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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361754

RESUMO

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.


Assuntos
Antipsicóticos/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Indóis/farmacologia , Nootrópicos/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Triptaminas/farmacologia , Animais , Antipsicóticos/síntese química , Família 2 do Citocromo P450/metabolismo , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/síntese química , Células Hep G2 , Humanos , Indóis/síntese química , Ligantes , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Nootrópicos/síntese química , Ligação Proteica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologia , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Inibidores de Captação de Serotonina/síntese química , Relação Estrutura-Atividade , Triptaminas/síntese química
2.
Neuropsychopharmacol Hung ; 23(2): 272-280, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34342419

RESUMO

Dopamine D3 receptors belong to the dopamine D2-like receptor family, which also includes D2 and D4 receptors. These receptors have limited anatomical distribution and are mainly expressed in brain regions and pathways that typically mediate the actions of antipsychotic drugs and medication used against Parkinson's disease (PD). The development of cariprazine, the fi rst D2/D3 partial agonist with prominent affi nity and preferential activity at D3 receptors over other dopamine receptor subtypes was a landmark that provided new insights into the neurochemical and physiological functions of D3 receptors. Preclinical studies and clinical trials provided evidence for the clinical advantages of cariprazine in the treatment of schizophrenia and bipolar disorder. Cariprazine became the fi rst antipsychotic drug approved for the treatment of manic, mixed and depressive episodes in bipolar I disorder. Antagonism of D3 receptors may play a role in ameliorating symptoms of levodopa-induced dyskinesia and psychosis in PD patients treated with levodopa/carbidopa. Accordingly, D3 receptors constitute attractive targets for developing novel drugs for the improved treatment of different psychiatric and neurological disorders. (Neuropsychopharmacol Hung 2021; 23(2): 272-280).


Assuntos
Antipsicóticos , Transtorno Bipolar , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Humanos , Receptores de Dopamina D2 , Receptores de Dopamina D3/uso terapêutico , Esquizofrenia/tratamento farmacológico
3.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201279

RESUMO

Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45ß, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45ß and Gilz gene expression and lurasidone normalized the Gadd45ß modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45ß gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45ß expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.


Assuntos
Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/metabolismo , Cloridrato de Lurasidona/farmacologia , Córtex Pré-Frontal/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico , Animais , Antipsicóticos/farmacologia , Modelos Animais de Doenças , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , RNA Mensageiro , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética
4.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299028

RESUMO

Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antipsicóticos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Sinergismo Farmacológico , Apoptose , Neoplasias da Mama/patologia , Proliferação de Células , Neoplasias do Colo/patologia , Quimioterapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas
5.
Clin Pharmacol Ther ; 110(3): 582-588, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34129738

RESUMO

Pharmacogenetics (PGx) research over the past 2 decades has produced extensive evidence for the influence of genetic factors on the efficacy and tolerability of antipsychotic treatment. However, the application of these findings to optimize treatment outcomes for patients in clinical practice has been limited. This paper presents a meta-review of key PGx findings related to antipsychotic response and common adverse effects, including antipsychotic-induced weight gain, tardive dyskinesia (TD), and clozapine-induced agranulocytosis (CIAG), and highlights advances and challenges in clinical implementation. Most robust findings from candidate gene and genomewide association studies were reported for associations between polymorphisms in CYP2D6 and exposure and response to specific antipsychotics. As a result, product labels and guidelines from various PGx expert groups have provided selection and dosing recommendations based on CYP2D6 metabolizer phenotypes for commonly prescribed antipsychotics. Other interesting genetic targets include DRD2 for antipsychotic response, SLC18A2 for TD, and the human leukocyte antigen (HLA) genes, HLA-DQB1 and HLA-B, for CIAG. Well-designed studies using large, well-characterized samples that leverages international collaborations are needed to validate previous findings, as well as discover new genetic variants involved in antipsychotic response and adverse effects.


Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Citocromo P-450 CYP2D6/genética , Variação Genética/efeitos dos fármacos , Variação Genética/genética , Antígenos HLA-B/genética , Humanos , Farmacogenética/métodos , Resultado do Tratamento
7.
Molecules ; 26(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073534

RESUMO

Schizophrenia is a severe psychiatric disorder affecting up to 1% of the worldwide population. Available therapy presents different limits comprising lack of efficiency in attenuating negative symptoms and cognitive deficits, typical features of schizophrenia and severe side effects. There is pressing requirement, therefore, to develop novel neuroleptics with higher efficacy and safety. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, appears to be implicated in the pathogenesis of schizophrenia. In particular, underproduction of this gaseous molecule is associated to this mental disease. The latter suggests that increment of nitrergic activity might be of utility for the medication of schizophrenia. Based on the above, molecules able to enhance NO production, as are NO donors, might represent a class of compounds candidates. Sodium nitroprusside (SNP) is a NO donor and is proposed as a promising novel compound for the treatment of schizophrenia. In the present review, we intended to critically assess advances in research of SNP for the therapy of schizophrenia and discuss its potential superiority over currently used neuroleptics.


Assuntos
Antipsicóticos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Humanos , Camundongos , Atividade Motora/efeitos dos fármacos , Óxido Nítrico/farmacologia , Nitroprussiato/química , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos
8.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073710

RESUMO

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.


Assuntos
Canabidiol/farmacologia , Isoxazóis/farmacologia , Neurônios/efeitos dos fármacos , Piperidinas/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Animais Recém-Nascidos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Canabidiol/uso terapêutico , Técnicas de Cultura de Células , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Feminino , Isoxazóis/uso terapêutico , Masculino , Neurônios/fisiologia , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Esquizofrenia/fisiopatologia , Caracteres Sexuais
9.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070699

RESUMO

Recently, accumulating preclinical findings suggest the possibility that functional abnormalities of tripartite synaptic transmission play important roles in the pathophysiology of schizophrenia and affective disorder. Therefore, to explore the novel mechanisms of mood-stabilizing effects associated with tripartite synaptic transmission, the present study determined the effects of mood-stabilizing antipsychotics, clozapine (CLZ), quetiapine (QTP) and brexpiprazole (BPZ), on the astroglial l-glutamate release and expression of connexin43 (Cx43) in the astroglial plasma membrane using cortical primary cultured astrocytes. Neither acute (for 120 min) nor subchronic (for 7 days) administrations of CLZ, QTP and BPZ affected basal astroglial l-glutamate release, whereas both acute and subchronic administration of CLZ, QTP and BPZ concentration-dependently enhanced astroglial l-glutamate release through activated hemichannels. Subchronic administration of therapeutic-relevant concentration of valproate (VPA), a histone deacetylase inhibiting mood-stabilizing antiepileptic drug, enhanced the stimulatory effects of therapeutic-relevant concentration of CLZ, QTP and BPZ on astroglial l-glutamate release through activated hemichannel. Subchronic administration of therapeutic-relevant concentration of CLZ, QTP and BPZ did not affect Cx43 protein expression in the plasma membrane during resting stage. After subchronic administration of VPA, acute and subchronic administration of therapeutic-relevant concentrations of CLZ increased Cx43 protein expression in the plasma membrane. Both acute administrations of therapeutic-relevant concentrations of QTP and BPZ did not affect, but subchronic administrations enhanced Cx43 protein expression in the astroglial plasma membrane. Furthermore, protein kinase B (Akt) inhibitor suppressed the stimulatory effects of CLZ and QTP, but did not affect Cx43 protein expression in the astroglial plasma membrane. These results suggest that three mood-stabilizing atypical antipsychotics, CLZ, QTP and BPZ enhance tripartite synaptic glutamatergic transmission due to enhancement of astroglial Cx43 containing hemichannel activities; however, the Cx43 activating mechanisms of these three mood-stabilizing antipsychotics were not identical. The enhanced astroglial glutamatergic transmission induced by CLZ, QTP and BPZ is, at least partially, involved in the actions of these three mood-stabilizing antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Astrócitos/metabolismo , Córtex Cerebral/metabolismo , Clozapina/farmacologia , Conexina 43/metabolismo , Fumarato de Quetiapina/farmacologia , Quinolonas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Tiofenos/farmacologia , Animais , Membrana Celular/metabolismo , Ratos , Ratos Sprague-Dawley
10.
ACS Chem Neurosci ; 12(12): 2218-2232, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34061513

RESUMO

Chemoinformatics appraisal and molecular docking were employed to investigate 225 complexes of 75 schizophrenia antipsychotics with the dopamine receptor subtypes D2R, D3R, and D4R. Considering the effective noncovalent interactions in the subtype-D2 receptor selectivity of antipsychotics, this study evaluated the possible physicochemical properties of ligands underlying the design of safer and more effective antipsychotics. The pan-assay interference compounds (PAINs) include about 25% of typical antipsychotics and 5% of atypicals. Popular antipsychotics like haloperidol, clozapine, risperidone, and aripiprazole are not PAINs. They have stronger interactions with D2R and D4R, but their interactions with D3R are slightly weaker, which is similar to the behavior of dopamine. In contrast to typical antipsychotics, atypical antipsychotics exhibit more noncovalent interactions with D4R than with D2R. These results suggest that selectivity to D2R and D4R comes from the synergy between hydrophobic and hydrogen-bonding interactions through their concomitant occurrence in the form of a hydrogen-bonding site adorned with hydrophobic contacts in antipsychotic-receptor complexes. All the antipsychotics had more synergic interactions with D2R and D4R in comparison with D3R. The atypical antipsychotics made a good distinction between the subtype D2 receptors with high selectivity to D4R. Among the popular antipsychotics, haloperidol, clozapine, and risperidone have hydrophobic-hydrogen-bonding synergy with D4R, while aripiprazole profits with D2R. The most important residue participating in the synergic interactions was threonine for D2R and cysteine for D4R. This work could be useful in informing and guiding future drug discovery and development studies aimed at receptor-specific antipsychotics.


Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Receptores de Dopamina D2 , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico
11.
Nat Commun ; 12(1): 2496, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941789

RESUMO

Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impair fear memory in male mice. Surprisingly, we demonstrate here the opposite effect of Tac2 blockade on enhancing fear memory consolidation in females. Furthermore, we show that CeA-testosterone in males, CeA-estradiol in females and Akt/GSK3ß/ß-Catenin signaling both mediate the opposite-sex differential Tac2 pathway regulation of fear memory.


Assuntos
Núcleo Central da Amígdala/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Consolidação da Memória/fisiologia , Precursores de Proteínas/antagonistas & inibidores , Taquicininas/antagonistas & inibidores , Animais , Antipsicóticos/farmacologia , Estradiol/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperidinas/farmacologia , Precursores de Proteínas/metabolismo , Fatores Sexuais , Transdução de Sinais , Taquicininas/metabolismo , Testosterona/metabolismo
12.
Comput Biol Med ; 134: 104452, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33984751

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is prevalent in patients receiving atypical antipsychotic drugs (AADs), but there are few effective interventions. The Traditional Chinese herbal decoction Liu-Yu-Tang (LYT) has achieved clinical improvement for AAD-induced MetS, but its pharmacological mechanism remains unclear. METHOD: A network pharmacology-based method was utilized in this study. First, the TCMSP and SwissTargetPrediction database were used to acquire plasma-absorbed components and putative targets of LYT, respectively. Second, an interaction network between shared targets of LYT and MetS was constructed using STRING online tool. Topological analyses were performed to extract hub gene targets. Finally, we did a pathway analysis of gene targets using the Kyoto Encyclopedia of Genes and Genomes (KEGG) to find biological pathways of LYT. RESULTS: We obtained 655 putative targets of LYT, 434 known targets of AADs, and 1577 MetS-related gene targets. There are 232 shared targets between LYT and MetS. Interaction network construction and topological analysis yielded 60 hub targets, of which 18 were major hub targets, among which IL-6, IL-8, TNF, PI3K, MAPK, and NF-κB (RELA) are the most important in LYT's treatment of AAD-induced MetS. Pathway enrichment analysis revealed a statistically high significance of the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis and the insulin resistance pathway. CONCLUSIONS: LYT may control activities of the pro-inflammatory cytokines IL-6, IL-8, TNF and the important signal transduction molecules PI3K, MAPKs, and NF-κB (RELA), regulating metabolic disturbance-related pathways like the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis, and the insulin resistance pathway, generating therapeutic effects for AAD-induced MetS.


Assuntos
Antipsicóticos , Aterosclerose , Medicamentos de Ervas Chinesas , Síndrome Metabólica , Antipsicóticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico
13.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805714

RESUMO

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.


Assuntos
Fármacos Cardiovasculares/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Trifluoperazina/farmacologia , Animais , Antipsicóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/induzido quimicamente , Hipóxia/genética , Hipóxia/fisiopatologia , Indóis/administração & dosagem , Monocrotalina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Survivina/genética , Survivina/metabolismo
14.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923479

RESUMO

Schizophrenia is a complex psychopathology whose treatment is still challenging. Given the limitations of existing antipsychotics, there is urgent need for novel drugs with fewer side effects. SEP-363856 (SEP-856) is a novel psychotropic agent currently under phase III clinical investigation for schizophrenia treatment. In this study, we investigated the ability of an acute oral SEP-856 administration to modulate the functional activity of specific brain regions at basal levels and under glutamatergic or dopaminergic-perturbed conditions in adult rats. We found that immediate-early genes (IEGs) expression was strongly upregulated in the prefrontal cortex and, to a less extent, in the ventral hippocampus, suggesting an activation of these regions. Furthermore, SEP-856 was effective in preventing the hyperactivity induced by an acute injection of phencyclidine (PCP), but not of d-amphetamine (AMPH). The compound effectively normalized the PCP-induced increase in IEGs expression in the PFC at all doses tested, whereas only the highest dose determined the major modulations on AMPH-induced changes. Lastly, SEP-856 acute administration corrected the cognitive deficits produced by subchronic PCP administration. Taken together, our data provide further insights on SEP-856, suggesting that modulation of the PFC may represent an important mechanism for the functional and behavioural activity of this novel compound.


Assuntos
Antipsicóticos/farmacologia , Cognição , Genes Precoces , Piranos/farmacologia , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Piranos/administração & dosagem , Piranos/uso terapêutico , Ratos , Ratos Sprague-Dawley
15.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920193

RESUMO

Atypical or second-generation antipsychotics are used in the treatment of psychosis and behavioral problems in older persons with dementia. However, these pharmaceutical drugs are associated with an increased risk of stroke in such patients. In this study, we evaluated the effects of risperidone treatment on phospholipid and sphingolipid composition and lipid raft function in peripheral blood mononuclear cells (PBMCs) of older patients (mean age >88 years). The results showed that the levels of dihydroceramides, very-long-chain ceramides, and lysophosphatidylcholines decreased in PBMCs of the risperidone-treated group compared with untreated controls. These findings were confirmed by in vitro assays using human THP-1 monocytes. The reduction in the levels of very-long-chain ceramides and dihydroceramides could be due to the decrease in the expression of fatty acid elongase 3, as observed in THP-1 monocytes. Moreover, risperidone disrupted lipid raft domains in the plasma membrane of PBMCs. These results indicated that risperidone alters phospholipid and sphingolipid composition and lipid raft domains in PBMCs of older patients, potentially affecting multiple signaling pathways associated with these membrane domains.


Assuntos
Ceramidas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Psicóticos/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/farmacologia , Membrana Celular/genética , Membrana Celular/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Metabolismo dos Lipídeos/genética , Lisofosfolipídeos/genética , Masculino , Olanzapina/farmacologia , Transtornos Psicóticos/sangue , Transtornos Psicóticos/patologia , Risperidona/farmacologia , Esfingolipídeos/genética
16.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922888

RESUMO

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.


Assuntos
Antipsicóticos/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/prevenção & controle , Animais , Antipsicóticos/uso terapêutico , D-Aminoácido Oxidase/antagonistas & inibidores , D-Aminoácido Oxidase/metabolismo , Antagonistas de Dopamina/uso terapêutico , Ácido Glutâmico/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Receptores Colinérgicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Esquizofrenia/metabolismo , Benzoato de Sódio/farmacologia , Ácido gama-Aminobutírico/metabolismo
17.
Molecules ; 26(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919175

RESUMO

Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI2-RSV1·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI2-RSV1·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal.


Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Aripiprazol/química , Aripiprazol/farmacologia , Modelos Moleculares , Cristalização , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular , Estrutura Molecular , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
18.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922377

RESUMO

Microglial cells are resident macrophages in the brain that have been implicated in the pathophysiology of schizophrenia. There is a lack of studies covering the effects of antipsychotics on microglial cells. The current literature points to a possible anti-inflammatory action without clear mechanisms of action. The aim of this study is to characterize the effects of haloperidol, risperidone and aripiprazole on BV-2 microglial cells in in vitro conditions. We have used immunofluorescence and flow cytometry to analyze the classical pro and anti-inflammatory markers, while a real-time metabolic assay (Seahorse) was used to assess metabolic function. We analyzed the expression of p70S6K to evaluate the mTOR pathway activity with Western blot. In this study, we demonstrate the varying effects of haloperidol, risperidone and aripiprazole administration in BV-2 microglial cells. All three tested antipsychotics were successful in reducing the pro-inflammatory action of microglial cells, although only aripiprazole increased the expression of anti-inflammatory markers. Most significant differences in the possible mechanisms of action were seen in the real-time metabolic assays and in the mTORC1 signaling pathway activity, with aripiprazole being the only antipsychotic to reduce the mTORC1 activity. Our results shed some new light on the effects of haloperidol, risperidone and aripiprazole action in microglial cells, and reveal a novel possible mechanism of action for aripiprazole.


Assuntos
Aripiprazol/farmacologia , Haloperidol/farmacologia , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Risperidona/farmacologia , Antipsicóticos/farmacologia , Sobrevivência Celular , Células Cultivadas , Humanos , Microglia/imunologia , Microglia/metabolismo
19.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572981

RESUMO

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Citalopram/farmacologia , Cloridrato de Lurasidona/farmacologia , Receptores de Serotonina/metabolismo , Vortioxetina/farmacologia , Animais , Antidepressivos/administração & dosagem , Antipsicóticos/administração & dosagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Citalopram/administração & dosagem , Ácido Glutâmico/metabolismo , Cloridrato de Lurasidona/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Vortioxetina/administração & dosagem
20.
Psychiatry Res ; 298: 113818, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33639407

RESUMO

Rap guanine nucleotide exchange factor 1 (RAPGEF1) is involved in cell adhesion and neuronal migration. Previously we found lower RAPGEF1 mRNA levels in Brodmann's area (BA) 9 in subjects with schizophrenia compared to controls. This study aimed to determine whether RAPGEF1 expression was altered in other brain regions implicated in schizophrenia and whether this was associated with suicide. Using qPCR, we measured the levels of RAPGEF1 in post-mortem BA 8 and 44 from 27 subjects with schizophrenia and 26 non-psychiatric control subjects. To address the effect of antipsychotic treatments, Rapgef1 mRNA levels were measured in the cortex from rats treated with typical antipsychotic drugs. There was no difference in RAPGEF1 normalised relative expression levels in BA 8 or 44. However, in BA 8, schizophrenia subjects had higher raw Ct RAPGEF1 levels compared to controls. There were higher RAPGEF1 levels in suicide completers compared to non-suicide schizophrenia subjects in BA 8. Rapgef1 expression levels in the rat cortex did not vary with antipsychotic treatment. Our findings suggest changes in RAPGEF1 expression may be limited to the dorsolateral prefrontal cortex from subjects with schizophrenia. Further investigation of the function of RAPGEF1 may lead to a greater understanding of the pathophysiology of schizophrenia.


Assuntos
Antipsicóticos , Esquizofrenia , Suicídio , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Córtex Cerebral , Córtex Pré-Frontal , Ratos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
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