RESUMO
Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.
Assuntos
Aminopiridinas , Autorreceptores , Hipocampo , Plasticidade Neuronal , Reconhecimento Fisiológico de Modelo , Piperidinas , Pirimidinas , Receptor 5-HT1A de Serotonina , Reconhecimento Psicológico , Agonistas do Receptor 5-HT1 de Serotonina , Aminopiridinas/farmacologia , Animais , Autorreceptores/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/fisiologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêuticoRESUMO
Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.
Assuntos
Diferenciação Celular , Doenças do Sistema Nervoso/patologia , Células Precursoras de Oligodendrócitos/patologia , Estresse Oxidativo , Animais , HumanosRESUMO
The high symptomatic and biological heterogeneity of major depressive disorder (MDD) makes it very difficult to find broadly efficacious treatments that work against all symptoms. Concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. The Research Domain Criteria (RDoC) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. Evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems RDoC domain. Cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. Psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. We propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. At the psychobiological level, we hypothesize that the negativity bias in MDD is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. Pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. Impairment in this process may underlie the negative cognitive bias in MDD by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. On the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. Together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. Based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in MDD.
Assuntos
Disfunção Cognitiva/fisiopatologia , Transtorno Depressivo Maior/tratamento farmacológico , Alucinógenos/uso terapêutico , Plasticidade Neuronal/fisiologia , Anedonia , Disfunção Cognitiva/psicologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Hipocampo/fisiopatologia , Humanos , Córtex Pré-Frontal/fisiopatologia , Psilocibina/uso terapêuticoRESUMO
Atypical antipsychotics fail to substantially improve cognitive impairment associated with schizophrenia (CIAS) and one strategy to improve it is to stimulate adult neurogenesis in hippocampus, because this structure is part of an altered circuitry that underlies aspects of CIAS. Deficits in hippocampal adult neurogenesis may disrupt cognitive processes that are dependent on newborn neurons, such as pattern separation (the formation of distinct representations of similar inputs). Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT(1A) receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus. We hypothesize that use of antipsychotics possessing 5-HT(1A) receptor agonist properties may protect against or attenuate CIAS by a dual mechanism: a favorable influence on adult neurogenesis that develops upon sustained drug treatment, and an increase in dopamine levels in the prefrontal cortex that starts upon acute treatment. This hypothesis is consistent with the beneficial properties of 5-HT(1A) activation reported from pilot clinical studies using 5-HT(1A) agonists as adjunct to antipsychotic treatments. Recent antipsychotics, including clozapine and aripiprazole, exhibit different levels of 5-HT(1A) receptor partial agonism and may, therefore, differentially elicit hippocampal adult neurogenesis and increases in prefrontal cortex dopamine. We suggest that comparative studies should elucidate correlations between effects of antipsychotics on adult neurogenesis and prefrontal cortex dopamine with effects on performance in translational cognitive tasks known to involve new born neurons, such as tasks involving pattern separation, and working memory tasks sensitive to prefrontal cortex dopamine levels.
Assuntos
Antipsicóticos/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Cognição/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Antipsicóticos/farmacologia , Cognição/fisiologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Esquizofrenia/complicações , Esquizofrenia/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
Excitatory amino acid transporters (EAATs) are important regulators of amino acid transport and in particular glutamate. Recently, more interest has arisen in these transporters in the context of neurodegenerative diseases. This calls for ways to modulate these targets to drive glutamate transport, EAAT2 and EAAT3 in particular. Several inhibitors (competitive and noncompetitive) exist to block glutamate transport; however, activators remain scarce. Recently, GT949 was proposed as a selective activator of EAAT2, as tested in a radioligand uptake assay. In the presented research, we aimed to validate the use of GT949 to activate EAAT2-driven glutamate transport by applying an innovative, impedance-based, whole-cell assay (xCELLigence). A broad range of GT949 concentrations in a variety of cellular environments were tested in this assay. As expected, no activation of EAAT3 could be detected. Yet, surprisingly, no biological activation of GT949 on EAAT2 could be observed in this assay either. To validate whether the impedance-based assay was not suited to pick up increased glutamate uptake or if the compound might not induce activation in this setup, we performed radioligand uptake assays. Two setups were utilized; a novel method compared to previously published research, and in a reproducible fashion copying the methods used in the existing literature. Nonetheless, activation of neither EAAT2 nor EAAT3 could be observed in these assays. Furthermore, no evidence of GT949 binding or stabilization of purified EAAT2 could be observed in a thermal shift assay. To conclude, based on experimental evidence in the present study GT949 requires specific assay conditions, which are difficult to reproduce, and the compound cannot simply be classified as an activator of EAAT2 based on the presented evidence. Hence, further research is required to develop the tools needed to identify new EAAT modulators and use their potential as a therapeutic target.
Assuntos
Transportador 2 de Aminoácido Excitatório , Ácido Glutâmico , Transportador 2 de Aminoácido Excitatório/metabolismo , Impedância Elétrica , Ácido Glutâmico/metabolismo , Transporte Biológico , Transportador 3 de Aminoácido Excitatório/metabolismoRESUMO
Kratom (Mitragyna speciosa) is a Southeast Asian plant containing various alkaloids that induce pharmacological effects in humans. In Western countries, online vendors sell a variety of different kratom strains which are marketed to have distinct effect profiles. However, as of yet such marketing claims are unsubstantiated, and therefore the current study investigated whether differently colored kratom products can induce distinct effects, as self-reported by users. Six hundred forty-four current kratom users were anonymously surveyed to compare the self-reported effects of and motivations for using kratom products sold as red, green, and white strains. Most of the survey respondents were customers of the same kratom vendor, the products of which had been analyzed for their alkaloid content by an independent laboratory. The survey respondents reported distinct subjective experiences for different kratom strains, in a manner congruent with common marketing descriptions. However, the product analyses revealed no significant cross-strain differences in alkaloid content, suggesting that the reported effect differences might be disproportionally influenced by marketing narratives and anecdotal reports. Future studies should engage a more diverse population and include kratom strains from various vendors. Controlled, blinded experiments could assess whether the reported effect differences stem from a placebo effect or from alternative factors, e.g., minor alkaloids and terpenes.
Assuntos
Mitragyna , Alcaloides de Triptamina e Secologanina , Humanos , Extratos VegetaisRESUMO
BACKGROUND: Although Post-SSRI Sexual Dysfunction (PSSD) has finally been recognized by the European Medicines Agency as a medical condition that can outlast discontinuation of SSRI and SNRI antidepressants, this condition is still largely unknown by patients, doctors, and researchers, and hence, poorly understood, underdiagnosed, and undertreated. OBJECTIVE: Becoming familiar with the symptomatology of PSSD and understanding the underlying mechanisms and treatment options. METHOD: We applied a design thinking approach to innovation to 1) provide insights into the medical condition as well as the personal needs and pains of a targeted patient; and 2) generate ideas for new solutions from the perspective of this particular patient. These insights and ideas informed a literature search on the potential pathophysiological mechanisms that could underlie the patient's symptoms. RESULTS: The 55-year-old male patient developed symptoms of low libido, delayed ejaculation, erectile dysfunction, 'brain zaps', overactive bladder and urinary inconsistency after discontinuation of the SNRI venlafaxine. In many of these symptoms a dysregulation in serotonergic activity has been implicated, with an important role of 5-HT1A receptor downregulation and possible downstream effects on neurosteroid and oxytocin systems. CONCLUSIONS: The clinical presentation and development of symptoms are suggestive of PSSD but need further clinical elaboration. Further knowledge of post-treatment changes in serotonergic - and possibly noradrenergic - mechanisms is required to improve our understanding of the clinical complaints and to inform appropriate treatment regimes.
Assuntos
Disfunção Erétil , Inibidores da Recaptação de Serotonina e Norepinefrina , Disfunções Sexuais Fisiológicas , Masculino , Humanos , Pessoa de Meia-Idade , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Disfunções Sexuais Fisiológicas/induzido quimicamente , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Antidepressivos/uso terapêutico , Disfunção Erétil/tratamento farmacológicoRESUMO
Central nervous system (CNS) drug discovery suffers from high attrition rates; translational neuroscience approaches aiming to reduce these high rates include the use of brain imaging technologies. However, there is a need to better understand what methods are being used and for what diseases and purposes. Our analysis of the literature found that magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) were the neuroimaging techniques used most often in clinical trials for the most prevalent CNS diseases: Alzheimer's disease (AD), Parkinson's disease (PD), depression, and schizophrenia. Moreover, the number of initiated clinical trials using MRI, PET, and SPECT increased over the period 1981-2021. Such insights indicate that the significant increase in the use of neuroimaging studies could decrease the attrition of novel drug candidates in late clinical development.
Assuntos
Neuroimagem , Ciência Translacional Biomédica , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , EncéfaloRESUMO
To develop therapies for Alzheimer's disease, we need accurate in vivo diagnostics. Multiple proteomic studies mapping biomarker candidates in cerebrospinal fluid (CSF) resulted in little overlap. To overcome this shortcoming, we apply the rarely used concept of proteomics meta-analysis to identify an effective biomarker panel. We combine ten independent datasets for biomarker identification: seven datasets from 150 patients/controls for discovery, one dataset with 20 patients/controls for down-selection, and two datasets with 494 patients/controls for validation. The discovery results in 21 biomarker candidates and down-selection in three, to be validated in the two additional large-scale proteomics datasets with 228 diseased and 266 control samples. This resulting 3-protein biomarker panel differentiates Alzheimer's disease (AD) from controls in the two validation cohorts with areas under the receiver operating characteristic curve (AUROCs) of 0.83 and 0.87, respectively. This study highlights the value of systematically re-analyzing previously published proteomics data and the need for more stringent data deposition.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Proteômica/métodos , Biomarcadores/líquido cefalorraquidiano , Curva ROCRESUMO
Understanding the interface between opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) is challenging. By use of a dimensional framework, such as research domain criteria, convergent and targetable neurobiological processes in OUD-PTSD comorbidity can be identified. We hypothesise that, in OUD-PTSD, circuitry that is implicated in two research domain criteria systems (ie, negative valence and cognitive control) underpins dysregulation of incentive salience, negative emotionality, and executive function. We also propose that the OUD-PTSD state might be systematically investigated with approaches outlined within a neuroclinical assessment framework for addictions and PTSD. Our dimensional analysis of the OUD-PTSD state shows how first-line therapeutic approaches (ie, partial µ-type opioid receptor [MOR1] agonism) modulate overlapping neurobiological and clinical features and also provides mechanistic rationale for evaluating polytherapeutic strategies (ie, partial MOR1 agonism, κ-type opioid receptor [KOR1] antagonism, and α-2A adrenergic receptor [ADRA2A] agonism). A combination of these therapeutic mechanisms is projected to facilitate recovery in patients with OUD-PTSD by mitigating negative valence states and enhancing executive control.
Assuntos
Encéfalo , Disfunção Cognitiva/fisiopatologia , Função Executiva , Rede Nervosa , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Recompensa , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/metabolismo , Comorbidade , Função Executiva/fisiologia , Humanos , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/metabolismo , Transtornos Relacionados ao Uso de Opioides/terapia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/terapiaRESUMO
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by cognitive, affective, and motor dysfunction. The main pathophysiological mechanisms are chronic neuroinflammation, hyper-phosphorylated tau (p-tau) accumulation and neurodegeneration. CTE is mostly caused by exposure to multiple mild traumatic brain injuries, placing people participating in, for example, high contact sports at increased risk. Currently, CTE can solely be diagnosed post mortem based on the spatial pattern of tau-accumulation. Herein, we review candidate imaging and molecular biomarkers for their sensitivity and specificity and we look whether these are sufficient for reliable ante mortem diagnosis. Of the imaging biomarkers, PET appears to have the best potential. Candidate fluid biomarkers consist of genes and proteins found in brain derived extracellular vesicles, as well as cerebrospinal fluid (CSF) p-tau levels. However, neither these biomarkers nor the imaging biomarkers have the discriminatory power to differentiate between CTE and other tauopathies, highlighting the need for further validation. Future research could incorporate machine learning methodologies to differentiate between the tau accumulation patterns detected by PET/fMRI in Alzheimer's and CTE patients. Additionally, proteomic and metabolomic profiling of CSF and plasma associated with chronic mild traumatic brain injuries could highlight potential biomarkers for identifying at risk patients.
Assuntos
Encefalopatia Traumática Crônica/diagnóstico , Biomarcadores/metabolismo , Encefalopatia Traumática Crônica/líquido cefalorraquidiano , Encefalopatia Traumática Crônica/genética , Vesículas Extracelulares/metabolismo , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Sensibilidade e Especificidade , Proteínas tau/metabolismoRESUMO
RATIONALE: Recent trials with psychedelics in major depressive disorder and treatment-resistant depression showed remarkable improvements in depressive symptoms that can last for up to several months after even a single administration. The lack of an appropriate placebo control group-as patients are often able to discriminate the subjective effects of the drug-and an incomplete understanding of the role of the hallucinogenic and mystical experience, hampers the interpretation of these therapeutic effects. OBJECTIVES: To control for these factors, we developed a translational framework based on establishing pharmacokinetic/pharmacodynamic (PK/PD) relationships in rodents and humans for hallucinogenic (i.e., discriminative stimulus effects in rodents and humans; head twitch responses in rodents; questionnaires in humans) and therapeutic effects. For the latter, we selected the pattern separation and attentional set-shifting tasks as measures for cognitive flexibility because of their high translational value. We predict that these PK/PD analyses will lead to a more objective evaluation of improvements in patients compared to relying only on the currently used self-reported questionnaires. We hypothesize that-if the role of the hallucinogenic experience is not central in the antidepressant effects of psychedelics-the ED50's for the therapeutic effects will be significantly lower than for the hallucinogenic and mystical effects. CONCLUSION: Our framework will help to inform future studies that aim at the elucidation of the mechanism(s) of action of psychedelics in depression, and the role of the acute subjective and/or hallucinogenic experience in their effects.
Assuntos
Transtorno Depressivo Maior , Alucinógenos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Alucinações/tratamento farmacológico , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Humanos , Dietilamida do Ácido Lisérgico/farmacologia , Psilocibina/farmacologia , Inquéritos e QuestionáriosRESUMO
Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC50 =3 nM) and hNET (IC50 =4 nM relative to hSERT(IC50 =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO50 (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction.
Assuntos
Dopamina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , 1-Naftilamina/análogos & derivados , Animais , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Camundongos , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a cluster of autoimmune rheumatic diseases occurring in children 16 years of age or less. While it is well-known that pain may be experienced during inflammatory and non-inflammatory states, much remains ambiguous regarding the molecular mechanisms that may drive JIA pain. Thus, in this pilot study, we explored the variability of the serum proteomes in relation to pain severity in a cohort of JIA patients. METHODS: Serum samples from 15 JIA patients (male and female, 12.7 ± 2.8 years of age) were assessed using liquid chromatography/mass spectrometry (LC/MS). Correlation analyses were performed to determine the relationships among protein levels and self-reported clinical pain severity. Additionally, how the expression of pain-associated proteins related to markers of inflammation (Erythrocyte Sedimentation Rate (ESR)) or morphological properties of the central nervous system (subcortical volume and cortical thickness) implicated in JIA were also evaluated. RESULTS: 306 proteins were identified in the JIA cohort of which 14 were significantly (p < 0.05) associated with clinical pain severity. Functional properties of the identified pain-associated proteins included but were not limited to humoral immunity (IGLV3.9), inflammatory response (PRG4) and angiogenesis (ANG). Associations among pain-associated proteins and ESR (IGHV3.9, PRG4, CST3, VWF, ALB), as well as caudate nucleus volume (BTD, AGT, IGHV3.74) and insular cortex thickness (BTD, LGALS3BP) were also observed. CONCLUSIONS: The current proteomic findings suggest both inflammatory- and non-inflammatory mediated mechanisms as potential factors associated with JIA pain. Validation of these preliminary observations using larger patient cohorts and a longitudinal study design may further point to novel serologic markers of pain in JIA.
Assuntos
Artrite Juvenil/sangue , Biomarcadores/sangue , Inflamação/sangue , Adolescente , Criança , Feminino , Humanos , Masculino , Medição da Dor , Projetos Piloto , ProteômicaRESUMO
BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin. OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD). METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts. RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor. CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.
Assuntos
Finasterida , Disfunções Sexuais Fisiológicas , Adolescente , Antidepressivos/efeitos adversos , Criança , Finasterida/efeitos adversos , Humanos , Isotretinoína/efeitos adversos , Masculino , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Disfunções Sexuais Fisiológicas/induzido quimicamente , Disfunções Sexuais Fisiológicas/diagnóstico , Disfunções Sexuais Fisiológicas/psicologiaRESUMO
The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/química , Quinolinas/química , Inibidores Seletivos de Recaptação de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos/metabolismo , Quinolinas/síntese química , Quinolinas/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaRESUMO
The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.
Assuntos
Aminas/síntese química , Inibidores da Captação de Dopamina , Desenho de Fármacos , Metano/síntese química , Norepinefrina , Serotonina , Aminas/química , Aminas/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Ciclização , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/farmacologia , Concentração Inibidora 50 , Metano/química , Metano/farmacologia , Camundongos , Estrutura Molecular , Norepinefrina/síntese química , Norepinefrina/química , Norepinefrina/farmacologia , Ratos , Serotonina/síntese química , Serotonina/química , Serotonina/farmacologia , EstereoisomerismoRESUMO
Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC(50) ≤ 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.
Assuntos
Aminas/síntese química , Inibidores da Captação de Dopamina , Desenho de Fármacos , Norepinefrina , Serotonina , Aminas/química , Aminas/farmacologia , Animais , Ciclização , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/farmacologia , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Norepinefrina/síntese química , Norepinefrina/química , Norepinefrina/farmacologia , Serotonina/síntese química , Serotonina/química , Serotonina/farmacologia , EstereoisomerismoRESUMO
The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.
Assuntos
Naftalenos/síntese química , Naftalenos/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Modelos Animais de Doenças , Dopamina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Camundongos , Norepinefrina/metabolismo , Serotonina/metabolismoRESUMO
INTRODUCTION: Pain is prevalent in juvenile idiopathic arthritis (JIA). Unknowns regarding the biological drivers of pain complicate therapeutic targeting. We employed neuroimaging to define pain-related neurobiological features altered in JIA. METHODS: 16 male and female JIA patients (12.7 ± 2.8 years of age) on active treatment were enrolled, together with age- and sex-matched controls. Patients were assessed using physical examination, clinical questionnaires, musculoskeletal MRI, and structural neuroimaging. In addition, functional magnetic resonance imaging (fMRI) data were collected during the resting-state, hand-motor task performance, and cold stimulation of the hand and knee. RESULTS: Patients with and without pain and with and without inflammation (joint and systemic) were evaluated. Pain severity was associated with more physical stress and poorer cognitive function. Corrected for multiple comparisons, morphological analysis revealed decreased cortical thickness within the insula cortex and a negative correlation between caudate nucleus volume and pain severity. Functional neuroimaging findings suggested alteration within neurocircuitry structures regulating emotional pain processing (anterior insula) in addition to the default-mode and sensorimotor networks. CONCLUSIONS: Patients with JIA may exhibit changes in neurobiological circuits related to pain. These preliminary findings suggest mechanisms by which pain could potentially become dissociated from detectable joint pathology and persist independently of inflammation or treatment status.