tests were performed, revealing the presentation of depressivelike behavior, and essential proteins in the kynurenine pathway were demonstrated to be upregulated at the mRNA level, suggesting that ds and frHMGB1 contributed to the development of this behavior via the kynurenine pathway. dsHMGB1 directly activated the kynurenine pathway and cytokines such as tumor necrosis factorα (TNFα) and interleukin1ß (IL1ß) in the hippocampal tissue. Conversely, frHMGB1 upregulated the aforementioned factors only following treatment with H2O2. These findings indicated that dsHMGB1 induced depression in a manner associated with the kynurenine pathway, whereas oxidation of frHMGB1 evoked activation of the kynurenine pathway, resulting in depressive behavior.
Asunto(s)
Conducta Animal/efectos de los fármacos , Depresión/genética , Proteína HMGB1/genética , Quinurenina/genética , Animales , Depresión/metabolismo , Depresión/patología , Trastorno Depresivo , Disulfuros/metabolismo , Ensayo de Inmunoadsorción Enzimática , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Peróxido de Hidrógeno/química , Interleucina-1beta/genética , Ratones , ARN Mensajero/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: Glucocorticoids (GCs) take a pivotal role during the stress response. Some clinical studies suggest short-term GCs intake improves exercise endurance. However, whether the rapid nongenomic effects of GCs are involved in acute exercise is still unknown. Here, we aimed to reveal the potential nongenomic effects of GCs in skeletal muscle of mice during exercise. METHODS: Adrenalectomized mice subjected to a weight-loaded forced swim were used for detecting the changes of time to exhaustion. Corticosterone (CORT) and other drugs were injected via the coccygeal vein before swimming. After exhaustion, the injury of skeletal muscle, nitric oxide generation, blood glucose and lactic acid were determined. RESULTS: The results demonstrated that CORT rapidly extended the time to exhaustion within 30 min (~30%), which could not be abolished by glucocorticoid receptor antagonist RU486. Pretreatment with the nitric oxide synthesis inhibitor L-NAME prior to CORT administration further increased exercise tolerance compared to the increase caused by CORT alone. Moreover, CORT contributed to protecting skeletal muscle from injury and maintaining blood glucose. CONCLUSIONS: Considered together, our results suggest that GCs rapidly improve exercise tolerance via its nongenomic mechanism, which is associated with the inhibition of nitric oxide generation. Pretreatment of GCs may be helpful to enhance exercise tolerance during acute exercise.
Asunto(s)
Corticosterona/farmacología , Glucocorticoides/farmacología , Resistencia Física/efectos de los fármacos , Natación/fisiología , Animales , Glucemia/análisis , Ácido Láctico/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Músculo Esquelético/fisiología , Óxido Nítrico/sangreRESUMEN
BACKGROUND: Depression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression. METHODS: After 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo. RESULTS: Four-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-κB signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia. CONCLUSIONS: These data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.
Asunto(s)
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Depresión/patología , Regulación de la Expresión Génica/fisiología , Hipocampo/metabolismo , Animales , Calgranulina A/antagonistas & inhibidores , Línea Celular Transformada , Citocinas/metabolismo , Depresión/tratamiento farmacológico , Depresión/etiología , Modelos Animales de Enfermedad , Preferencias Alimentarias/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inmunosupresores/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Microglía/efectos de los fármacos , Microglía/metabolismo , Quinolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estrés Psicológico/complicaciones , Sacarosa/administración & dosificación , Sulfonamidas/farmacologíaRESUMEN
Our previous study implied the role of central high mobility group box 1 (HMGB1) in lipopolysaccharide (LPS)-induced depressive-like behaviors that could partially abrogate by glycyrrhizic acid (GZA). Here, we considered the potential mechanism underlying GZA ameliorating chronic stress-induced depression both in vivo and in vitro. Depression model was established with the 4-week chronic unpredictable mild stress (CUMS) mice. Sucrose preference test, tail suspension test and open field test were performed to reflect depressive-like behaviors. Enzyme activity of indoleamine-2,3-dioxygenase (IDO) was recorded with the ratio of kynurenine (KYN) / tryptophan (Trp). Transcription of gene was evaluated by RT-PCR. Along with depressive-like behaviors, IDO, the rate-limiting enzyme of the kynurenine pathway (KP), was upregulated at the level of mRNA expression, and enzyme activity was also elevated in stressed hippocampi and LPS/HMGB1-treated hippocampus slices. Treatment of mice with GZA, the inhibitor of HMGB1, prevented the activated enzymes in KP and the development of depressive-like behaviors. These experiments demonstrate that GZA may restrain HMGB1 thus improving chronic stress-induced depressive behavior through regulating KP.
Asunto(s)
Antidepresivos/farmacología , Trastorno Depresivo/tratamiento farmacológico , Ácido Glicirrínico/farmacología , Proteína HMGB1/antagonistas & inhibidores , Quinurenina/metabolismo , Animales , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Proteína HMGB1/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Ratones Endogámicos BALB C , Distribución Aleatoria , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Técnicas de Cultivo de Tejidos , Triptófano/metabolismoRESUMEN
Our previous study has reported that the proactive secretion and role of central high mobility group box 1 (HMGB1) in lipopolysaccharide-induced depressive behavior. Here, the potential mechanism of HMGB1 mediating chronic-stress-induced depression through the kynurenine pathway (KP) was further explored both in vivo and in vitro. Depression model was established with the 4-week chronic unpredictable mild stress (CUMS). Sucrose preference and Barnes maze test were performed to reflect depressive behaviors. The ratio of kynurenine (KYN)/tryptophan (Trp) represented the enzyme activity of indoleamine-2,3-dioxygenase (IDO). Gene transcription and protein expression were assayed by real-time RT-PCR and western-blot or ELISA kit respectively. Along with depressive behaviors, HMGB1 concentrations in the hippocampus and serum substantially increased post 4-week CUMS exposure. Concurrent with the upregulated HMGB1 protein, the regulator of translocation of HMGB1, sirtuin 1 (SIRT1) concentration in the hippocampus remarkably increased. In addition to HMGB1 and SIRT1, IDO, the rate limiting enzyme of KP, was upregulated at the level of mRNA expression and enzyme activity in stressed hippocampi and LPS/HMGB1-treated hippocampal slices. The gene transcription of kynurenine monooxygenase (KMO) and kynureninase (KYNU) in the downstream of KP also increased both in vivo and in vitro. Mice treated with ethyl pyruvate (EP), the inhibitor of HMGB1 releasing, were observed with lower tendency of developing depressive behaviors and reduced activation of enzymes in KP. All of these experiments demonstrate that the role of HMGB1 on the induction of depressive behavior is mediated by KP activation.
Asunto(s)
Depresión/metabolismo , Proteína HMGB1/metabolismo , Animales , Depresión/fisiopatología , Trastorno Depresivo/metabolismo , Proteína HMGB1/fisiología , Hipocampo/metabolismo , Hidrolasas/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/genética , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Actividad Motora , Piruvatos/farmacología , Sirtuina 1/metabolismo , Estrés Psicológico/metabolismo , Triptófano/metabolismoRESUMEN
BACKGROUND: Abundant reports indicated that depression was often comorbid with type 2 diabetes and even metabolic syndrome. Considering they might share common biological origins, it was tentatively attributed to the chronic cytokine-mediated inflammatory response which was induced by dysregulation of HPA axis and overactivation of innate immunity. However, the exact mechanisms remain obscure. Herein, we mainly focused on the function of the NLRP3 inflammasome to investigate this issue. METHODS: Male C57BL/6 mice were subjected to 12 weeks of chronic unpredictable mild stress (CUMS), some of which were injected with glyburide or fluoxetine. After CUMS procedure, behavioral and metabolic tests were carried out. In order to evaluate the systemic inflammation associated with inflammasome activation, IL-1ß and inflammasome components in hippocampi and pancreases, as well as corticosterone and IL-1ß in serum were detected separately. Moreover, immunostaining was performed to assess morphologic characteristics of pancreases. RESULTS: In the present study, we found that 12 weeks' chronic stress resulted in depressive-like behavior comorbid with insulin resistance. Furthermore, antidiabetic drug glyburide, an inhibitor of the NLRP3 inflammasome, was discovered to be effective in preventing the experimental comorbidity. In brief, it improved behavioral performance, ameliorated insulin intolerance as well as insulin signaling in the hippocampus possibly through inhibiting NLRP3 inflammasome activation by suppressing the expression of TXNIP. CONCLUSIONS: All these evidence supported our hypothesis that chronic stress led to comorbidity of depressive-like behavior and insulin resistance via long-term mild inflammation. More importantly, based on the beneficial effects of blocking the activation of the NLRP3 inflammasome, we provided a potential therapeutic target for clinical comorbidity and a new strategy for management of both diabetes and depression.
Asunto(s)
Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Gliburida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina/fisiología , Animales , Comorbilidad , Trastorno Depresivo/psicología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. METHODS: We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. RESULTS: Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1ß protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1ß levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. CONCLUSIONS: These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF-κB protein complex activation in depression mouse model. Further researches targeting the NLRP3 inflammasome-signaling pathway might be under a promising future in the prevention and treatment of depression.
Asunto(s)
Trastorno Depresivo/inmunología , Inflamasomas/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Animales , Peso Corporal , Enfermedad Crónica , Trastorno Depresivo/patología , Sacarosa en la Dieta , Modelos Animales de Enfermedad , Conducta Alimentaria , Hipocampo/inmunología , Hipocampo/patología , Interleucina-1beta/sangre , Masculino , Ratones Endogámicos C57BL , Actividad Motora , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Estrés Psicológico/inmunología , Estrés Psicológico/patología , IncertidumbreRESUMEN
High mobility group box 1 (HMGB1) has been implicated as a key factor in several neuroinflammatory conditions. Our previous study suggested that the release of central HMGB1 acts as a late-phase mediator in lipopolysaccharide (LPS)-induced depression. Recent findings indicate that the redox state of HMGB1 is a critical determinant of its immunomodulatory properties. Here, we aimed to investigate the potential mechanisms that link the redox states of HMGB1 to depression in mice. Distinct redox forms of recombinant HMGB1 (rHMGB1) were used that included fully reduced HMGB (fr-HMGB1), which acted as a chemokine, and disulfide-HMGB1 (ds-HMGB1), which possessed cytokine activity. Fr-HMGB1 in vivo was partially oxidized into ds-HMGB1; thus, the mutant protein non-oxidizable chemokine-HMGB (nonoxid-HMGB1) was applied. Concurrent with depressive behavior induced by four-week stress exposure, the HMGB1 concentrations in the serum and cerebral cortex substantially increased. Therefore, a single dose of rHMGB1 (200ng/5µl/mice) or vehicle was administered to mice via intracerebroventricular (i.c.v.) injection. The receptor inhibitors of TLR4/RAGE/CXCR4 (TAK-242/FPS-ZM1/AMD3100) (3mg/kg) were intraperitoneally injected 30min prior to rHMGB1 treatment. Depressive-like behavior was measured 20h post i.c.v. injection. Administration of fr-HMGB1 prolonged the immobility duration in the tail suspension test (TST) and decreased sucrose preference. In addition to depressive behavior, the hippocampal TNF-α protein slightly increased. These depressive behaviors and upregulation of hippocampal TNF-α were alleviated or abrogated by pretreatment with the inhibitors AMD3100, FPS-ZM1, and TAK-242. Alternatively, nonoxid-HMGB1 failed to induce TNF-α protein or prolong the immobility duration. As expected, ds-HMGB1 administration substantially upregulated hippocampal TNF-α protein, increased the immobility time in the TST and decreased sucrose preference. Moreover, both glycyrrhizin and TAK-242 improved ds-HMGB1-induced depressive behavior. Furthermore, TAK-242 significantly blocked the upregulation of hippocampal TNF-α protein and protected hippocampal myelin basic protein from ds-HMGB1-induced reduction. These drugs had no effect on the total or central distance in the open field test. Collectively, this initial experiment demonstrates the role and receptor mechanisms of HMGB1 under different redox states on the induction of depressive-like behavior. Both ds-HMGB1 and fr-HMGB1 may induce depressive-like behavior in vivo mainly via neuroinflammatory response activation.
Asunto(s)
Depresión/inducido químicamente , Depresión/psicología , Proteína HMGB1/genética , Proteína HMGB1/farmacología , Inflamación/inducido químicamente , Inflamación/psicología , Anhedonia , Animales , Proteína HMGB1/química , Suspensión Trasera , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos BALB C , Actividad Motora , Oxidación-Reducción , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Estrés Psicológico/psicología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Insomnia is a widespread and debilitating condition that affects sleep quality and daily productivity. Although mindfulness meditation (MM) has been suggested as a potentially effective supplement to medical treatment for insomnia, no comprehensively quantitative research has been conducted in this field. Therefore, we performed a meta-analysis on the findings of related randomized controlled trials (RCTs) to evaluate the effects of MM on insomnia. METHODS: Related publications in PubMed, EMBASE, the Cochrane Library and PsycINFO were searched up to July 2015. To calculate the standardized mean differences (SMDs) and 95% confidence intervals (CIs), we used a fixed effect model when heterogeneity was negligible and a random effect model when heterogeneity was significant. RESULTS: A total of 330 participants in 6 RCTs that met the selection criteria were included in this meta-analysis. Analysis of overall effect revealed that MM significantly improved total wake time and sleep quality, but had no significant effects on sleep onset latency, total sleep time, wake after sleep onset, sleep efficiency, total wake time, ISI, PSQI and DBAS. Subgroup analyses showed that although there were no significant differences between MM and control groups in terms of total sleep time, significant effects were found in total wake time, sleep onset latency, sleep quality, sleep efficiency, and PSQI global score (absolute value of SMD range: 0.44-1.09, all p<0.05). CONCLUSIONS: The results suggest that MM may mildly improve some sleep parameters in patients with insomnia. MM can serve as an auxiliary treatment to medication for sleep complaints.
Asunto(s)
Meditación/métodos , Meditación/psicología , Atención Plena/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Trastornos del Inicio y del Mantenimiento del Sueño/psicología , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , HumanosRESUMEN
Glucocorticoids (GCs) are a class of steroid hormones that regulate multiple aspects of glucose homeostasis. In skeletal muscle, it is well established that prolonged GC excess inhibits glucose uptake and utilization through glucocorticoid receptor (GR)-mediated transcriptional changes. However, it remains obscure that whether the rapid non-genomic effects of GC on glucose uptake are involved in acute exercise stress. Therefore, we used electric pulse stimulation (EPS)-evoked contracting myotubes to determine whether the non-genomic actions of GC were involved and its underlying mechanism(s). Pretreatment with dexamethasone (Dex, 10 µM) significantly prevented contraction-stimulated glucose uptake and glucose transporter 4 (Glut4) translocation within 20 min in C2C12 myotubes. Neither GC nuclear receptor antagonist (RU486) nor protein synthesis inhibitor (cycloheximide, Chx) affected the rapid inhibition effects of Dex. AMPK and CaMKII-dependent signaling pathways were associated with the non-genomic effects of Dex. These results provide evidence that GC rapidly suppresses glucose uptake in contracting myotubes via GR-independent non-genomic mechanisms. AMPK and CaMKII-mediated Glut4 translocation may play a critical role in GC-induced rapid inhibition of glucose uptake.
Asunto(s)
Dexametasona/química , Glucosa/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antiinflamatorios/química , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Diferenciación Celular , Línea Celular , Membrana Celular/metabolismo , Cicloheximida/química , Genómica , Transportador de Glucosa de Tipo 4/metabolismo , Ratones , Mifepristona/química , Músculo Esquelético/metabolismo , Fosforilación , Condicionamiento Físico Animal , Transporte de Proteínas , Receptores de Glucocorticoides/metabolismo , Transducción de Señal , Esteroides/química , Transcripción GenéticaRESUMEN
Depression is often preceded by exposure to stressful life events. Chronic stress causes perturbations in the immune system, and up-regulates production of proinflammatory cytokines, which has been proposed to be associated with the pathogenesis of clinical depression. However, the potential mechanisms by which stress-induced proinflammatory cytokines lead to the development of depression are not well understood. Here, we sought to screen the main proinflammatory cytokines and the potential mechanisms linking inflammation to depression-like behavior during unpredictable, chronic, mild stress (UCMS), in vivo. Mice were allocated into four groups in each separate experiment: saline-control, saline-UCMS, drug-control and drug-UCMS. Development of depression-like behavior was reflected as a reduction in sucrose preference, and increased immobility in both the forced swim and tail suspension tests. The following drugs were administered intraperitoneally: the pan-anti-inflammatory tetracycline derivative, minocycline (30 mg/kg, daily), the tumor necrosis factor (TNF)α monoclonal antibody, infliximab (10 mg/kg, twice weekly), and the indoleamine 2, 3-dioxygenase (IDO) inhibitor, 1-methyltryptophan (1-MT, 10 mg/mouse, daily). Plasma TNFα, IL-1ß and IL-18 increased significantly after the four-week UCMS exposure. Pretreatment of mice with minocycline completely blocked any upregulation. Concurrent with development of depression-like behaviors, the concentration of TNFα in plasma and the cerebral cortex increased remarkably. The tryptophan-degrading enzyme IDO was up-regulated in the cortex following UCMS exposure. Treatment of mice with minocycline, infliximab or 1-MT prevented the development of depression-like behaviors. Furthermore, blockade of TNFα inhibited expression of IDO and protected cortical neurons from UCMS-induced damage. These results suggest that TNFα plays a critical role in mediating UCMS-induced depression through up-regulation of IDO and subsequent damage of cortical neurons.