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1.
Eur Arch Psychiatry Clin Neurosci ; 273(1): 129-155, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35829812

RESUMO

Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine's and classical hallucinogens' antidepressant effect. The PROSPERO ID for this study is CRD42021249089.


Assuntos
Transtorno Depressivo Resistente a Tratamento , Alucinógenos , Ketamina , Humanos , Ketamina/farmacologia , Alucinógenos/uso terapêutico , Depressão/tratamento farmacológico , Antidepressivos/farmacologia , Transtorno Depressivo Resistente a Tratamento/terapia , Biomarcadores
2.
Cell Mol Neurobiol ; 42(1): 225-242, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33839994

RESUMO

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite ß-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.


Assuntos
Antidepressivos , Inibidores da Monoaminoxidase , Fármacos Neuroprotetores , Fenelzina , Animais , Antidepressivos/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Fenelzina/farmacologia , Ratos , Ratos Sprague-Dawley
3.
CNS Spectr ; : 1-14, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35837681

RESUMO

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

4.
Acta Neuropsychiatr ; 32(4): 177-185, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31791436

RESUMO

The past decade has seen a surge of reports and investigations into cases of autoimmune-mediated encephalitis. The increasing recognition of these disorders is especially of relevance to the fields of neurology and psychiatry. Autoimmune encephalitis involves antibodies against synaptic receptors, neuronal cell surface proteins and intracellular targets. These disorders feature prominent symptoms of cognitive impairment and behavioural changes, often associated with the presence of seizures. Early in the clinical course, autoimmune encephalitis may manifest as psychiatric symptoms of psychosis and involve psychiatry as an initial point of contact. Although commonly associated with malignancy, these disorders can present in the absence of an inciting neoplasm. The identification of autoimmune encephalitis is of clinical importance as a large proportion of individuals experience a response to immunotherapy. This review focuses on the current state of knowledge on n-methyl-d-aspartate (NMDA) receptor-associated encephalitis and limbic encephalitis, the latter predominantly involving antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the γ-aminobutyric acid (GABA)B receptor and leucine-rich glioma-inactivated 1 (LGI1) protein. In addition, we briefly describe anti-dopamine D2 receptor encephalitis. A summary of the literature will focus on common clinical presentations and course, diagnostic approaches and response to treatment. Since a substantial proportion of patients with autoimmune encephalitis exhibit symptoms of psychosis, the relevance of this disorder to theories of psychosis and schizophrenia will also be discussed.


Assuntos
Sintomas Afetivos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Encefalite/imunologia , Transtornos Mentais/imunologia , Neuroimunomodulação/imunologia , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/terapia , Encéfalo/imunologia , Encefalite/diagnóstico , Encefalite/terapia , Humanos , Prognóstico , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/imunologia , Transtornos Psicóticos/terapia , Receptores de Neurotransmissores/imunologia , Esquizofrenia/diagnóstico , Esquizofrenia/imunologia , Esquizofrenia/terapia
5.
J Neurochem ; 148(6): 761-778, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30613984

RESUMO

Inflammatory insult to the central nervous system (CNS) can lead to development of depression, and subsequently depression is the most frequent psychiatric comorbidity following ischemic stroke, often limiting recovery and rehabilitation in patients. The initiators of inflammatory pathways in the CNS are microglia activated in response to acute ischemic stress, and anti-depressants have been shown to have anti-inflammatory effects in the CNS, promoting neuronal survival following ischemic insult. We have previously shown that the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and citalopram promote neuronal survival after oxygen-glucose deprivation, an in vitro model of ischemia, by attenuating the release of glutamate and D-serine from activated microglia. Interestingly, we found that fluoxetine-treated microglial cultures contained fewer numbers of cells compared to other groups and hypothesized that fluoxetine and citalopram attenuated the release of glutamate and D-serine by promoting the apoptosis of microglia. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and SSRIs) on microglial apoptosis. Primary microglia were treated with 1 µg/mL lipopolysaccharide and/or 10 µM antidepressants, and various apoptotic markers were assayed. Fluoxetine and its metabolite norfluoxetine decreased protein levels in cell lysates, decreased cell viability of microglia, and increased the expression of the apoptotic marker cleaved-caspase 3 in microglia. Live/dead nuclear staining also showed that fluoxetine- or norfluoxetine-treated cultures contained greater numbers of dying microglial cells compared to vehicle-treated cultures. Cultures treated with citalopram, phenelzine, or imipramine showed no evidence of inducing microglial apoptosis. Our results demonstrate that fluoxetine and norfluoxetine induce the apoptotic death of microglia, which may serve as a mechanism to attenuate the release of glutamate and D-serine from activated microglia. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.


Assuntos
Apoptose/efeitos dos fármacos , Fluoxetina/farmacologia , Microglia/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Antidepressivos de Segunda Geração/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Fluoxetina/análogos & derivados , Microglia/patologia , Ratos , Ratos Sprague-Dawley
6.
Biochem Biophys Res Commun ; 511(2): 454-459, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803762

RESUMO

Biological sex exerts distinct influences on brain levels of the ß-amyloid (Aß) peptide in both clinical depression and Alzheimer disease (AD), yet studies in animal models focus primarily on males. We examined behavioral 'despair'/depression (using the tail-suspension test) and memory (using the novel object recognition task) in J20 (hAPPSwe/Ind) mice. Three month-old male (but not female) J20 mice exhibited less despair-like behavior, but more evidence of cognitive deficits. In young J20 mice, only soluble Aß peptides -primarily Aß(1-40)- were detected. There was no evidence of an effect on despair-like behavior in the six month-old J20 mice, although cognitive deficits were now evident in both sexes, and coincided with a greater proportion of the neurotoxic Aß(1-42) species (in soluble as well as insoluble fractions). This age-dependent shift in Aß peptide profile coincided with reduced expression of glycosylated species of ADAM-10 (α-secretase) and BACE1 (ß-secretase), and an increased co-immunoprecipitation of presenilin-1 with nicastrin (components of the γ-secretase complex). Sex-dependent changes in depression-related monoaminergic, e.g. serotonin and dopamine (but not noradrenaline), systems were evident already in young J20 mice. It is critical to acknowledge that sex-dependent APP-related phenotypes might differentially influence modifiable depression-related monoaminergic signalling at some of the earliest pathological stages of clinical AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Disfunção Cognitiva/patologia , Depressão/patologia , Fragmentos de Peptídeos/análise , Envelhecimento , Doença de Alzheimer/complicações , Animais , Encéfalo/patologia , Disfunção Cognitiva/complicações , Depressão/complicações , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos
7.
Can J Psychiatry ; 64(1): 18-29, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29685068

RESUMO

The focus on the ß-amyloid (Aß) peptide in clinical Alzheimer disease (AD) as well as in animal models of AD has perhaps biased our understanding of what contributes to the heterogeneity in disease onset and progression. Part of this heterogeneity could reflect the various neuropsychiatric risk factors that present with common symptomatology and can predispose the brain to AD-like changes. One such risk factor is depression. Animal models, particularly mouse models carrying variants of AD-related gene(s), many of which lead to an accumulation of Aß, suggest that a fundamental shift in depression-related monoaminergic systems (including serotonin and noradrenaline) is a strong indicator of the altered cellular function associated with the earlier(est) stages of AD-related pathology. These changes in monoaminergic neurochemistry could provide for relevant targets for intervention in clinical AD and/or could support a polypharmacy strategy, which might include the targeting of Aß, in vulnerable populations. Future studies must also include female mice as well as male mice in animal model studies on the relationship between depression and AD.


Assuntos
Doença de Alzheimer/complicações , Depressão/complicações , Modelos Animais de Doenças , Animais
8.
Can J Psychiatry ; 64(1): 5-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29742910

RESUMO

Schizophrenia is a heterogeneous psychiatric disorder that is poorly treated with current therapies. In this brief review, we provide an update regarding the use of animal models to study schizophrenia in an attempt to understand its aetiology and develop novel therapeutic strategies. Tremendous progress has been made developing and validating rodent models that replicate the aetiologies, brain pathologies, and behavioural abnormalities associated with schizophrenia in humans. Here, models are grouped into 3 categories-developmental, drug induced, and genetic-to reflect the heterogeneous risk factors associated with schizophrenia. Each of these models is associated with varied but overlapping pathophysiology, endophenotypes, behavioural abnormalities, and cognitive impairments. Studying schizophrenia using multiple models will permit an understanding of the core features of the disease, thereby facilitating preclinical research aimed at the development and validation of better pharmacotherapies to alter the progression of schizophrenia or alleviate its debilitating symptoms.


Assuntos
Modelos Animais de Doenças , Esquizofrenia/etiologia , Animais , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Esquizofrenia/terapia
9.
J Korean Med Sci ; 34(46): e297, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31779058

RESUMO

Accumulated evidence suggests that sporadic cases of Alzheimer's disease (AD) make up more than 95% of total AD patients, and diabetes has been implicated as a strong risk factor for the development of AD. Diabetes shares pathological features of AD, such as impaired insulin signaling, increased oxidative stress, increased amyloid-beta (Aß) production, tauopathy and cerebrovascular complication. Due to shared pathologies between the two diseases, anti-diabetic drugs may be a suitable therapeutic option for AD treatment. In this article, we will discuss the well-known pathologies of AD, including Aß plaques and tau tangles, as well as other mechanisms shared in AD and diabetes including reactive glia and the breakdown of blood brain barrier in order to evaluate the presence of any potential, indirect or direct links of pre-diabetic conditions to AD pathology. In addition, clinical evidence of high incidence of diabetic patients to the development of AD are described together with application of anti-diabetic medications to AD patients.


Assuntos
Doença de Alzheimer/patologia , Diabetes Mellitus Tipo 2/patologia , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Astrócitos/citologia , Astrócitos/metabolismo , Encéfalo/metabolismo , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Cloreto de Lítio/uso terapêutico , Pioglitazona/uso terapêutico
10.
Glia ; 65(10): 1590-1606, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28707358

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Neurosteroids are reported to exert anti-inflammatory effects in several neurological disorders. We investigated the expression and actions of the neurosteroid, dehydroepiandrosterone (DHEA), and its more stable 3ß-sulphated ester, DHEA-S, in MS and associated experimental models. CNS tissues from patients with MS and animals with experimental autoimmune encephalomyelitis (EAE) displayed reduced DHEA concentrations, accompanied by diminished expression of the DHEA-synthesizing enzyme CYP17A1 in oligodendrocytes (ODCs), in association with increased expression of inflammatory genes including interferon (IFN)-γ and interleukin (IL)-1ß. CYP17A1 was expressed variably in different human neural cell types but IFN-γ exposure selectively reduced CYP17A1 detection in ODCs. DHEA-S treatment reduced IL-1ß and -6 release from activated human myeloid cells with minimal effect on lymphocyte viability. Animals with EAE receiving DHEA-S treatment showed reduced Il1b and Ifng transcript levels in spinal cord compared to vehicle-treated animals with EAE. DHEA-S treatment also preserved myelin basic protein immunoreactivity and reduced axonal loss in animals with EAE, relative to vehicle-treated EAE animals. Neurobehavioral deficits were reduced in DHEA-S-treated EAE animals compared with vehicle-treated animals with EAE. Thus, CYP17A1 expression in ODCs and its product DHEA were downregulated in the CNS during inflammatory demyelination while DHEA-S provision suppressed neuroinflammation, demyelination, and axonal injury that was evident as improved neurobehavioral performance. These findings indicate that DHEA production is an immunoregulatory pathway within the CNS and its restoration represents a novel treatment approach for neuroinflammatory diseases.


Assuntos
Sistema Nervoso Central/patologia , Citocinas/metabolismo , Esclerose Múltipla/patologia , Neurotransmissores/metabolismo , Oligodendroglia/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Desidroepiandrosterona/metabolismo , Desidroepiandrosterona/uso terapêutico , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Feto/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esteroide 17-alfa-Hidroxilase/metabolismo
11.
Retrovirology ; 14(1): 47, 2017 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-29037245

RESUMO

BACKGROUND: In patients with HIV/AIDS receiving antiretroviral therapy (ART), HIV-1 persistence in brain tissue is a vital and unanswered question. HIV-1 infects and replicates in resident microglia and trafficking macrophages within the brain although the impact of individual ART drugs on viral infection within these brain myeloid cells is unknown. Herein, the effects of contemporary ART drugs were investigated using in vitro and in vivo models of HIV-1 brain infection. RESULTS: The EC50 values for specific ART drugs in HIV-infected human microglia were significantly higher compared to bone marrow-derived macrophages and peripheral blood mononuclear cells. Intracellular ART drug concentrations in microglia were significantly lower than in human lymphocytes. In vivo brain concentrations of ART drugs in mice were 10 to 100-fold less in brain tissues compared with plasma and liver levels. In brain tissues from untreated HIV-infected BLT mice, HIV-encoded RNA, DNA and p24 were present in human leukocytes while ART eradicated viral RNA and DNA in both brain and plasma. Interruption of ART resulted in detectable viral RNA and DNA and increased human CD68 expression in brains of HIV-infected BLT mice. In aviremic HIV/AIDS patients receiving effective ART, brain tissues that were collected within hours of last ART dosing showed HIV-encoded RNA and DNA with associated neuroinflammatory responses. CONCLUSIONS: ART drugs show variable concentrations and efficacies in brain myeloid cells and tissues in drug-specific manner. Despite low drug concentrations in brain, experimental ART suppressed HIV-1 infection in brain although HIV/AIDS patients receiving effective ART had detectable HIV-1 in brain. These findings suggest that viral suppression in brain is feasible but new approaches to enhancing ART efficacy and concentrations in brain are required for sustained HIV-1 eradication from brain.


Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Encéfalo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1 , Latência Viral/efeitos dos fármacos , Adulto , Animais , Fármacos Anti-HIV/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/virologia , Técnicas de Cultura de Células , Modelos Animais de Doenças , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microglia/efeitos dos fármacos , Microglia/virologia , Pessoa de Meia-Idade , Replicação Viral/efeitos dos fármacos
12.
Amino Acids ; 49(1): 57-65, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27686223

RESUMO

A review of studies on the body fluid levels of neuroactive amino acids, including glutamate, glutamine, taurine, gamma-aminobutyric acid (GABA), glycine, tryptophan, D-serine, and others, in autism spectrum disorders (ASD) is given. The results reported in the literature are generally inconclusive and contradictory, but there has been considerable variation among the previous studies in terms of factors such as age, gender, number of subjects, intelligence quotient, and psychoactive medication being taken. Future studies should include simultaneous analyses of a large number of amino acids [including D-serine and branched-chain amino acids (BCAAs)] and standardization of the factors mentioned above. It may also be appropriate to use saliva sampling to detect amino acids in ASD patients in the future-this is noninvasive testing that can be done easily more frequently than other sampling, thus providing more dynamic monitoring.


Assuntos
Aminoácidos/metabolismo , Transtorno do Espectro Autista/metabolismo , Líquidos Corporais/química , Transtorno do Espectro Autista/fisiopatologia , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Glicina/metabolismo , Humanos , Serina/metabolismo , Taurina/metabolismo , Triptofano/metabolismo , Ácido gama-Aminobutírico/metabolismo
13.
J Neuroinflammation ; 13(1): 142, 2016 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-27282914

RESUMO

BACKGROUND: Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear. We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS. METHODS: We used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs. RESULTS: Mice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity-but did not significantly attenuate the loss of PNNs. CONCLUSIONS: These findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.


Assuntos
Encefalomielite Autoimune Experimental/complicações , Neuralgia/etiologia , Neuralgia/patologia , Limiar da Dor/fisiologia , Córtex Somatossensorial/patologia , Sinapses/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Feminino , Adjuvante de Freund/toxicidade , Hiperalgesia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Neuralgia/tratamento farmacológico , Neurônios/citologia , Neurônios/metabolismo , Neurônios/ultraestrutura , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Parvalbuminas/metabolismo , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Fenelzina/farmacologia , Fenelzina/uso terapêutico , Lectinas de Plantas/metabolismo , Receptores de N-Acetilglucosamina/metabolismo , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/ultraestrutura , Sinapses/patologia , Sinapses/ultraestrutura
14.
Nutr Neurosci ; 19(8): 337-345, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26086200

RESUMO

OBJECTIVES: Western-style diets high in saturated fat and refined carbohydrate have been shown to alter gut microbiota as well as being associated with altered behaviour and learning ability. The objective of this study was to determine the effects of short-term intake of a Western-style diet on intestinal cytokine expression, tryptophan metabolism, and levels of neurotransmitters in the brain. METHODS: At 7 weeks of age, 129S1/SvImJ mice were placed on a standard chow or Western-style diet (fat 33%, refined carbohydrates 49%) for 3 weeks. Anxiety-like behaviour was assessed by the latency to step-down test and exploration assessed in a Barnes maze. Neurotransmitter levels in forebrains were analysed by high-pressure liquid chromatography. Liver metabolism was examined by 1H nuclear magnetic resonance (NMR). Cytokine expression in the intestine was measured using MesoScale discovery platform. mRNA levels of tryptophan hydroxylase (Tph) and indoleamine 2,3-dioxygenase (IDO) in the brain and intestine were measured using qPCR. RESULTS: Results showed that mice fed the Western diet displayed reduced exploratory and anxiety-like behaviour. Anxiolytic effects correlated with increased hippocampal brain-derived neurotrophic factor (BDNF) and tryptophan levels. Brain serotonin was not altered. These changes were associated with reduced expression of small intestinal indoleamine 2,3-dioxygenase, a tryptophan-processing enzyme. Western diet-fed mice exhibited low-grade systemic and intestinal inflammation along with altered liver metabolic profiles. DISCUSSION: In conclusion, diets high in fat and refined sugar are associated with increased levels of brain BDNF and tryptophan and decreased exploratory and anxiety-like behaviour. These behavioural changes correlated with altered intestinal tryptophan metabolism and liver metabolic profiles.


Assuntos
Ansiedade/etiologia , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Doenças Metabólicas/etiologia , Prosencéfalo/metabolismo , Triptofano/metabolismo , Animais , Ansiedade/imunologia , Ansiedade/metabolismo , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Comportamento Exploratório , Regulação Enzimológica da Expressão Gênica , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mucosa Intestinal/enzimologia , Mucosa Intestinal/imunologia , Intestino Delgado/enzimologia , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Fígado/imunologia , Fígado/metabolismo , Masculino , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Camundongos da Linhagem 129 , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/enzimologia , Neurônios/imunologia , Neurônios/metabolismo , Prosencéfalo/enzimologia , Prosencéfalo/imunologia , Organismos Livres de Patógenos Específicos , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
15.
BMC Neurosci ; 16: 9, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25887360

RESUMO

BACKGROUND: Better treatments for schizophrenia are urgently needed. The therapeutic use of the nitric oxide (NO)-donor sodium nitroprusside (SNP) in patients with schizophrenia has shown promising results. The role of NO in schizophrenia is still unclear, and NO modulation is unexplored in ketamine (KET) animal models to date. In the present study, we compared the behavioral effects of pre- and post-treatment with SNP, glyceryl trinitrate (GTN), and methylene blue (MB) in the acute KET animal model of schizophrenia. The present study was designed to test whether acute SNP, GTN, and MB treatment taken after (therapeutic effect) or before (preventive effect) a single KET injection would influence the behavior of rats in the sucrose preference test, object recognition task and open field. RESULTS: The results showed that KET induced cognitive deficits and hyperlocomotion. Long- term memory improvement was seen with the therapeutic GTN and SNP treatment, but not with the preventive one. MB pretreatment resulted in long-term memory recovery. GTN pre-, but not post-treatment, tended to increase vertical and horizontal activity in the KET model. Therapeutic and preventive SNP treatment consistently decreased KET-induced hyperlocomotion. CONCLUSION: NO donors - especially SNP - are promising new pharmacological candidates in the treatment of schizophrenia. In addition, we showed that the potential impact of NO-related compounds on KET-induced behavioral changes may depend on the temporal window of drug administration.


Assuntos
Antipsicóticos/farmacologia , Azul de Metileno/farmacologia , Nitroglicerina/farmacologia , Nitroprussiato/farmacologia , Esquizofrenia/tratamento farmacológico , Doença Aguda , Animais , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Sacarose Alimentar/administração & dosagem , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Masculino , Atividade Motora , Doadores de Óxido Nítrico/farmacologia , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Percepção Gustatória/efeitos dos fármacos , Resultado do Tratamento
16.
Int J Neuropsychopharmacol ; 19(1)2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26316187

RESUMO

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. METHODS: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. RESULTS: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. CONCLUSIONS: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.


Assuntos
Encéfalo/efeitos dos fármacos , Moclobemida/farmacologia , Inibidores da Monoaminoxidase/farmacocinética , Monoaminoxidase/metabolismo , Fenelzina/farmacologia , Adulto , Encéfalo/diagnóstico por imagem , Isótopos de Carbono/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Harmina/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Adulto Jovem
17.
J Neurosci ; 33(38): 15285-94, 2013 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-24048857

RESUMO

The meso-striatal dopamine system influences responses to rewards and the motivation to seek them out. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex. Here we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy young people. Participants were 24 (17 male, 7 female; age 23.0 ± 6.2 years) stimulant drug-naive subjects who underwent PET [(11)C]raclopride scans with 0.3 mg/kg d-amphetamine orally and placebo, and an anatomical MRI scan for measuring cortical thickness. As expected, d-amphetamine produced significant reductions in [(11)C]raclopride binding potential in the striatum as a percentage of the value in the placebo condition. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. The association was strongest in the anterior part of the right lateral prefrontal cortex and bilateral supplementary motor area. A thicker cortex was correlated with a smaller dopamine response. Together, this work demonstrates in humans an association between cortical thickness and the striatal dopamine response to drugs of abuse. Although prefrontal regulation of striatal function has been well studied, it was unclear whether the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is.


Assuntos
Corpo Estriado/efeitos dos fármacos , Dextroanfetamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Individualidade , Córtex Pré-Frontal/anatomia & histologia , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Mapeamento Encefálico , Isótopos de Carbono/farmacocinética , Corpo Estriado/diagnóstico por imagem , Antagonistas de Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Neurológicos , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/diagnóstico por imagem , Racloprida/farmacocinética , Estatística como Assunto , Adulto Jovem
18.
J Neurophysiol ; 111(1): 145-63, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24068759

RESUMO

Spinal cord transection leads to elimination of brain stem-derived monoamine fibers that normally synthesize most of the monoamines in the spinal cord, including serotonin (5-hydroxytryptamine, 5-HT) synthesized from tryptophan by enzymes tryptophan hydroxylase (TPH, synthesizing 5-hydroxytryptophan, 5-HTP) and aromatic l-amino acid decarboxylase (AADC, synthesizing 5-HT from 5-HTP). Here we examine whether spinal cord caudal to transection remains able to manufacture and metabolize 5-HT. Immunolabeling for AADC reveals that, while most AADC is confined to brain stem-derived monoamine fibers in spinal cords from normal rats, caudal to transection AADC is primarily found in blood vessel endothelial cells and pericytes as well as a novel group of neurons (NeuN positive and GFAP negative), all of which strongly upregulate AADC with injury. However, immunolabeling for 5-HT reveals that there is no detectable endogenous 5-HT synthesis in any structure in the spinal cord caudal to a chronic transection, including in AADC-containing vessels and neurons, consistent with a lack of TPH. In contrast, when we applied exogenous 5-HTP (in vitro or in vivo), AADC-containing vessels and neurons synthesized 5-HT, which contributed to increased motoneuron activity and muscle spasms (long-lasting reflexes, LLRs), by acting on 5-HT2 receptors (SB206553 sensitive) located on motoneurons (TTX resistant). Blocking monoamine oxidase (MAO) markedly increased the sensitivity of the motoneurons (LLR) to 5-HTP, more than it increased the sensitivity of motoneurons to 5-HT, suggesting that 5-HT synthesized from AADC is largely metabolized in AADC-containing neurons and vessels. In summary, after spinal cord injury AADC is upregulated in vessels, pericytes, and neurons but does not endogenously produce 5-HT, whereas when exogenous 5-HTP is provided AADC does produce functional amounts of 5-HT, some of which is able to escape metabolism by MAO, diffuse out of these AADC-containing cells, and ultimately act on 5-HT receptors on motoneurons.


Assuntos
Descarboxilases de Aminoácido-L-Aromático/metabolismo , Serotonina/biossíntese , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Descarboxilases de Aminoácido-L-Aromático/genética , Tronco Encefálico/metabolismo , Feminino , Neurônios Motores/metabolismo , Especificidade de Órgãos , Pericitos/metabolismo , Ratos , Serotonina/metabolismo , Serotonina/farmacologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos
19.
J Neurosci Res ; 92(9): 1187-98, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24801011

RESUMO

Primary human fetal neurons and astrocytes (HFNs and HFAs, respectively) provide relevant cell types with which to study in vitro the mechanisms involved in various human neurological diseases, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. However, the limited availability of human fetal cells poses a significant problem for the study of these diseases when a human cell model system is required. Thus, generating a readily available alternative cell source with the essential features of human neurons and astrocytes is necessary. The human teratoma-derived NTera2/D1 (NT2) cell line is a promising tool from which both neuronal and glial cells can be generated. Nevertheless, a direct comparison of NT2 neurons and primary HFNs in terms of their morphology physiological and chemical properties is still missing. This study directly compares NT2-derived neurons and primary HFNs using immunocytochemistry, confocal calcium imaging, high-performance liquid chromatography, and high-content analysis techniques. We investigated the morphological similarities and differences, levels of relevant amino acids, and internal calcium fluctuations in response to certain neurotransmitters/stimuli. We also compared NT2-derived astrocytes and HFAs. In most of the parameters tested, both neuronal and astrocytic cell types exhibited similarities to primary human fetal neurons and astrocytes. NT2-derived neurons and astrocytes are reliable in vitro tools and a renewable cell source that can serve as a valid alternative to HFNs/HFAs for mechanistic studies of neurological diseases.


Assuntos
Astrócitos/fisiologia , Diferenciação Celular/fisiologia , Neurônios/fisiologia , Aminoácidos/metabolismo , Encéfalo/citologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Tamanho Celular , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Feto , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Receptores de Neurotransmissores/metabolismo , Teratoma/patologia , Tubulina (Proteína)/metabolismo
20.
FASEB J ; 27(2): 725-37, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23150523

RESUMO

Neurosteroids are cholesterol-derived molecules synthesized within the brain, which exert trophic and protective actions. Infection by human and feline immunodeficiency viruses (HIV and FIV, respectively) causes neuroinflammation and neurodegeneration, leading to neurological deficits. Secretion of neuroinflammatory host and viral factors by glia and infiltrating leukocytes mediates the principal neuropathogenic mechanisms during lentivirus infections, although the effect of neurosteroids on these processes is unknown. We investigated the interactions between neurosteroid-mediated effects and lentivirus infection outcomes. Analyses of HIV-infected (HIV(+)) and uninfected human brains disclosed a reduction in neurosteroid synthesis enzyme expression. Human neurons exposed to supernatants from HIV(+) macrophages exhibited suppressed enzyme expression without reduced cellular viability. HIV(+) human macrophages treated with sulfated dehydroepiandrosterone (DHEA-S) showed suppression of inflammatory gene (IL-1ß, IL-6, TNF-α) expression. FIV-infected (FIV(+)) animals treated daily with 15 mg/kg body weight. DHEA-S treatment reduced inflammatory gene transcripts (IL-1ß, TNF-α, CD3ε, GFAP) in brain compared to vehicle-(ß-cyclodextrin)-treated FIV(+) animals similar to levels found in vehicle-treated FIV(-) animals. DHEA-S treatment also increased CD4(+) T-cell levels and prevented neurobehavioral deficits and neuronal loss among FIV(+) animals, compared to vehicle-treated FIV(+) animals. Reduced neuronal neurosteroid synthesis was evident in lentivirus infections, but treatment with DHEA-S limited neuroinflammation and prevented neurobehavioral deficits. Neurosteroid-derived therapies could be effective in the treatment of virus- or inflammation-mediated neurodegeneration.


Assuntos
Complexo AIDS Demência/imunologia , Complexo AIDS Demência/virologia , Encéfalo/imunologia , Encéfalo/virologia , Sulfato de Desidroepiandrosterona/imunologia , Imunidade Inata , Complexo AIDS Demência/metabolismo , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Gatos , Sulfato de Desidroepiandrosterona/metabolismo , Sulfato de Desidroepiandrosterona/farmacologia , Síndrome de Imunodeficiência Adquirida Felina/imunologia , Síndrome de Imunodeficiência Adquirida Felina/psicologia , Síndrome de Imunodeficiência Adquirida Felina/virologia , Feminino , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Vírus da Imunodeficiência Felina/imunologia , Vírus da Imunodeficiência Felina/patogenicidade , Gravidez , Virulência/efeitos dos fármacos , Virulência/imunologia , Replicação Viral
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