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BACKGROUND: Chronic hand eczema (CHE) is a burdensome disease, and new well-documented, safe and efficacious treatments are warranted. In a recent CHE phase IIa trial, the pan-Janus kinase (JAK) inhibitor delgocitinib in an ointment formulation was found to be efficacious and well tolerated. OBJECTIVES: This trial assessed the dose response, efficacy and safety of delgocitinib cream in CHE. METHODS: In this double-blind, phase IIb dose-ranging trial, adults with CHE and a recent history of inadequate response or contraindication to topical corticosteroids were randomized to delgocitinib cream 1, 3, 8, 20 mg g-1 or vehicle treatment twice daily for 16 weeks. The primary endpoint was the Investigator's Global Assessment for CHE (IGA-CHE) treatment success [0 (clear) or 1 (almost clear) with a ≥ two-point improvement from baseline to week 16]. Secondary endpoints were the time to IGA-CHE treatment success and changes in Hand Eczema Severity Index (HECSI); other endpoints were itch and pain numerical rating scale (NRS) scores, and Patient's Global Assessment (PaGA) at week 16. RESULTS: Patients (n = 258) were randomized 1 : 1 : 1 : 1 : 1 to delgocitinib cream 1, 3, 8, 20 mg g-1 or vehicle. A significant dose-response relationship was established for IGA-CHE (P < 0.025). IGA-CHE treatment success at week 16 was achieved in 21.2% (1 mg g-1 ), 7.8% (3 mg g-1 ), 36.5% (8 mg g-1 ), 37.7% (20 mg g-1 ) and 8.0% (vehicle) of patients. Delgocitinib 8 and 20 mg g-1 showed a treatment effect against vehicle (P < 0.001). Similarly, there were improvements in HECSI, itch and pain NRS scores, and PaGA. Delgocitinib cream was well tolerated with the majority of adverse events being mild or moderate and considered unrelated to treatment. The most frequently reported adverse events were nasopharyngitis (17.3-29.4% in delgocitinib groups vs. 40% in vehicle group), eczema (5.8-11.3% in delgocitinib groups vs. 16.0% in vehicle group) and headache (3.8-11.5% in delgocitinib groups vs. 4.0% in vehicle group). CONCLUSIONS: In this trial, delgocitinib cream showed a dose-response relationship in terms of efficacy and was well tolerated.
Assuntos
Dermatite Atópica , Eczema , Inibidores de Janus Quinases , Adulto , Dermatite Atópica/tratamento farmacológico , Método Duplo-Cego , Eczema/induzido quimicamente , Eczema/tratamento farmacológico , Emolientes/uso terapêutico , Humanos , Imunoglobulina A , Dor/induzido quimicamente , Prurido/induzido quimicamente , Pirróis , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
SCOPE: Probiotics exert immunomodulatory effects and may influence tryptophan metabolism in the host. Deficiency of nutrients related to C1 metabolism might stimulate inflammation by enhancing the kynurenine pathway. This study used Sprague Dawley rats to investigate whether a methyl-deficient diet (MDD) may influence tryptophan/kynurenine pathways and cytokines and whether probiotics can mitigate these effects. METHODS AND RESULTS: Rats are fed a control or MDD diet. Animals on the MDD diet received vehicle, probiotics (L. helveticus R0052 and B. longum R0175), choline, or probiotics + choline for 10 weeks (n = 10 per group). Concentrations of plasma kynurenine metabolites and the methylation and inflammatory markers in plasma and liver are measured. RESULTS: MDD animals (vs controls) show upregulation of plasma kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyxanthranilic acid, quinolinic acid, nicotinic acid, and nicotinamide (all p < 0.05). In the MDD rats, the probiotics (vs vehicle) cause lower anthranilic acid and a trend towards lower kynurenic acid and picolinic acid. Compared to probiotics alone, probiotics + choline is associated with a reduced enrichment of the bacterial strains in cecum. The interventions have no effect on inflammatory markers. CONCLUSIONS: Probiotics counterbalance the effect of MDD diet and downregulate downstream metabolites of the kynurenine pathway.
Assuntos
Deficiência de Colina/metabolismo , Cinurenina/metabolismo , Probióticos/farmacologia , Animais , Colina/administração & dosagem , Deficiência de Ácido Fólico/metabolismo , Masculino , Metionina/deficiência , Metilação , Ratos , Ratos Sprague-Dawley , Triptofano/metabolismoRESUMO
Several studies have reported beneficial effects of probiotics on behavior and stress in humans and animals. The multi-strain probiotic product Ecologic® Barrier has shown antidepressant-like effects in rats when given in combination with high-fat diet. To circumvent the need for high-fat diet for future clinical use, the present study aimed to potentiate the behavioral effects of Ecologic® Barrier by developing a customized product that includes four additional bacterial species known to be associated with depression. Flinders Sensitive Line (FSL) rats, an animal model of depression, were randomized to receive vehicle, Ecologic® Barrier, or the customized product Ecologic® Barrier + 4. The control strain, Flinders Resistant Line rats, received vehicle to ascertain the depressive-like phenotype of FSL rats. Behavior was tested in the Elevated Plus Maze, Y-Maze, Novel Object Recognition Test, Open Field, and Forced Swim Test; HPA-axis reactivity was assessed by the Dexamethasone Suppression Test. Our results indicate that both probiotic products reduced open arm exploration in the Elevated Plus Maze, suggesting a reduction in risk-taking behavior. There were no intervention effects on cognition, locomotion, or depressive-like behavior. Moreover, all intervention groups had similar plasma corticosterone concentrations following the Dexamethasone Suppression Test. There was no difference between the two probiotic products, suggesting that the addition of four bacterial strains to Ecologic® Barrier did not potentiate its effect. Future studies should further investigate the effects of probiotics on risk-taking behavior and gain more mechanistic insights by studying individual strains and their cumulative contributions to the overall effect of a multi-strain product.
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Depressão/dietoterapia , Aprendizagem em Labirinto/fisiologia , Probióticos/uso terapêutico , Assunção de Riscos , Animais , Peso Corporal/fisiologia , Corticosterona/sangue , Depressão/sangue , Dexametasona/farmacologia , Ingestão de Líquidos , Ingestão de Alimentos , Comportamento Exploratório/fisiologia , Locomoção/fisiologia , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos , Ratos Sprague-Dawley , Reconhecimento Psicológico/fisiologia , Natação/psicologiaRESUMO
RATIONALE: The gut microbiota is increasingly recognized as a potential mediator of psychiatric diseases. Depressed patients have been shown to have a different microbiota composition compared with healthy controls, and several lines of research now aim to restore this dysbiosis. To develop novel treatments, preclinical models may provide novel mechanistic insights. OBJECTIVE AND METHODS: We characterized the gut microbiota of male adult Flinders sensitive line (FSL) rats, an animal model of depression, and their controls, Flinders resistant line (FRL) rats using 16S rRNA amplicon sequencing. Moreover, we performed fecal microbiota transplantation (using saline or pooled FRL/FSL feces) to study if the potential strain-specific differences could be transferred from one strain to the other, and if these differences were reflected in their depressive-like behavior in the forced swim test. RESULTS: FSL rats tended to have lower bacterial richness and altered relative abundances of several bacterial phyla, families, and species, including higher Proteobacteria and lower Elusimicrobia and Saccharibacteria. There was a clear separation between FRL and FSL rat strains, but no effect of treatment, i.e., the bacterial composition of FSL rats receiving FRL feces was still more similar to FSL and not FRL rats. Similarly, the transplantation did not reverse behavioral differences in the forced swim test, although FSL feces significantly increased immobility compared with saline. CONCLUSIONS: Our study showed that the gut microbiota composition of the depressive-like rats markedly differed from their controls, which may be of value for future microbiota-targeted work in this and similar animal models.
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Depressão/microbiologia , Depressão/psicologia , Modelos Animais de Doenças , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Animais , Depressão/genética , Masculino , RNA Ribossômico 16S/genética , Ratos , Ratos Transgênicos , Natação/fisiologia , Natação/psicologiaRESUMO
INTRODUCTION: Major depressive disorder is the leading source of disability globally and current pharmacological treatments are less than adequate. Animal models such as the Flinders Sensitive Line (FSL) rats are used to mimic aspects of the phenotype in the human disorder and to characterise candidate antidepressant agents. Communication between the gut microbiome and the brain may play an important role in psychiatric disorders such as depression. Interventions targeting the gut microbiota may serve as potential treatments for depression, and this drives increasing research into the effect of probiotics and prebiotics in neuropsychiatric disorders. Prebiotics, galacto-oligosaccharides and fructooligosaccharides that stimulate the activity of gut bacteria have been reported to have a positive impact, reducing anxiety and depressive-like phenotypes and stress-related physiology in mice and rats, as well as in humans. Bimuno, the commercially available beta-galacto-oligosaccharide, has been shown to increase gut microbiota diversity. AIM: Here, we aim to investigate the effect of Bimuno on rat anxiety-like and depressive-like behaviour and gut microbiota composition in the FSL model, a genetic model of depression, in comparison to their control, the Flinders Resistant Line (FRL) rats. METHODS: Sixty-four male rats aged 5-7 weeks, 32 FSL and 32 FRL rats, will be randomised to receive Bimuno or control (4 g/kg) daily for 4 weeks. Animals will be tested by an experimenter unaware of group allocation on the forced swim test to assessed depressive-like behaviour, the elevated plus maze to assess anxiety-like behaviour and the open field test to assess locomotion. Animals will be weighed and food and water intake, per kilogram of bodyweight, will be recorded. Faeces will be collected from each animal prior to the start of the experiment and on the final day to assess the bacterial diversity and relative abundance of bacterial genera in the gut. All outcomes and statistical analysis will be carried out blinded to group allocation, group assignments will be revealed after raw data have been uploaded to Open Science Framework. Two-way analysis of variance will be carried out to investigate the effect of treatment (control or prebiotic) and strain (FSL or FRL) on depressive-like and anxiety-like behaviours.
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Depression is associated with dysregulation of methyl group metabolism such as low S-adenosylmethionine (SAM). We previously reported that Flinders Sensitive Line (FSL) rats, an animal model of depression, had lower concentrations of liver SAM than the control rats, Flinders Resistant Line (FRL) rats. The present study investigated if SAM supplementation may correct liver SAM and behavioral abnormalities in this model. Moreover, we compared one-carbon (C1) metabolites, neurotransmitters, and gastrointestinal (GI) transit in SAM-treated versus imipramine (IMI)-treated animals. FSL rats received vehicle, IMI, SAM, or IMI + SAM (n = 9-10 per group) once daily through oral gavage for 4 weeks; FRL rats received vehicle. Behavior was assessed using standard tests for locomotion, cognition, and depressive-like behavior. Monoamine neurotransmitters and C1 metabolites were measured using UHPLC-ECD and UPLC-MS/MS, respectively. Compared to FRL rats, FSLs had lower liver SAM, higher plasma serotonin, lower hippocampal dopamine and serotonin turnover, and faster GI transit. Behaviorally, FSL rats showed impaired cognitive performance as well as increased depressive-like behavior compared to FRLs. Coadministration of IMI and SAM seemed to have adverse effects on spatial memory. SAM or IMI administration did not reverse C1 metabolites, neurotransmitters, or GI transit in FSLs. Despite low liver SAM in FSL rats, orally administered SAM did not show antidepressant effects in this specific animal model of depression.
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Depressão/metabolismo , Imipramina/farmacologia , S-Adenosilmetionina/farmacologia , Animais , Antidepressivos/farmacologia , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Hipocampo/metabolismo , Imipramina/metabolismo , Masculino , Ratos , Ratos Endogâmicos , S-Adenosilmetionina/metabolismo , Serotonina/metabolismo , Memória Espacial/efeitos dos fármacosRESUMO
Neuropeptide S (NPS) has shown anxiolytic-like effects in rodents after acute administration, but its long-term effects remain unknown. Gene therapy enables the targeted delivery of DNA to cell nuclei, and recombinant adeno-associated viral (rAAV) vectors have been identified as suitable tools for stable overexpression. Thus, to explore the effects of long-term expression of NPS, the present study examined anxiety- and depressive-like effects after rAAV-mediated NPS overexpression in the rat amygdala. Compared to rats injected with an empty control vector (rAAV-Empty), rAAV-NPS treatment was associated with reduced anxiety-like behavior in the elevated plus maze and light-dark box, but did not affect depressive-like behavior in the forced swim test. Importantly, rAAV-NPS did not cause confounding effects on locomotion or bodyweight as opposed to currently used anxiolytic drugs. Immunohistochemical stainings revealed NPS-positive cells in the central and basolateral region of the amygdala in rAAV-NPS but not rAAV-Empty rats, indicating successful transduction. Our study provides novel evidence for sustained anxiolytic-like properties of NPS by transgenic overexpression. These data suggest that rAAV-NPS application deserves further attention as a potential treatment strategy for anxiety in humans.
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Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Depressão/metabolismo , Neuropeptídeos/metabolismo , Animais , Peso Corporal/fisiologia , Dependovirus , Modelos Animais de Doenças , Vetores Genéticos , Locomoção/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
SCOPE: Probiotics may influence one-carbon (C1) metabolism, neurotransmitters, liver function markers, or behavior. METHODS AND RESULTS: Male adult Flinders Sensitive Line rats (model of depression, FSL; n = 22) received Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (109 or 1010 colony-forming units per day) or vehicle for 10 weeks. The controls, Flinders Resistant Line rats (FRL, n = 8), only received vehicle. C1-related metabolites were measured in plasma, urine, and different tissues. Monoamine concentrations were measured in plasma, hippocampus, and prefrontal cortex. Vehicle-treated FSL rats had higher plasma concentrations of betaine, choline, and dimethylglycine, but lower plasma homocysteine and liver S-adenosylmethionine (SAM) than FRLs. FSL rats receiving high-dose probiotics had lower plasma betaine and higher liver SAM compared to vehicle-treated FSL rats. FSLs had higher concentrations of norepinephrine, dopamine, and serotonin than FRLs across various brain regions. Probiotics decreased plasma dopamine in FSLs in a dose-dependent manner. There were no detectable changes in liver function markers or behavior. CONCLUSIONS: Probiotics reduced the flow of methyl groups via betaine, increased liver SAM, and decreased plasma dopamine and norepinephrine. Since these changes in methylation and catecholamine pathways are known to be involved in several diseases, future investigation of the effect of probiotics is warranted.
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Antidepressivos/uso terapêutico , Bifidobacterium longum/crescimento & desenvolvimento , Depressão/terapia , Hipocampo/metabolismo , Lactobacillus helveticus/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Probióticos/uso terapêutico , Animais , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Comportamento Animal , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Depressão/sangue , Depressão/metabolismo , Depressão/urina , Dopamina/sangue , Dopamina/metabolismo , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/efeitos adversos , Antagonistas de Dopamina/uso terapêutico , Liofilização , Homocisteína/antagonistas & inibidores , Homocisteína/sangue , Fígado/metabolismo , Masculino , Metilação , Neurônios/metabolismo , Norepinefrina/antagonistas & inibidores , Norepinefrina/sangue , Norepinefrina/metabolismo , Probióticos/administração & dosagem , Probióticos/efeitos adversos , Distribuição Aleatória , Ratos Mutantes , S-Adenosilmetionina/antagonistas & inibidores , S-Adenosilmetionina/metabolismoRESUMO
N-methyl-D-aspartate receptor (NMDA-R) antagonists and nitric oxide inhibitors have shown promising efficacy in depression but commonly induce adverse events. To circumvent these, a more indirect disruption of the nitric oxide synthase/postsynaptic density protein 95 kDa complex at the NMDA-R has been proposed. This disruption can be achieved using small molecule inhibitors such as ZL006, which has attracted attention as ischemic stroke therapy in rodents and has been proposed as a potential novel treatment for depression. Based on this, our aim was to translate these findings to animal models of depression to elucidate antidepressant-like properties in more detail. In the present study, we administered ZL006 to two established animal models of depression and control rodents. Following treatment, we measured locomotion in the Open Field and depressive-like behavior in the Forced Swim Test and Tail Suspension Test. Our experimental designs included the use of different species (rats, mice), strains (Flinders Sensitive Line rats, Flinders Resistant Line rats, Wistar Kyoto rats, Wistar Hanover rats, Sprague Dawley rats, B6NTac mice), routes of administration (intraperitoneal, intracerebroventricular), times of administration (single injection, repeated injections), treatment regimens (acute, sustained), and doses (5, 10, 15, 50 mg/kg). ZL006 did not affect behavior in any of the described settings. On a molecular level, ZL006 significantly reduced total nitrate/nitrite concentrations in the cerebellum, supporting that it is capable of reducing nitric oxide metabolites in the brain. Future studies using different experimental parameters are needed to further investigate the behavioral profile of ZL006.
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Ácidos Aminossalicílicos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Benzilaminas/administração & dosagem , Depressão/genética , Depressão/psicologia , Ácidos Aminossalicílicos/farmacologia , Animais , Benzilaminas/farmacologia , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Predisposição Genética para Doença , Infusões Intraventriculares , Injeções Intraperitoneais , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Resultado do TratamentoRESUMO
Immunotherapy with the cytokine interferon-alpha (IFN-α) can induce symptoms of depression, and it is likely that the tryptophan-kynurenine pathway may be involved in this regard. In this study we investigated the effects of IFN-α on depression-like behaviour and central metabolites of the tryptophan-kynurenine pathway in rats. Secondly, we explored the modulating effects of an antidepressant (imipramine) and anti-inflammatory drug (celecoxib) on IFN-α-induced behavioural and pathophysiological changes in the brain. The following treatment groups were used: Control (saline), IFN-α (6×10(4)IU/kg s.c.), IFN-α+imipramine or IFN-α+celecoxib. Drugs were administered daily for 1 week. IFN-α treatment induced depression-like behaviour by increasing immobility in the forced swim test (FST), and decreased tryptophan levels in the brain. There was a trend for an increased kynurenine/tryptophan ratio, indicative of indoleamine 2,3-dioxygenase (IDO) activation, and increased quinolinic acid in the hippocampus. Imipramine decreased immobility in the FST, but did not reverse the IFN-α-induced changes in the tryptophan-kynurenine pathway. There was a trend for celecoxib to decrease immobility and to reverse the IFN-α-induced increase in the kynurenine/tryptophan ratio. Thus, our study provides further evidence for IFN-α-induced depression-like behaviour through central changes of the tryptophan-kynurenine pathway.