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1.
J Toxicol Sci ; 45(7): 391-399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612007

RESUMO

This study was aimed at examining propofol- (a known anesthetic) induced emotion-related behavioral disorders in mice, and exploring the possible molecular mechanisms. A total of 60 mice were divided into two groups: control and propofol group. Mice were injected with propofol (150 mg/kg, ip) at 8:00 a.m. (once a day, lasting for 30 days). During the 30 days, loss of righting reflex (LORR) and return of righting reflex (RORR) of mice were recorded every day. At the 1st (T1) and 30th (T2) day of drug discontinuance (T2), 15 mice of each group were selected to perform the open field test; then the mice underwent perfusion fixation, and the midbrain and corpus striatum were separated for immunofluorescence assay with anti-tyrosine hydroxylase (Th) and anti- dopamine transporter (DAT) antibodies. Results showed that after propofol injection, LORR and RORR increased and decreased, respectively. Long-term use of propofol resulted in decreased activities of mice (activity trajectory, line crossing, rearing time, scratching times and defecating frequency). Immunofluorescence assay showed long-term use of propofol induced decrease of Th and DAT. Collectively, our present work suggested long-term abuse of propofol induces neuropsychiatric function impairments, and the possible mechanisms are related to dopamine dyssynthesis via down-regulating tyrosine hydroxylase and dopamine transporter.


Assuntos
Anestésicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Transtornos Mentais/induzido quimicamente , Propofol/toxicidade , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia , Anestésicos/efeitos adversos , Animais , Neurônios Dopaminérgicos/metabolismo , Emoções/efeitos dos fármacos , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Camundongos Endogâmicos C57BL , Propofol/efeitos adversos , Reflexo de Endireitamento/efeitos dos fármacos
2.
PLoS One ; 15(7): e0235956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678850

RESUMO

Patients with severe mental illness (SMI) have a higher burden of premature cardio-metabolic abnormalities, including diabetes mellitus, hypertension, hyperlipidemia, and obesity resulting into a 3-fold increase in mortality, and up to 20% reduction in life expectancy compared to the general population. Although over 30% of Ugandans have some form of mental illness, there are no national or hospital-based screening guidelines for cardio-metabolic abnormalities among these patients a general trend in most low-income countries. The screening rates for cardio-metabolic abnormalities in most low-income countries are at only 0.6%. The objective of this study was to describe the cardio-metabolic abnormalities among patients with SMI at Mbarara Regional Referral Hospital. Through a cross-sectional study, we recruited 304 patients with SMI and evaluated them for cardio-metabolic abnormalities using the National Cholesterol Education Programme Adult Treatment Panel III criteria for dyslipidemias, World Health Organisation criteria for diabetes mellitus, obesity, and the Joint national committee criteria for hypertension. We then determined the proportion of participants who met the criteria for each of the individual cardio-metabolic abnormalities. Of the 304 participants, 44.41% were male and 55.59% female with a mean age of 38.56±13.66 years. Almost half (46.38%) of the participants were either overweight or obese, 33.22% had abdominal obesity, 40.46% were hypertensive, 34.11% had low high-density lipoproteins, 37.42% had hypertriglyceridemia and 34.77% had hypercholesterolemia. Based on fasting blood sugar, 11.18% and 9.87% had pre-diabetes and diabetes respectively. There is a high level of cardio-metabolic abnormalities among patients with psychiatric disorders and thus metabolic screening for these abnormalities should be done routinely during psychiatric reviews. There is a need for national guidelines for screening of metabolic abnormalities among patients with SMI so that these abnormalities can be detected early enough at stages where they can be either reversed or delayed to progress to cardiovascular disease.


Assuntos
Hospitais/estatística & dados numéricos , Transtornos Mentais/metabolismo , Encaminhamento e Consulta , Adulto , Feminino , Cardiopatias/complicações , Humanos , Masculino , Transtornos Mentais/complicações , Uganda
3.
Nat Commun ; 11(1): 3593, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681096

RESUMO

During pregnancy, maternal endocrine signals drive fetal development and program the offspring's physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child's risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.


Assuntos
Relógios Circadianos/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Exposição Materna/efeitos adversos , Transtornos Mentais/etiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ansiedade , Comportamento/efeitos dos fármacos , Feminino , Glucocorticoides/administração & dosagem , Humanos , Recém-Nascido Prematuro/psicologia , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Cuidado Pré-Natal , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo
4.
PLoS One ; 15(6): e0233418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574218

RESUMO

Common mental disorders (CMD) among mothers cause disability, negatively affect child development, and have high long-term economic costs. Little is known about how factors across multiple life dimensions, modeled together, are differentially related to maternal mental health in high poverty contexts. Further, there is limited evidence on determinants of CMD in areas where self-help groups (SHGs) exist to promote women's wellbeing. Filling this evidence gap is important given the high prevalence of CMD and the rapid expansion of SHGs in rural India. Cross-sectional data were collected from 1644 mother-infant pairs living in disadvantaged rural villages across five Indian states-Jharkhand, Madhya Pradesh, West Bengal, Odisha, and Chhattisgarh-surveyed in the Women Improving Nutrition through Group-based Strategies study. CMD were assessed using the 20-item Self Reporting Questionnaire (SRQ). We examined 31 factors across four life dimensions: work (work type, time spent in labor, domestic and caretaking activities), agency (SHG membership, decision-making, gender attitudes), health/nutrition (underweight, fertility, diet diversity, child illness), and household/environment (dependency ratio, wealth, food security, shocks, water, sanitation). Survey-adjusted multivariate logistic and ordinary least squares regression models were fit to examine predictors of CMD or SRQ score. On average, mothers were 26 (range 18-46) years old and their children were 15 (range 6-24) months old. CMD defined as ≥ 8 positive SRQ responses were reported by 262 women (16%). Protective factors included being engaged in agricultural labor as a main occupation relative to being a housewife (AOR 0.18, 95% CI 0.10-0.32), more time working (0.85, 0.77-0.93), higher decision-making (0.33, 0.16-0.69), SHG membership (0.73, 0.56-0.96), and having an improved toilet (0.49, 0.33-0.72). Risk factors included food insecurity (1.13, 1.07-1.20) and shocks to non-farm livelihoods (2.04, 1.10-3.78). Practitioners and policymakers should aim to improve food security, economic wellbeing and social capital, such as that created through SHG membership, to improve maternal mental health. Future research should aim to understand why working outside the home, albeit in agricultural work, appears to protect maternal mental health in this context.


Assuntos
Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Mães/psicologia , Adulto , Estudos Transversais/métodos , Dieta Saudável/psicologia , Feminino , Abastecimento de Alimentos , Humanos , Transtornos Mentais/metabolismo , Saúde Mental/etnologia , Pessoa de Meia-Idade , Estado Nutricional/etnologia , Pobreza , Fatores de Risco , Saúde da População Rural/etnologia , População Rural , Grupos de Autoajuda , Populações Vulneráveis/etnologia
5.
Adv Exp Med Biol ; 1195: 237-247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468482

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules of about 20-22 nucleotides. After their posttranscriptional maturation, miRNAs are loaded into the ribonucleoprotein complex RISC and modulate gene expression by binding to the 3' untranslated region of their target mRNAs through base-pairing, which in turn triggers mRNA degradation or translational inhibition. There is mounting evidence that miRNAs regulate various biological processes, including cell proliferation, differentiation, and apoptosis. Several studies have shown that miRNAs play an important role in neurogenesis and brain development.This review discusses recent progress on understanding the implication of precisely regulated miRNA expression in normal brain development and function. In addition, it reports known cases of dysregulation of miRNA expression and function implicated in the pathogenesis of neurodevelopmental disorders, craniofacial dysmorphic syndromes, neurodegenerative diseases, and psychiatric disorders. Current knowledge regarding the role of miRNAs in the brain in conjunction with the complex interplay between genetic and epigenetic factors are discussed.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Humanos , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , MicroRNAs/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurogênese/genética
6.
Artigo em Inglês | MEDLINE | ID: mdl-32161213

RESUMO

Memory retrieval is not a passive process. When a memory is retrieved, the retrieved memory is destabilized, similar to short-term memory just after learning, and requires memory reconsolidation to re-stabilize the memory. Recent studies characterizing destabilization and reconsolidation showed that a retrieved memory is not always destabilized and that there are boundary conditions that determine the induction of destabilization and reconsolidation according to certain parameters, such as the duration of retrieval and the memory strength and age. Moreover, the reconsolidation of contextual fear memory is not independent of memory extinction; rather, these memory processes interact with each other. There is an increasing number of findings suggesting that destabilization following retrieval facilitates the modification, weakening, or strengthening of the original memory, and the resultant updated memory is stabilized through reconsolidation. Reconsolidation could be targeted therapeutically to improve emotional disorders such as post-traumatic stress disorder and phobia. Thus, this review summarizes recent findings to understand the mechanisms and function of reconsolidation.


Assuntos
Extinção Psicológica/fisiologia , Consolidação da Memória/fisiologia , Animais , Encéfalo , Medo , Humanos , Transtornos da Memória/metabolismo , Transtornos Mentais/metabolismo , Transtornos Fóbicos/metabolismo , Transdução de Sinais , Transtornos de Estresse Traumático/metabolismo
7.
J Clin Neurosci ; 73: 1-7, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32001110

RESUMO

This review focuses on the studies that have been reviewed to determine the influence of the thalamic reticular nucleus on neuropsychiatric diseases and deep brain stimulation. The literature reviewed to date describes how alterations in the thalamic reticular nucleus affect several functions that regulated brain rhythms and provokes symptoms of many disorders. The observations as the basis for the renewed interest in the thalamic reticular nucleus in experimental models and testing its effectiveness in patients with resistant neuropsychiatric disorders. The preclinical studies showed that deep brain stimulation in the thalamic reticular nucleus could have beneficial effects on EEG activity, including synchronization and desynchronization activity of the brain, as well as promoting an alleviate to neuropsychiatric diseases. These observations open up the possibility of studying the role played by neurotransmitters in the pathologic process and the deep brain stimulation in the thalamic reticular nucleus in experimental animal models and offer evidence of its possible action in the human brain.


Assuntos
Estimulação Encefálica Profunda/métodos , Transtornos Mentais/fisiopatologia , Transtornos Mentais/terapia , Núcleos Talâmicos/fisiologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Humanos , Transtornos Mentais/metabolismo , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Núcleos Talâmicos/metabolismo
8.
Psychiatr Genet ; 30(2): 39-48, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32097233

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is a polymodal cation channel gated by a large array of chemical and physical stimuli and distributed across different brain regions on neuronal and glial cells. Preclinical studies indicate that TRPV1 might be a target for the treatment of anxiety, depression and addictive disorders. The aim of this narrative review is to focus on studies examining the effects of TRPV1 antagonism on neuroinflammation, neuroprotection and epigenetic regulation. Results suggest that TRPV1 modulation leads to pro- or anti-inflammatory effects depending on the cytokine environment and that the TRPV1 antagonism can switch the microglia towards an anti-inflammatory phenotype. Moreover, TRPV1 inhibitors have neuroprotective properties through the regulation of calcium levels. Finally, TRPV1 antagonism exerts regulatory effects on genes involved in synaptic and cognitive functions through histone deacetylase 2 inhibition. These findings highlight different mechanisms that may underlie the efficacy of TRPV1 antagonists in animal models of severe psychiatric disorders.


Assuntos
Transtornos Mentais/metabolismo , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/fisiologia , Cálcio/metabolismo , Epigênese Genética , Humanos , Transtornos Mentais/terapia , Neuroproteção , Transdução de Sinais/fisiologia , Canais de Cátion TRPV/antagonistas & inibidores
9.
Am J Physiol Gastrointest Liver Physiol ; 318(1): G130-G143, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682158

RESUMO

Gastrointestinal (GI) comorbidities are common in individuals with mood and behavioral dysfunction. Similarly, patients with GI problems more commonly suffer from co-morbid psychiatric diagnoses. Although the central and enteric nervous systems (CNS and ENS, respectively) have largely been studied separately, there is emerging interest in factors that may contribute to disease states involving both systems. There is strong evidence to suggest that serotonin may be an important contributor to these brain-gut conditions. Serotonin has long been recognized for its critical functions in CNS development and function. The majority of the body's serotonin, however, is produced in the GI tract, where it plays key roles in ENS development and function. Further understanding of the specific impact that enteric serotonin has on brain-gut disease may lay the foundation for the creation of novel therapeutic targets. This review summarizes the current data focusing on the important roles that serotonin plays in ENS development and motility, with a focus on novel aspects of serotonergic signaling in medical conditions in which CNS and ENS co-morbidities are common, including autism spectrum disorders and depression.


Assuntos
Encéfalo/metabolismo , Sistema Nervoso Entérico/metabolismo , Gastroenteropatias/metabolismo , Motilidade Gastrointestinal , Trato Gastrointestinal/inervação , Transtornos Mentais/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Adolescente , Comportamento do Adolescente , Afeto , Fatores Etários , Animais , Encéfalo/fisiopatologia , Criança , Comportamento Infantil , Sistema Nervoso Entérico/fisiopatologia , Gastroenteropatias/epidemiologia , Gastroenteropatias/fisiopatologia , Gastroenteropatias/psicologia , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Humanos , Transtornos Mentais/embriologia , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Neurogênese , Receptores de Serotonina/metabolismo , Fatores de Risco
10.
Redox Biol ; 28: 101332, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581069

RESUMO

Mice deficient in glucose-6-phosphate dehydrogenase (G6PD) cannot replenish the cellular antioxidant glutathione, which detoxifies neurodegenerative reactive oxygen species (ROS). To determine the functional consequences of G6PD deficiency, young and aging G6PD-deficient mice were evaluated for brain G6PD activity, DNA damage (comets, γH2AX), Purkinje cell loss, brain function (electrophysiology, behaviour) and lifespan. DNA comet formation was increased and Purkinje cell counts were decreased in a G6pd gene dose-dependent fashion. γH2AX formation varied by age, sex and brain region, with increased levels in G6PD-deficient young and aging females, and in aging males. Aging male G6PD-deficient mice exhibited synaptic dysfunction in hippocampal slices. G6PD-deficient young and aging females exhibited deficits in executive function, and young deficient mice exhibited deficits in social dominance. Conversely, median lifespan in G6PD-deficient females and males was enhanced. Enhanced ROS-initiated brain damage in G6PD deficiency has functional consequences, suggesting that G6PD protects against ROS-mediated neurodegenerative disorders.


Assuntos
Dano ao DNA , Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/genética , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Animais , Encéfalo/metabolismo , Quebras de DNA de Cadeia Dupla , Quebras de DNA de Cadeia Simples , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Masculino , Camundongos , Oxirredução , Células de Purkinje/metabolismo
11.
Dokl Biochem Biophys ; 488(1): 304-306, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31768846

RESUMO

A new derivative of 3,7-diazabicyclo[3.3.1]nonane, which showed a high activity as a positive allosteric modulator of AMPA receptors of the CNS, was studied in electrophysiological experiments. At doses of 0.01 mg/kg, this compound significantly improved the memory of experimental animals disturbed by maximal electric shock. The results indicate that this compound is a promising candidate for preclinical trials and clinical studies as a drug for treatment of a number of psychoneurological diseases.


Assuntos
Hipocampo/metabolismo , Transtornos Mentais , Doenças do Sistema Nervoso , Nootrópicos , Receptores de AMPA , Regulação Alostérica , Animais , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Nootrópicos/química , Nootrópicos/farmacologia , Ratos , Receptores de AMPA/agonistas , Receptores de AMPA/química , Receptores de AMPA/metabolismo
12.
Molecules ; 24(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752279

RESUMO

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as µ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the µ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate µ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of µORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.


Assuntos
Imagem Molecular , Receptores Opioides/metabolismo , Animais , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalopatias/diagnóstico por imagem , Encefalopatias/etiologia , Encefalopatias/metabolismo , Humanos , Ligantes , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Imagem Molecular/métodos , Neuroimagem/métodos , Peptídeos/química , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Receptores Opioides/agonistas , Receptores Opioides/química
13.
Neurotoxicol Teratol ; 76: 106839, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31644947

RESUMO

Recent developments in the field of insecticide exposure have led to a renewed interest in alternative antioxidant therapy. The present study was to investigate the neuroprotective role of syringic acid (SA, 25 mg/kg/day) on the neurotoxicity and oxidative damage induced by deltamethrin (DTM, 1.28 mg/kg/day during two months) in CA1/3 pyramidal neurons. Animals were divided into 4 groups (n = 16/group) (250-270 g) for control, DTM, SA and DTM + SA. DTM and SA were administered by oral gavage daily. Rats that were given sub-chronic DTM had revealed a significant increase in caspase-3 levels, impaired recognition memory, reduced antioxidant activity and enhanced free radicals in the hippocampus. The results showed that SA ameliorated neurobehavioral alterations, reduced reactive oxygen/nitrogen species, pyknosis in the CA1/3 and increased antioxidant enzyme activity. In conclusion, SA (25 mg/kg/day) had potential neuroprotective and therapeutic impacts against sub-chronic DTM exposure via its antioxidant and antiapoptotic efficacy. Therefore, it can be used as a neuroprotective natural plant-derived agent against DTM-induced neurotoxicity.


Assuntos
Ácido Gálico/análogos & derivados , Hipocampo/patologia , Inseticidas/toxicidade , Transtornos Mentais/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Nitrilos/toxicidade , Piretrinas/toxicidade , Animais , Apoptose/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Ácido Gálico/uso terapêutico , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/metabolismo , Síndromes Neurotóxicas/psicologia , Estresse Oxidativo/efeitos dos fármacos , Células Piramidais , Ratos , Ratos Wistar
14.
Dialogues Clin Neurosci ; 21(2): 119-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31636486

RESUMO

This review addresses novel approaches for influencing the transcriptome, the epigenome, the microbiome, the proteome, and the energy metabolome. These innovations help develop psychotropic medications which will directly reach the molecular targets, leading to beneficial effects, and which will be individually adapted to provide more efficacy and less toxicity. The series of advances described here show that these once utopian goals for psychiatric treatment are now real themes of research, indicating that the future path for psychopharmacology might not be as narrow and grim as considered during the last few decades.
.


Assuntos
Desenvolvimento de Medicamentos , Transtornos Mentais/tratamento farmacológico , Psicofarmacologia/métodos , Psicotrópicos/uso terapêutico , Epigenoma , Humanos , Transtornos Mentais/metabolismo , Transtornos Mentais/microbiologia , Metaboloma , Microbiota , Proteoma , Transcriptoma
15.
Prog Mol Biol Transl Sci ; 167: 143-157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31601402

RESUMO

Stress activates many brain nuclei and causes acute changes in several physiological and behavioral responses to restore homeostasis in affected organisms. While this response is protective, chronic stress exposure causes the sustained activation of these nuclei, leading to maladaptive physiological changes that underlie pathological mood and affective states. Hence, chronic stress may produce anxiety and mood disorders by promoting neuronal plasticity within these stress-responsive nuclei. A growing body of evidence attributes neuropeptide systems in mediating not only the physiological stress response but also pathological states that develop following chronic stress exposure. Recent preclinical data suggest that pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptors (PAC1, VPAC1, and VPAC2) play an important role in the behavioral and endocrine responses to stress, as well as in mood and affective disorders. Human studies also point out the significance of the PACAP/PAC1 receptor system in these disorders. For instance, PACAP through PAC1 receptor up-regulates the expression of DISC1 (disrupted in schizophrenia 1) and impedes its association with its interacting protein. Interestingly, the DISC1 gene mutation is linked to schizophrenia and depression. Moreover, a link between PACAP blood titer and fear physiology, post-traumatic stress disorder (PTSD) diagnosis and symptoms has been reported in heavily traumatized female patients. Additionally, in the peripheral blood, methylation of the gene encoding the PAC1 receptor is also associated with PTSD. This book chapter describes the emerging evidence that entails PACAP in the stress response and stress-mediated neuropsychiatric disorders.


Assuntos
Transtornos Mentais/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Animais , Humanos , Transtornos Mentais/metabolismo , Doenças do Sistema Nervoso/metabolismo
16.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581684

RESUMO

Progress in iPSC-based cellular systems provides new insights into human brain development and early neurodevelopmental deviations in psychiatric disorders. Among these, studies on schizophrenia (SCZ) take a prominent role owing to its high heritability and multifarious evidence that it evolves from a genetically induced vulnerability in brain development. Recent iPSC studies on patients with SCZ indicate that functional impairments of neural progenitor cells (NPCs) in monolayer culture extend to brain organoids by disrupting neocorticogenesis in an in vitro model. In addition, the formation of hippocampal circuit-like structures in vitro is impaired in patients with SCZ as is the case for glia development. Intriguingly, chimeric-mice experiments show altered oligodendrocyte and astrocyte development in vivo that highlights the importance of cell-cell interactions in the pathogenesis of early-onset SCZ. Likewise, cortical imbalances in excitatory-inhibitory signaling may result from a cell-autonomous defect in cortical interneuron (cIN) development. Overall, these findings indicate that genetic risk in SCZ impacts neocorticogenesis, hippocampal circuit formation, and the development of distinct glial and neuronal subtypes. In light of this remarkable progress, we discuss current limitations and further steps necessary to harvest the full potential of iPSC-based investigations on psychiatric disorders.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Modelos Biológicos , Animais , Hipocampo/embriologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Células-Tronco Neurais/metabolismo , Neurogênese
17.
NMR Biomed ; 32(10): e4172, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31478594

RESUMO

In the last 25 years 13 C MRS has been established as the only noninvasive method for measuring glutamate neurotransmission and cell specific neuroenergetics. Although technically and experimentally challenging 13 C MRS has already provided important new information on the relationship between neuroenergetics and neuronal function, the high energy cost of brain function in the resting state and the role of altered neuroenergetics and neurotransmitter cycling in disease. In this paper we review the metabolic and neurotransmitter pathways that can be measured by 13 C MRS and key findings on the linkage between neuroenergetics, neurotransmitter cycling, and brain function. Applications of 13 C MRS to neurological and psychiatric disease as well as brain cancer are reviewed. Recent technological developments that may help to overcome spatial resolution and brain coverage limitations of 13 C MRS are discussed.


Assuntos
Neoplasias Encefálicas/metabolismo , Isótopos de Carbono/química , Espectroscopia de Ressonância Magnética , Transtornos Mentais/metabolismo , Neurotransmissores/metabolismo , Animais , Neoplasias Encefálicas/fisiopatologia , Humanos , Transtornos Mentais/fisiopatologia , Transmissão Sináptica
18.
Curr Top Med Chem ; 19(16): 1365-1380, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553283

RESUMO

The dopamine D1 receptor (D1R) is essential for neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Not surprisingly, the D1R has been validated as a promising drug target for over 40 years and selective activation of this receptor may provide novel neurotherapeutics for neurodegenerative and neuropsychiatric disorders. Several pharmacokinetic challenges with previously identified small molecule D1R agonists have been recently overcome with the discovery and advancement of new ligands, including drug-like non-catechol D1R agonists and positive allosteric modulators. From this, several novel molecules and mechanisms have recently entered clinical studies. Here we review the major classes of D1R selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive allosteric modulators, highlighting their structure-activity relationships and medicinal chemistry. Recent chemistry breakthroughs and innovative approaches to selectively target and activate the D1R also hold promise for creating pharmacotherapy for several neurological diseases.


Assuntos
Agonistas de Dopamina/farmacologia , Transtornos Mentais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Receptores de Dopamina D1/agonistas , Animais , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/química , Humanos , Ligantes , Transtornos Mentais/metabolismo , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Receptores de Dopamina D1/metabolismo
19.
Transl Psychiatry ; 9(1): 227, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515504

RESUMO

Immune dysregulation due to chronic inflammation is a hypothesized risk factor underlying psychiatric disorders and suicidal behavior. Whether tonsillectomy and acute appendicitis used, respectively, as proxies for chronic and acute inflammation within the mucosa-associated lymphoid tissue (MALT) are associated with psychiatric disorders and suicidal behavior is currently unknown. A birth cohort study was conducted including 3,052,875 individuals born in Sweden between 1973 and 2003. We identified 210,686 individuals ever exposed to tonsillectomy and 86,928 individuals ever exposed to acute appendicitis, as well as 317,214 clusters of siblings discordant for tonsillectomy, and 160,079 sibling clusters discordant for acute appendicitis. Outcomes were an aggregate risk of 'any psychiatric disorder', 'any suicidal behavior', 12 individual psychiatric disorders, suicide attempts and deaths by suicide. Tonsillectomy was associated with increased odds of 'any psychiatric disorder' (adjusted odds ratio [aOR] = 1.39; 95% confidence interval (CI) = 1.38-1.41) and 'any suicidal behavior' (aOR = 1.41; 95% CI = 1.37-1.44), and most individual disorders. Acute appendicitis also increased the odds of 'any psychiatric disorder' and 'any suicidal behavior' (aOR = 1.23; 95% CI = 1.20-1.25, and aOR = 1.32; 95% CI = 1.28-1.37, respectively). Exposure to both tonsillectomy and appendicitis was associated with the highest odds of 'any psychiatric disorder' (aOR = 1.70; 95% CI = 1.59-1.82) and 'any suicidal behavior' (aOR = 1.90; 95% CI = 1.70-2.12). In sibling comparisons, the associations were attenuated but remained significant. We conclude that inflammation within the MALT, particularly when chronic, is robustly associated with a broad range of psychiatric disorders and suicidal behavior.


Assuntos
Apendicite/epidemiologia , Inflamação/epidemiologia , Tecido Linfoide/metabolismo , Transtornos Mentais/epidemiologia , Ideação Suicida , Tentativa de Suicídio , Adolescente , Adulto , Apendicite/metabolismo , Apendicite/patologia , Comorbidade , Feminino , Humanos , Incidência , Inflamação/metabolismo , Inflamação/patologia , Tecido Linfoide/patologia , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Suécia/epidemiologia , Tonsilectomia , Adulto Jovem
20.
Transl Psychiatry ; 9(1): 233, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534116

RESUMO

Inflammation is a natural defence response of the immune system against environmental insult, stress and injury, but hyper- and hypo-inflammatory responses can trigger diseases. Accumulating evidence suggests that inflammation is involved in multiple psychiatric disorders. Using inflammation-related factors as biomarkers of psychiatric disorders requires the proof of reproducibility and specificity of the changes in different disorders, which remains to be established. We performed a cross-disorder study by systematically evaluating the meta-analysis results of inflammation-related factors in eight major psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depression disorder (MDD), post-trauma stress disorder (PTSD), sleeping disorder (SD), obsessive-compulsive disorder (OCD) and suicide. A total of 43 meta-analyses involving 704 publications on 44 inflammation-related factors were included in the study. We calculated the effect size and statistical power for every inflammation-related factor in each disorder. Our analyses showed that well-powered case-control studies provided more consistent results than underpowered studies when one factor was meta-analysed by different researchers. After removing underpowered studies, 30 of the 44 inflammation-related factors showed significant alterations in at least one disorder based on well-powered meta-analyses. Eleven of them changed in patients of more than two disorders when compared with the controls. A few inflammation-related factors showed unique changes in specific disorders (e.g., IL-4 increased in BD, decreased in suicide, but had no change in MDD, ASD, PTSD and SCZ). MDD had the largest number of changes while SD has the least. Clustering analysis showed that closely related disorders share similar patterns of inflammatory changes, as genome-wide genetic studies have found. According to the effect size obtained from the meta-analyses, 13 inflammation-related factors would need <50 cases and 50 controls to achieve 80% power to show significant differences (p < 0.0016) between patients and controls. Changes in different states of MDD, SCZ or BD were also observed in various comparisons. Studies comparing first-episode SCZ to controls may have more reproducible findings than those comparing pre- and post-treatment results. Longitudinal, system-wide studies of inflammation regulation that can differentiate trait- and state-specific changes will be needed to establish valuable biomarkers.


Assuntos
Biomarcadores , Inflamação/genética , Transtornos Mentais/genética , Humanos , Inflamação/metabolismo , Transtornos Mentais/metabolismo , Metanálise como Assunto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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