RESUMO
Nicotinamide adenine dinucleotide (NAD) is a cofactor in redox reactions and an essential mediator of energy metabolism. The redox balance between NAD+ and NADH affects various diseases, cell differentiation, and aging, and in recent years there has been a growing need for measurement techniques with improved accuracy. However, NAD(H) measurements, representing both NAD+ and NADH, have been limited by the compound's properties. We achieved highly sensitive simultaneous measurement of NAD+ and NADH under non-ion pairing, mobile phase conditions of water, or methanol containing 5 mM ammonium acetate. These were achieved using a simple pre-treatment and 7-min analysis time. Use of the stable isotope 13C5-NAD+ as an internal standard enabled validation close to BMV criteria and demonstrated the robustness of NAD(H) determination. Measurements using this method showed that brain NAD(H) levels correlate strongly with plasma NAD(H) levels in the same mouse, indicating that NAD(H) concentrations in brain tissue are reflected in plasma. As NAD(H) is involved in various neurodegenerative diseases and cerebral ischemia, as well as brain diseases such as mitochondrial myopathies, monitoring changes in NADH levels in plasma after drug administration will be useful for development of future diagnostics and therapeutics.
Assuntos
Encefalopatias , NAD , Camundongos , Animais , NAD/metabolismo , Cromatografia Líquida , Espectrometria de Massa com Cromatografia Líquida , Espectrometria de Massas em Tandem , Encéfalo/metabolismo , OxirreduçãoRESUMO
Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the precise mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring, and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8 (9)-EpETrE in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.
Assuntos
Transtorno Autístico/induzido quimicamente , Glicina/análogos & derivados , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Animais , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Glicina/efeitos adversos , Masculino , Camundongos , Gravidez , GlifosatoRESUMO
Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca2+ concentration-multiple calcium channel expression and ADP-ribose synthesis-were attenuated in Myh11ΔK/ΔK aortas. We suggest that the impairment of the Ca2+ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.
Assuntos
Aneurisma da Aorta Torácica , Cálcio , Camundongos , Animais , Cálcio/metabolismo , Multiômica , Aorta/metabolismo , Aneurisma da Aorta Torácica/metabolismo , Aorta Torácica/patologiaRESUMO
PLX5622, a brain-penetrant highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in the brain. Considering the role of microglia and gut microbiota in the brain homeostasis, this study was undertaken to investigate whether repeated intragastric administration of PLX5622 (65 mg/kg/day for consecutive 7 days) could affect the composition of gut microbiota and the concentration of short-chain fatty acids (SCFAs) in fresh feces of adult mice. Repeated administration of PLX5622 caused significant reductions of the expression of genes and proteins for microglial markers in the prefrontal cortex (PFC) and hippocampus compared to control mice although the elimination of brain's microglia was partial. There was a significant alteration in the ß-diversity of intestine microbiota in the PLX5622-treated group. Linear discriminant analysis effect size identified eight significant enriched bacteria as microbial markers for PLX5622-treated group. Repeated administration of PLX5622 affected the relative abundance of several bacteria at the genus and species levels. Furthermore, repeated administration of PLX5622 caused a significant change in lactic acid compared to control group. Interestingly, we found significant correlations between microglial markers in the brain and the relative abundance of several bacteria, suggesting microbiome-microglia crosstalk through the brain-gut axis. These data demonstrate that repeated administration of PLX5622 leads to an abnormal composition of the gut microbiota and lactic acid in adult mice. Therefore, abnormalities in the composition of gut microbiota after repeated treatment of PLX5622 should be considered for behavioral and biological functions in animals treated with CSF1R inhibitors.
Assuntos
Microbioma Gastrointestinal , Fator Estimulador de Colônias de Macrófagos , Compostos Orgânicos , Animais , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Compostos Orgânicos/farmacologiaRESUMO
Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.
Assuntos
Epóxido Hidrolases/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Animais , Epóxido Hidrolases/genética , Feminino , Camundongos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/prevenção & controle , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Esquizofrenia/induzido quimicamente , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/prevenção & controleRESUMO
The spleen is a large immune organ that plays a key role in the immune system. The precise molecular mechanisms underlying the relationship between the spleen and stress-related psychiatric disorders are unknown. Here we investigated the role of spleen in stress-related psychiatric disorders. FACS analysis was applied to determine the contribution of the spleen to susceptibility and resilience in mice that were subjected to chronic social defeat stress (CSDS). We found a notable increase in splenic volume and weight in CSDS-susceptible mice compared to control (no CSDS) mice and CSDS-resilient mice. The number of granulocytes, but not of T cells and B cells, in the spleen of susceptible mice was higher than in the spleen of both control and resilient mice. Interestingly, NKG2D (natural killer group 2, member D) expression in the spleen of CSDS-susceptible mice was higher than that in control mice and CSDS-resilient mice. In addition, NKG2D expression in the spleen of patients with depression was higher than that in controls. Both increased splenic weight and increased splenic NKG2D expression in CSDS-susceptible mice were ameliorated after a subsequent administration of (R)-ketamine. The present findings indicate a novel role of splenic NKG2D in stress susceptibility versus resilience in mice subjected to CSDS. Furthermore, abnormalities in splenic functions in CSDS-susceptible mice were ameliorated after subsequent injection of (R)-ketamine. Thus, the brain-spleen axis might, at least in part, contribute to the pathogenesis of stress-related psychiatric disorders such as depression.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/imunologia , Suscetibilidade a Doenças/imunologia , Ketamina/farmacologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/efeitos dos fármacos , Resiliência Psicológica , Derrota Social , Baço/efeitos dos fármacos , Baço/imunologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/imunologia , Animais , Antidepressivos/administração & dosagem , Autopsia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Ketamina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Lobo Parietal/imunologia , Baço/patologiaRESUMO
BACKGROUND: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion. METHODS: The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. RESULTS: The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. CONCLUSIONS: These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.
Assuntos
Anedonia/efeitos dos fármacos , Antibacterianos/farmacologia , Depressão/microbiologia , Lactobacillus , Limosilactobacillus reuteri , Nervo Vago/microbiologia , Animais , Depressão/sangue , Microbioma Gastrointestinal , Interleucina-6/sangue , Camundongos , Atividade Motora/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/microbiologiaRESUMO
BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) reduce depressive symptoms through an anti-inflammatory effect, and injection of both omega-3 PUFAs and estradiol (E2) induces antidepressant-like effects in rats by regulating the expression of inflammatory cytokines. The aims of this study were to examine the association of increased E2 during pregnancy with depressive symptoms and with inflammatory cytokines in women who were and were not supplemented with omega-3 PUFAs. METHODS: Pregnant women with Edinburgh Postnatal Depression Scale scores ≥9 were recruited at 12-24â¯weeks of gestation. The participants were randomly assigned to receive 1800â¯mg omega-3 fatty acids (containing 1206â¯mg eicosapentaenoic acid [EPA]) or placebo for 12â¯weeks. E2, omega-3 PUFAs, high-sensitivity C-reactive protein, interleukin-6, and adiponectin were measured at baseline and at the 12-week follow-up. Multivariable regression analyses were conducted to examine the association of the changes of E2 and omega-3 PUFAs with the changes in depressive symptoms and with the changes of inflammatory cytokines at follow-up by intervention group. RESULTS: Of the 108 participants in the trial, 100 (92.6%) completed the follow-up assessment including blood sampling. Multivariable regression analyses revealed that the increase of EPA and E2 was significantly associated with a decrease in depressive symptoms among the participants assigned to the omega-3 group, but not among those assigned to the placebo group. Neither E2 nor any PUFAs were associated with a change in inflammatory cytokines. CONCLUSION: Supplementation with EPA and increased levels of E2 during pregnancy might function together to alleviate antenatal depression through a mechanism other than anti-inflammation.
Assuntos
Ácidos Graxos Ômega-3 , Gestantes , Animais , Antidepressivos , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Estradiol , Feminino , Humanos , Plasma , Gravidez , RatosRESUMO
OBJECTIVE: Abnormalities in neurotransmission via N-methyl-D-aspartic acid receptor (NMDAR) play a role in the pathophysiology of neuropsychiatric disorders. The impact of repetitive transcranial magnetic stimulation (rTMS) on NMDAR-related amino acids remains unknown. We aim to investigate the effects of rTMS on NMDAR-related amino acids in serum of post-stroke patients. METHODS: Ninety-five consecutive post-stroke patients with upper limb hemiparesis were recruited. In 27 patients, the Beck Depression Inventory (BDI) score was 10 or higher. Twelve depressed patients underwent rehabilitation in combination with rTMS and 15 non-depressed patients underwent rehabilitation only without rTMS for 14 days. 1 Hz rTMS was applied to the primary motor area in the non-lesional hemisphere. BDI was conducted before and after treatment. Serum glutamine, glutamate, glycine, L-serine, and D-serine levels were measured before and after treatment. RESULTS: There were no differences between depressed patients and non-depressed patients in clinical characteristics, levels of the five amino acids in serum, and the ratio of amino acids. However, in 27 depressed patients there was a significant correlation between levels of glutamate in serum and BDI (ρ=0.428ãp=0.026). BDI decreased significantly in depressed patients after treatment with or without rTMS. D-serine decreased in the rehabilitation with rTMS group, but increased in the rehabilitation without rTMS group. L-serine increased in the rehabilitation with rTMS group, but decreased in the rehabilitation without rTMS group. CONCLUSIONS: The results suggest that rTMS can modulate NMDAR-related amino acids in blood, producing beneficial effects.
RESUMO
Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.
Assuntos
Depressão/tratamento farmacológico , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/genética , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Estresse Psicológico/genética , Animais , Antidepressivos/farmacologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/metabolismo , Humanos , Inflamação/complicações , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxilipinas/metabolismo , Compostos de Fenilureia/farmacocinética , Piperidinas/farmacocinética , Ratos Mutantes , Comportamento Social , Estresse Psicológico/tratamento farmacológicoRESUMO
Background: An imbalance in the inflammatory tumor necrosis factor system, including soluble tumor necrosis factor receptor 2 (sTNFR2), may contribute to the pathophysiology of schizophrenia. Methods: We measured the plasma levels of sTNFR2 in 256 healthy controls and 250 patients with schizophrenia including antipsychotic drug-free patients and treatment-resistant patients. We also explored the possible association between plasma sTNFR2 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition, the Wechsler Memory Scale-Revised, and the Rey Auditory Verbal Learning Test. An association between plasma sTNFR2 levels and hippocampal volume in controls and patients with schizophrenia was also investigated via MRI. Results: We found that the plasma levels of sTNFR2 were significantly higher in patients with schizophrenia, including both antipsychotic drug-free patients and treatment-resistant patients. We found a significant negative association between plasma sTNFR2 levels and cognitive performance in controls and patients with schizophrenia. Hippocampal volume was also negatively associated with plasma sTNFR2 levels in patients with schizophrenia. Conclusion: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased sTNFR2 levels are associated with a smaller hippocampal volume and cognitive impairment.
Assuntos
Disfunção Cognitiva/fisiopatologia , Hipocampo/patologia , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Esquizofrenia/sangue , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Adulto , Idoso , Disfunção Cognitiva/etiologia , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esquizofrenia/complicaçõesRESUMO
AIM: The aims of this study were to determine whether the serum levels of precursor brain-derived neurotrophic factor (proBDNF), mature BDNF (mBDNF), and matrix metalloproteinase-9 (MMP-9) are altered in patients with eating disorders (ED), including anorexia nervosa (AN) and bulimia nervosa (BN), and to explore whether those levels are associated with decision-making abilities. METHODS: Nineteen women with AN, 28 women with BN, and 22 age-matched healthy control women (HC) were enrolled in the current study. All participants had their decision-making abilities assessed using the Iowa Gambling Task (IGT). Their eating-related pathophysiology and depressive/anxiety symptoms were also evaluated. RESULTS: The MMP-9 level in AN was significantly lower than that in either BN or HC, but the serum levels of proBDNF and mBDNF did not differ among the three groups. Investigation of the serum levels of proBDNF and MMP-9 in patients with ED and controls revealed a significant correlation between them. In the BN, there were positive correlations between mBDNF level and IGT performance and also between MMP-9 level and IGT performance, but these correlations did not occur in AN. The MMP-9 level was positively associated with the Symptom Scale, one of the subscales of the Bulimic Investigatory Test, Edinburgh, only in AN. CONCLUSION: These results suggest that the serum level of MMP-9 plays a role in the pathophysiology of AN, and both the serum levels of mBDNF and MMP-9 may be associated with decision-making abilities in patients with BN.
Assuntos
Tomada de Decisões/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/sangue , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Metaloproteinase 9 da Matriz/sangue , Adolescente , Adulto , Fator Neurotrófico Derivado do Encéfalo/sangue , Feminino , Humanos , Testes Neuropsicológicos , Precursores de Proteínas/sangue , Adulto JovemRESUMO
Postnatal dexamethasone (DEX) therapy has been used to treat or prevent chronic lung disease after premature births. However, there are many reports of long-term negative neurodevelopmental sequelae following this treatment. In contrast, hydrocortisone (HYD), which has fewer neurodevelopment adverse effects, is used as an alternative for DEX. In this study, we report that neonatal DEX exposure (days 1-3) caused alterations of amino acids affecting N-methyl-d-aspartate (NMDA) receptor neurotransmission in mouse brains. Neonatal DEX, but not HYD, exposure (days 1-3) significantly decreased the GluN2B subunit of NMDA receptor in the hippocampus at juvenile and adult stages. Mice treated with DEX showed cognitive deficits, as well as anxiety and depressive-like behavior at juvenile and adult stages. In contrast, mice treated with HYD (days 1-3) showed no behavioral abnormalities at these stages. In the DEX suppression test, plasma levels of corticosterone in mice exposed neonatally to DEX and HYD were significantly higher at juvenile, but not adult stages. Pretreatment with Ro 63-1908, an antagonist at GluN2B subunit, 30min before each injection of DEX, prevented cognitive deficits, as well as anxiety and depressive-like behavior in juvenile and adult mice. Interestingly, subsequent repeated (days 29-33) administration of Ro 63-1908 or L701324, an antagonist of the glycine modulatory site on the NMDA receptor, significantly suppressed behavioral abnormalities in juvenile and adult mice after neonatal DEX exposure. These results indicate that neonatal DEX, but not HYD, exposure produced behavioral abnormalities in juvenile and adult mice by altering glutamatergic neurotransmission via the NMDA receptor. The NMDA receptor antagonists may prevent or treat these DEX-induced neonatal behavioral abnormalities in later life.
Assuntos
Ansiedade/induzido quimicamente , Transtornos Cognitivos/induzido quimicamente , Depressão/induzido quimicamente , Dexametasona/toxicidade , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Ansiedade/metabolismo , Química Encefálica , Transtornos Cognitivos/metabolismo , Depressão/metabolismo , Feminino , Lobo Frontal , Hipocampo/metabolismo , Hidrocortisona/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacosRESUMO
Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) has a detrimental effect on long-term kidney graft survival. However, the pathogenesis of TAC nephrotoxicity remains largely unknown. We explored it by focusing on metabolic changes in renal tissues. In this study, mice were separated into TAC and control groups (n = 5/group). TAC was administered to the TAC group (1 mg/kg/d for 28 days) subcutaneously. The control group was similarly treated with normal saline. Renal tissue metabolomes were evaluated. Renal fibrosis was observed only in the TAC group. Metabolomic analysis showed that carnitine and related metabolites were substantially lower in the TAC group than in the control group, presumably due to impaired biosynthesis and reabsorption. Low carnitine levels impair antioxidation in renal tissues and ß-oxidation in mitochondria, which may lead to renal tissue damage. This metabolomic analysis revealed that carnitine deficiency in renal tissue appears to explain TAC nephrotoxicity.
RESUMO
Accumulating evidence suggests a role of inflammation in the pathophysiology of a number of neuropsychiatric diseases. The second generation antibiotic drug minocycline has potent neuroprotective and anti-inflammatory effects. We reported that minocycline could attenuate behavioral abnormalities and dopaminergic neurotoxicity in mice after administration of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Furthermore, we reported that minocycline was effective in the animal models of schizophrenia. Moreover, a double-blind, placebo-control, cross-over study showed that minocycline was effective in the rewarding effects in healthy human subjects. In this article, we would like to discuss minocycline as a potential therapeutic drug for methamphetamine-related disorders.
Assuntos
Antibacterianos/uso terapêutico , Metanfetamina/toxicidade , Minociclina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Antibacterianos/química , Ensaios Clínicos como Assunto , Humanos , Minociclina/químicaRESUMO
This report describes a case of shock symptoms in a 72-year-old woman with epilepsy who had been in a state of polypharmacy, taking multiple antipsychotic drugs. After receiving a normal dose of periciazine, she exhibited impaired consciousness, hypothermia, and hypotension and was admitted to hospital. Despite poor response to vasopressors, conservative treatment led to gradual improvement. Subsequent pharmacokinetic analysis showed non-toxic blood concentrations of periciazine, suggesting that even small doses of phenothiazines could result in toxic symptoms. This case highlights the importance of monitoring for adverse reactions when prescribing multiple antipsychotic drugs, particularly in older polypharmacy patients.
RESUMO
(R, S)-ketamine has prophylactic antidepressant-like effects in rodents; however, the precise molecular mechanisms underlying its action remain unknown. Using RNA-sequencing analysis, we searched novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R, S)-ketamine. Pretreatment with (R)-ketamine (10 mg/kg, 6 days before) significantly ameliorated body weight loss, splenomegaly, and increased immobility time of forced swimming test in lipopolysaccharide (LPS: 1.0 mg/kg)-treated mice. RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent IPA (Ingenuity Pathway Analysis) revealed that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of (R)-ketamine. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated the increased gene expression of NFATc4 signaling (Nfatc4, Cd4, Cd79b, H2-ab1, H2-aa) in the PFC of LPS-treated mice. Furthermore, pretreatment with NFAT inhibitors (i.e., NFAT inhibitor and cyclosporin A) showed prophylactic effects in the LPS-treated mice. Similar to (R)-ketamine, gene knockdown of Nfatc4 gene by bilateral injection of adeno-associated virus (AAV) into the mPFC could elicit prophylactic effects in the LPS-treated mice. In conclusion, our data implicate a novel NFATc4 signaling pathway in the PFC underlying the prophylactic effects of (R)-ketamine for inflammation-related depression.
Assuntos
Ketamina , Animais , Antidepressivos , Depressão , Ketamina/farmacologia , Lipopolissacarídeos , Camundongos , Córtex Pré-Frontal , Linfócitos TRESUMO
AIMS: Acute lung injury (ALI) is an acute inflammatory disorder. However, the precise mechanisms underlying the pathology of ALI remain elusive. An increasing evidence suggests the role of the gut-microbiota axis in the pathology of lung injury. This study aimed to investigate whether antibiotic-induced microbiome depletion could affect ALI in mice after lipopolysaccharide (LPS) administration. MAIN METHODS: The effects of antibiotic cocktail (ABX) on ALI in the mice after intratracheally administration of LPS (5 mg/kg) were examined. Furthermore, 16s rRNA analysis and measurement of short-chain fatty acids in feces samples and metabolomics analysis of blood samples were performed. KEY FINDINGS: LPS significantly increased the interleukin-6 (IL-6) levels in the bronchoalveolar lavage fluid (BALF) of water-treated mice. Interestingly, an ABX significantly attenuated the LPS-induced increase in IL-6 in BALF and lung injury scores. Furthermore, ABX and/or LPS treatment markedly altered the α- and ß-diversity of the gut microbiota. There were significant differences in the α- and ß-diversity of the water + LPS group and ABX + LPS group. LEfSe analysis identified Enterococusfaecalis, Clostriumtertium, and Bacteroidescaecimyris as potential microbial markers for ABX + LPS group. Untargeted metabolomics analysis identified several plasma metabolites responsible for discriminating water + LPS group from ABX + LPS group. There were correlations between the relative abundance of the microbiome and plasma metabolites. Integrative network analysis showed correlations between IL-6 levels in BALF and several gut microbes (or plasma metabolites). SIGNIFICANCE: These data suggest that ABX-induced microbiome depletion could protect against LPS-induced ALI via the gut-microbiota-lung axis.
Assuntos
Lesão Pulmonar Aguda , Microbiota , Lesão Pulmonar Aguda/metabolismo , Animais , Antibacterianos , Líquido da Lavagem Broncoalveolar , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , ÁguaRESUMO
Psoriasis is a chronic, inflammatory skin disease. Although the precise etiology of psoriasis remains unclear, gut-microbiota axis might play a role in the pathogenesis of the disease. Here we investigated whether the composition of microbiota in the intestine and skin is altered in the imiquimod (IMQ)-treated mouse model of psoriasis. Topical application of IMQ to back skin caused significant changes in the composition of microbiota in the intestine and skin of IMQ-treated mice compared to control mice. The LEfSe algorithm identified the species Staphylococcus lentus as potential skin microbial marker for IMQ group. Furthermore, there were correlations for several microbes between the intestine and skin, suggesting a role of skin-gut-microbiota in IMQ-treated mice. Levels of succinic acid and lactic acid in feces from IMQ-treated mice were significantly higher than control mice. Moreover, the predictive functional analysis of the microbiota in the intestine and skin showed that IMQ caused alterations in several KEGG pathways. In conclusion, the current data indicated that topical application with IMQ to skin alters the composition of the microbiota in the gut and skin of host. It is likely that skin-gut microbiota axis plays a role in pathogenesis of psoriasis.
Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Imiquimode/farmacologia , Microbiota/efeitos dos fármacos , Animais , Dermatite/patologia , Modelos Animais de Doenças , Feminino , Imiquimode/metabolismo , Ácido Láctico/análise , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/microbiologia , Staphylococcus/metabolismo , Staphylococcus/patogenicidade , Ácido Succínico/análiseRESUMO
BACKGROUND: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF. METHODS: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age- and sex-matched controls. RESULTS: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples. LIMITATIONS: Sample sizes are relatively low. CONCLUSIONS: Our data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.