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1.
J Pers Med ; 11(3)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668817

RESUMO

A close epidemiological link has been reported between cannabis use and schizophrenia (SCZ). However, biochemical markers in living humans related to the impact of cannabis in this disease are still missing. Olfactory neuroepithelium (ON) cells express neural features and offer a unique advantage to study biomarkers of psychiatric diseases. The aim of our study was to find exclusively deregulated proteins in ON cells of SCZ patients with and without a history of cannabis use. Thus, we compared the proteomic profiles of SCZ non-cannabis users (SCZ/nc) and SCZ cannabis users (SCZ/c) with control subjects non-cannabis users (C/nc) and control cannabis users (C/c). The results revealed that the main cascades affected in SCZ/nc were cell cycle, DNA replication, signal transduction and protein localization. Conversely, cannabis use in SCZ patients induced specific alterations in metabolism of RNA and metabolism of proteins. The levels of targeted proteins in each population were then correlated with cognitive performance and clinical scores. In SCZ/c, the expression levels of 2 proteins involved in the metabolism of RNA (MTREX and ZNF326) correlated with several cognitive markers and clinical signs. Moreover, use duration of cannabis negatively correlated with ZNF326 expression. These findings indicate that RNA-related proteins might be relevant to understand the influence of cannabis use on SCZ.

2.
Mol Neurobiol ; 58(4): 1695-1710, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33237429

RESUMO

Cannabis is the third most commonly used psychoactive substance of abuse, yet it also receives considerable attention as a potential therapeutic drug. Therefore, it is essential to fully understand the actions of cannabis in the human brain. The olfactory neuroepithelium (ON) is a peripheral nervous tissue that represents an interesting surrogate model to study the effects of drugs in the brain, since it is closely related to the central nervous system, and sensory olfactory neurons are continually regenerated from populations of stem/progenitor cells that undergo neurogenesis throughout life. In this study, we used ON cells from chronic cannabis users and healthy control subjects to assess alterations in relevant cellular processes, and to identify changes in functional proteomic pathways due to cannabis consumption. The ON cells from cannabis users exhibited alterations in the expression of proteins that were related to the cytoskeleton, cell proliferation and cell death, as well as, changes in proteins implicated in cancer, gastrointestinal and neurodevelopmental pathologies. Subsequent studies showed cannabis provoked an increase in cell size and morphological alterations evident through ß-Tubulin III staining, as well as, enhanced beta-actin expression and a decrease in the ability of ON cells to undergo cell attachment, suggesting abnormalities of the cytoskeleton and cell adhesion system. Furthermore, these cells proliferated more and underwent less cell death. Our results indicate that cannabis may alter key processes of the developing brain, some of which are similar to those reported in mental disorders like DiGeorge syndrome, schizophrenia and bipolar disorder.


Assuntos
Apoptose , Biomarcadores/metabolismo , Cannabis/efeitos adversos , Citoesqueleto/patologia , Células Neuroepiteliais/patologia , Bulbo Olfatório/patologia , Transtornos Relacionados ao Uso de Substâncias/patologia , Adulto , Atenção , Adesão Celular , Diferenciação Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Masculino , Proteoma/metabolismo , Proteômica
3.
Schizophr Bull ; 46(6): 1547-1557, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249318

RESUMO

Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB1R-5-HT2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that heteromer expression was enhanced in both SCZ groups vs HC/nc. Additionally, pooling all 4 groups together, heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive impairment. Remarkably, the previously reported signaling properties of CB1R-5-HT2AR heteromers in ON cells were absent, specifically in SCZ/nc treated with clozapine. These findings were mimicked in cells from HC/nc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB1R-5-HT2AR heteromer in SCZ/nc patients. In contrast, cells from SCZ/c showed enhanced heteromer functionality similar to HC/c. Our data highlight a molecular marker of the interaction between antipsychotic medication and cannabis use in SCZ with relevance for future studies evaluating its association with specific neuropsychiatric alterations.


Assuntos
Antipsicóticos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Uso da Maconha , Células Neuroepiteliais , Neurônios Receptores Olfatórios , Receptor CB1 de Canabinoide , Receptor 5-HT2A de Serotonina , Esquizofrenia/metabolismo , Adulto , Agonistas de Receptores de Canabinoides/sangue , Células Cultivadas , Clozapina/farmacologia , Estudos Transversais , Dronabinol/sangue , Feminino , Humanos , Masculino , Células Neuroepiteliais/efeitos dos fármacos , Células Neuroepiteliais/metabolismo , Neurônios Receptores Olfatórios/efeitos dos fármacos , Neurônios Receptores Olfatórios/metabolismo , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Adulto Jovem
4.
Neuropharmacology ; 170: 108030, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32171677

RESUMO

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized by muscle weakness and wasting and by important central nervous system-related symptoms including impairments in executive functions, spatial abilities and increased anxiety and depression. The Mbnl2 gene has been implicated in several phenotypes consistent with DM1 neuropathology. In this study, we developed a tissue-specific knockout mouse model lacking the Mbnl2 gene in forebrain glutamatergic neurons to examine its specific contribution to the neurobiological perturbations related to DM1. We found that these mice exhibit long-term cognitive deficits and a depressive-like state associated with neuronal loss, increased microglia and decreased neurogenesis, specifically in the dentate gyrus (DG). Chronic treatment with the atypical antidepressant mirtazapine (3 and 10 mg/kg) for 21 days rescued these behavioral alterations, reduced inflammatory microglial overexpression, and reversed neuronal loss in the DG. We also show that mirtazapine re-established 5-HT1A and histaminergic H1 receptor gene expression in the hippocampus. Finally, metabolomics studies indicated that mirtazapine increased serotonin, noradrenaline, gamma-aminobutyric acid and adenosine production. These data suggest that loss of Mbnl2 gene in the glutamatergic neurons of hippocampus and cortex may underlie the most relevant DM1 neurobiological and behavioral features, and provide evidence that mirtazapine could be a novel potential candidate to alleviate these debilitating symptoms in DM1 patients.


Assuntos
Ácido Glutâmico , Mirtazapina/uso terapêutico , Distrofia Miotônica/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Prosencéfalo/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Animais , Animais Geneticamente Modificados , Drosophila , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mirtazapina/farmacologia , Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Prosencéfalo/metabolismo , Proteínas de Ligação a RNA/metabolismo
5.
Biomolecules ; 10(2)2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32092878

RESUMO

Schizophrenia (SCZ) is a neurodevelopmental disorder with a high genetic component, but the presence of environmental stressors can be important for its onset and progression. Cannabis use can be a major risk factor for developing SCZ. However, despite the available data on the neurobiological underpinnings of SCZ, there is an important lack of studies in human neuronal tissue and living cells addressing the effects of cannabis in SCZ patients. In this study, we analysed the most relevant bio-macromolecular constituents in olfactory neuroepithelium (ON) cells of healthy controls non-cannabis users, healthy cannabis users, SCZ patients non-cannabis users, and SCZ patients cannabis users using Synchrotron Radiation-Fourier Transform Infrared (SR-FTIR) spectrometry and microscopy. Our results revealed that SCZ patients non-cannabis users, and healthy cannabis users exhibit similar alterations in the macromolecular profile of ON cells, including disruption in lipid composition, increased lipid membrane renewal rate and lipid peroxidation, altered proteins containing more ß-sheet structures, and showed an increase in DNA and histone methylation. Notably, these alterations were not observed in SCZ patients who use cannabis regularly. These data suggest a differential effect of cannabis in healthy controls and in SCZ patients in terms of the macromolecular constituents of ON cells.


Assuntos
Cannabis/efeitos adversos , Lipídeos/análise , Fumar Maconha/efeitos adversos , Mucosa Nasal/efeitos dos fármacos , Proteínas/análise , Esquizofrenia/patologia , Adulto , Células Cultivadas , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Fumar Maconha/metabolismo , Fumar Maconha/patologia , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/patologia , Proteínas/metabolismo , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Síncrotrons , Adulto Jovem
6.
Cereb Cortex ; 29(7): 2978-2997, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-30060068

RESUMO

Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting muscle and central nervous system (CNS) function. The cellular mechanisms underlying CNS alterations are poorly understood and no useful treatments exist for the neuropsychological deficits observed in DM1 patients. We investigated the progression of behavioral deficits present in male and female muscleblind-like 2 (Mbnl2) knockout (KO) mice, a rodent model of CNS alterations in DM1, and determined the biochemical and electrophysiological correlates in medial prefrontal cortex (mPFC), striatum and hippocampus (HPC). Male KO exhibited more cognitive impairment and depressive-like behavior than female KO mice. In the mPFC, KO mice showed an overexpression of proinflammatory microglia, increased transcriptional levels of Dat, Drd1, and Drd2, exacerbated dopamine levels, and abnormal neural spiking and oscillatory activities in the mPFC and HPC. Chronic treatment with methylphenidate (MPH) (1 and 3 mg/kg) reversed the behavioral deficits, reduced proinflammatory microglia in the mPFC, normalized prefrontal Dat and Drd2 gene expression, and increased Bdnf and Nrf2 mRNA levels. These findings unravel the mechanisms underlying the beneficial effects of MPH on cognitive deficits and depressive-like behaviors observed in Mbnl2 KO mice, and suggest that MPH could be a potential candidate to treat the CNS deficiencies in DM1 patients.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Disfunção Cognitiva/genética , Depressão/genética , Metilfenidato/farmacologia , Microglia/efeitos dos fármacos , Distrofia Miotônica , Afeto/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Proteínas de Ligação a RNA/genética , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo
7.
J Psychopharmacol ; 33(3): 347-354, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30451567

RESUMO

BACKGROUND: The unprecedented proliferation of new psychoactive substances (NPS) threatens public health and challenges drug policy. Information on NPS pharmacology and toxicity is, in most cases, unavailable or very limited and, given the large number of new compounds released on the market each year, their timely evaluation by current standards is certainly challenging. AIMS: We present here a metabolomics-targeted approach to predict the pharmacological profile of NPS. METHODS: We have created a machine learning algorithm employing the quantification of monoamine neurotransmitters and steroid hormones in rats to predict the similarity of new drugs to classical ones of abuse (MDMA (3,4-methyl enedioxy methamphetamine), methamphetamine, cocaine, heroin and Δ9-tetrahydrocannabinol). RESULTS: We have characterized each classical drug of abuse and two examples of NPS (mephedrone and JWH-018) following alterations observed in the targeted metabolome profile (monoamine neurotransmitters and steroid hormones) in different brain areas, plasma and urine at 1 h and 4 h post drug/vehicle administration. As proof of concept, our model successfully predicted the pharmacological profile of a synthetic cannabinoid (JWH-018) as a cannabinoid-like drug and synthetic cathinone (mephedrone) as a MDMA-like psychostimulant. CONCLUSION: Our approach allows a fast NPS pharmacological classification which will benefit both drug risk evaluation policies and public health.


Assuntos
Encéfalo/efeitos dos fármacos , Aprendizado de Máquina , Metabolômica/métodos , Psicotrópicos/farmacologia , Algoritmos , Animais , Encéfalo/metabolismo , Canabinoides/farmacologia , Alucinógenos/farmacologia , Masculino , Metanfetamina/análogos & derivados , Metanfetamina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Ratos , Ratos Wistar
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