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1.
J Med Chem ; 65(6): 4727-4751, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35245051

RESUMO

By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 µM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 µM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.


Assuntos
Monoaminoxidase , Fármacos Neuroprotetores , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ligantes , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Resveratrol/farmacologia
2.
Cell Biol Toxicol ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448959

RESUMO

Autophagy is a conserved intracellular catabolic pathway that removes cytoplasmic components to contribute to neuronal homeostasis. Accumulating evidence has increasingly shown that the induction of autophagy improves neuronal health and extends longevity in several animal models. Therefore, there is a great interest in the identification of effective autophagy enhancers with potential nutraceutical or pharmaceutical properties to ameliorate age-related diseases, such as neurodegenerative disorders, and/or promote longevity. Queen bee acid (QBA, 10-hydroxy-2-decenoic acid) is the major fatty acid component of, and is found exclusively in, royal jelly, which has beneficial properties for human health. It is reported that QBA has antitumor, anti-inflammatory, and antibacterial activities and promotes neurogenesis and neuronal health; however, the mechanism by which QBA exerts these effects has not been fully elucidated. The present study investigated the role of the autophagic process in the protective effect of QBA. We found that QBA is a novel autophagy inducer that triggers autophagy in various neuronal cell lines and mouse and fly models. The beclin-1 (BECN1) and mTOR pathways participate in the regulation of QBA-induced autophagy. Moreover, our results showed that QBA stimulates sirtuin 1 (SIRT1), which promotes autophagy by the deacetylation of critical ATG proteins. Finally, QBA-mediated autophagy promotes neuroprotection in Parkinson's disease in vitro and in a mouse model and extends the lifespan of Drosophila melanogaster. This study provides detailed evidences showing that autophagy induction plays a critical role in the beneficial health effects of QBA.

3.
Transl Psychiatry ; 10(1): 331, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989216

RESUMO

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.


Assuntos
Banisteriopsis , Células-Tronco Neurais , Animais , Camundongos , N,N-Dimetiltriptamina , Neurogênese , Chá
4.
Aging (Albany NY) ; 12(17): 16690-16708, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32903216

RESUMO

The research of new biomarkers for Parkinson's disease is essential for accurate and precocious diagnosis, as well as for the discovery of new potential disease mechanisms and drug targets. The main objective of this work was to identify metabolic changes that might serve as biomarkers for the diagnosis of this neurodegenerative disorder. For this, we profiled the plasma metabolome from mice with neurotoxin-induced Parkinson's disease as well as from patients with familial or sporadic Parkinson's disease. By using mass spectrometry technology, we analyzed the complete metabolome from healthy volunteers compared to patients with idiopathic or familial (carrying the G2019S or R1441G mutations in the LRRK2 gene) Parkinson's disease, as well as, from mice treated with 6-hydroxydopamine to induce Parkinson disease. Both human and murine Parkinson was accompanied by an increase in plasma levels of unconjugated bile acids (cholic acid, deoxycholic acid and lithocholic acid) and purine base intermediary metabolites, in particular hypoxanthine. The comprehensive metabolomic analysis of plasma from Parkinsonian patients underscores the importance of bile acids and purine metabolism in the pathophysiology of this disease. Therefore, plasma measurements of certain metabolites related to these pathways might contribute to the diagnosis of Parkinson's Disease.

5.
Mikrochim Acta ; 187(6): 338, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32430539

RESUMO

The published version of this article, unfortunately, contains errors. Corrections in references were incorrectly carried out. Also, the reduction of graphene oxide was carried out between the potential of -1.5 and 0.5 V, instead of 0.5 and 1.5 V.

6.
Mikrochim Acta ; 187(5): 288, 2020 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-32333119

RESUMO

A label-free biosensor is developed for the determination of plasma-based Aß1-42 biomarker in Alzheimer's disease (AD). The platform is based on highly conductive dual-layer of graphene and electrochemically reduced graphene oxide (rGO). The modification of dual-layer with 1-pyrenebutyric acid N-hydroxysuccinimide ester (Pyr-NHS) is achieved to facilitate immobilization of H31L21 antibody. The effect of these modifications were studied with morphological, spectral and electrochemical techniques. The response of the biosensor was evaluated using differential pulse voltammetry (DPV). The data was acquired at a working potential of ~ 180 mV and a scan rate of 50 mV s-1. A low limit of detection (LOD) of 2.398 pM is achieved over a wide linear range from 11 pM to 55 nM. The biosensor exhibits excellent specificity over Aß1-40 and ApoE ε4 interfering species. Thus, it provides a viable tool for electrochemical determination of Aß1-42. Spiked human and mice plasmas were used for the successful validation of the sensing platform in bio-fluidic samples. The results obtained from mice plasma analysis concurred with the immunohistochemistry (IHC) and magnetic resonance imaging (MRI) data obtained from brain analysis. Graphical abstract Schematic representation of the electrochemical system proposed for Aß1-42 determination: (a) modification of graphene screen-printed electrode (SPE) with monolayer graphene oxide (GO) followed by its electrochemical reduction generating graphene/reduced graphene oxide (rGO) dual-layer (b), modification of dual-layer with linker (c), Aß1-42 antibody (H31L21) (d), bovine serum albumin (BSA) (e) and Aß1-42 peptide (f).


Assuntos
Peptídeos beta-Amiloides/sangue , Técnicas Biossensoriais , Técnicas Eletroquímicas , Grafite/química , Fragmentos de Peptídeos/sangue , Animais , Biomarcadores/sangue , Humanos , Camundongos , Estrutura Molecular , Oxirredução
7.
Eur J Med Chem ; 190: 112090, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32018096

RESUMO

New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MT1R and MT2R, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and co-planarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MT1R and MT2R, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours.


Assuntos
Fator 2 Relacionado a NF-E2/agonistas , Neurogênese/efeitos dos fármacos , Oxidiazóis/farmacologia , Quinona Redutases/metabolismo , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Células CHO , Linhagem Celular Tumoral , Cricetulus , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Ligantes , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Naftalenos/síntese química , Naftalenos/metabolismo , Naftalenos/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/metabolismo , Ligação Proteica
8.
Mol Neurobiol ; 57(2): 806-822, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31473904

RESUMO

Parkinson's disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3', 5'-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson's disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease. Here, we have used in vitro and in vivo models of Parkinson's disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , Animais , Apoptose , Linhagem Celular , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/genética , Modelos Animais de Doenças , Neurônios Dopaminérgicos/enzimologia , Neurônios Dopaminérgicos/patologia , Embrião de Mamíferos/enzimologia , Humanos , Masculino , Mesencéfalo/enzimologia , Mesencéfalo/patologia , Neuroglia/enzimologia , Neuroglia/patologia , Oxidopamina , Regiões Promotoras Genéticas/genética , Ratos Wistar , Substância Negra/enzimologia , Substância Negra/patologia
9.
J Enzyme Inhib Med Chem ; 34(1): 712-727, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852270

RESUMO

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid - DBMA hybrids (1-13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer's disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), ß-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). After a funnel-type screening, 6,7-dimethoxychromone - DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Metilaminas/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flavonoides/química , Humanos , Masculino , Metilaminas/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química
10.
Int J Mol Sci ; 20(3)2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30743990

RESUMO

Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer's and Parkinson's diseases. A progressive neurodegenerative process and neuroinflammation occur, and no current therapies can prevent, slow, or halt disease progression. To date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. Therefore, early diagnosis and the discovery of new targets and novel therapies are of upmost importance. Neurodegenerative diseases, like in other age-related disorders, the progression of pathology begins many years before the onset of symptoms. Many efforts in this field have led to the conclusion that exits some similar events among these diseases that can explain why the aging brain is so vulnerable to suffer neurodegenerative diseases. This article reviews the current knowledge about these diseases by summarizing the most common features of major neurodegenerative disorders, their causes and consequences, and the proposed novel therapeutic approaches.


Assuntos
Doença de Alzheimer/terapia , Doença de Parkinson/terapia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Biomarcadores , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Gerenciamento Clínico , Humanos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Eur J Med Chem ; 156: 534-553, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30025348

RESUMO

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ1R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in σ1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.


Assuntos
Doença de Alzheimer/enzimologia , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Indanos/farmacologia , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Receptores sigma/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Donepezila , Inibidores Enzimáticos/química , Flavonoides/química , Humanos , Indanos/química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Modelos Moleculares , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/química , Piperidinas/química
12.
Sci Rep ; 7(1): 13526, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-29051532

RESUMO

The CCAAT/Enhancer binding protein ß (C/EBPß) is a transcription factor involved in numerous physiological as well as pathological conditions in the brain. However, little is known regarding its possible role in neurodegenerative disorders. We have previously shown that C/EBPß regulates the expression of genes involved in inflammatory processes and brain injury. Here, we have analyzed the effects of C/EBPß interference in dopaminergic cell death and glial activation in the 6-hydroxydopamine model of Parkinson's disease. Our results showed that lentivirus-mediated C/EBPß deprivation conferred marked in vitro and in vivo neuroprotection of dopaminergic cells concomitant with a significant attenuation of the level of the inflammatory response and glial activation. Additionally, C/EBPß interference diminished the induction of α-synuclein in the substantia nigra pars compacta of animals injected with 6-hydroxydopamine. Taking together, these results reveal an essential function for C/EBPß in the pathways leading to inflammatory-mediated brain damage and suggest novel roles for C/EBPß in neurodegenerative diseases, specifically in Parkinson's disease, opening the door for new therapeutic interventions.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Doença de Parkinson/patologia , Animais , Apoptose/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/antagonistas & inibidores , Proteína beta Intensificadora de Ligação a CCAAT/genética , Células Cultivadas , Modelos Animais de Doenças , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Masculino , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Oxidopamina/farmacologia , Doença de Parkinson/metabolismo , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , alfa-Sinucleína/metabolismo
13.
Sci Rep ; 7(1): 5309, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28706205

RESUMO

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.


Assuntos
Alcaloides/farmacologia , Banisteriopsis/química , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Alcaloides/isolamento & purificação , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Harmalina/farmacologia , Harmina/análogos & derivados , Harmina/farmacologia , Camundongos
14.
Future Med Chem ; 9(8): 731-748, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28485668

RESUMO

AIM: Since neuroinflammation is partially mediated by cAMP levels and PDE10A enzyme is able to regulate these levels being highly expressed in striatum, its inhibitors emerged as useful drugs to mitigate this inflammatory process and hence the neuronal death associated with Parkinson's disease (PD). Methodology & results: To study the utility of PDE10A as a pharmacological target for PD, in this work we propose the search and development of new PDE10A inhibitors that could be useful as pharmacological tools in models of the disease and presumably as potential drug candidates. By using different medicinal chemistry approaches we have discovered imidazole-like PDE10A inhibitors and showed their neuroprotective actions. CONCLUSION: Here, we demonstrate the neuroprotective effect of PDE10A inhibitors in cellular models of PD. [Formula: see text].


Assuntos
Imidazóis/farmacologia , Doença de Parkinson/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Doença de Parkinson/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química
15.
J Med Chem ; 60(12): 4983-5001, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28548834

RESUMO

Glycogen synthase kinase 3 ß (GSK-3ß) is a central target in several unmet diseases. To increase the specificity of GSK-3ß inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3ß activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3ß are presented here. Furthermore, we show how allosteric binders may overcome the ß-catenin side effects associated with strong GSK-3ß inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3ß may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3ß inhibition exhibits therapeutic effects.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Sítio Alostérico , Técnicas de Química Sintética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/patologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/patologia , Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/patologia , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , beta Catenina/metabolismo
16.
ACS Omega ; 2(8): 5215-5220, 2017 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30023743

RESUMO

Parkinson's disease (PD), an age-related neurodegenerative disorder that results from a progressive loss of dopaminergic neurons has an enormous economical and human cost. Unfortunately, only symptomatic treatment such as dopamine replacement therapy is available. Therefore, drugs with new mechanisms of action able to protect against neuronal cell death are an urgent need. We here report the in vivo efficacy on dopaminergic neuronal protection in a PD mouse model and the lack of toxicity in zebrafish and Ames test of benzothiazole-based casein kinase-1δ (CK-1δ) nanomolar inhibitors. On the basis of these results, we propose protein kinase CK-1δ inhibitors as the possible disease-modifying drugs for PD, benzothiazole 4 being a promising drug candidate for further development as a new therapy of this neurodegenerative disease.

17.
Stem Cells ; 35(2): 458-472, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27538853

RESUMO

The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling intracellular levels of cyclic adenosine 3',5'-monophosphate in the immune and central nervous system. We have previously shown that inhibitors of this enzyme are potent neuroprotective and anti-inflammatory agents. In addition, we also demonstrated that PDE7 inhibition induces endogenous neuroregenerative processes toward a dopaminergic phenotype. Here, we show that PDE7 inhibition controls stem cell expansion in the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the subventricular zone (SVZ) in the adult rat brain. Neurospheres cultures obtained from SGZ and SVZ of adult rats treated with PDE7 inhibitors presented an increased proliferation and neuronal differentiation compared to control cultures. PDE7 inhibitors treatment of neurospheres cultures also resulted in an increase of the levels of phosphorylated cAMP response element binding protein, suggesting that their effects were indeed mediated through the activation of the cAMP/PKA signaling pathway. In addition, adult rats orally treated with S14, a specific inhibitor of PDE7, presented elevated numbers of proliferating progenitor cells, and migrating precursors in the SGZ and the SVZ. Moreover, long-term treatment with this PDE7 inhibitor shows a significant increase in newly generated neurons in the olfactory bulb and the hippocampus. Also a better performance in memory tests was observed in S14 treated rats, suggesting a functional relevance for the S14-induced increase in SGZ neurogenesis. Taken together, our results indicate for the first time that inhibition of PDE7 directly regulates proliferation, migration and differentiation of neural stem cells, improving spatial learning and memory tasks. Stem Cells 2017;35:458-472.


Assuntos
Envelhecimento/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Hipocampo/enzimologia , Hipocampo/crescimento & desenvolvimento , Ventrículos Laterais/enzimologia , Ventrículos Laterais/crescimento & desenvolvimento , Neurogênese , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Giro Denteado/citologia , Hipocampo/efeitos dos fármacos , Ventrículos Laterais/efeitos dos fármacos , Masculino , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenótipo , Inibidores de Fosfodiesterase/farmacologia , Ratos Wistar , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo
18.
Neuropharmacology ; 116: 132-141, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28017790

RESUMO

Alterations in motor functions are well-characterized features observed in humans and experimental animals with thyroid hormone dysfunctions during development. We have previously suggested the implication of the endocannabinoid system in the hyperlocomotor phenotype observed in developmentally induced hypothyroidism in rats. In this work we have further analyzed the implication of endocannabinoids in the effect of hypothyroidism on locomotor activity. To this end, we evaluated the locomotor activity in adult mice lacking the cannabinoid receptor type 1 (CB1R-/-) and in their wild type littermates (CB1R+/+), whose hypothyroidism was induced in day 12 of gestation and maintained during the experimental period. Our results show that hypothyroidism induced a hyperlocomotor phenotype only in CB1R+/+, but not in CB1R-/- mice. In contrast with our previous results in rats, the expression of CB1R in striatum and the motor response to the cannabinoid agonist HU210 was unaltered in hypothyroid CB1R+/+ mice suggesting that the cannabinoid system is not altered by hypothyroidism. Also, no effect of HU210 was observed in locomotion of CB1R-/- mice. Finally, since the dopaminergic system plays a major role in the control of locomotor activity we studied its function in hypothyroid wild type and knockout animals. Our results show no alteration in the behavioral response induced by the dopamine D1 receptor agonist SKF38393. However we observed a decreased response to the dopamine D2 receptor antagonist haloperidol only in hypothyroid CB1R+/+ mice, which might indicate potential alterations in D2R signaling in these animals. In conclusion, our data suggest that the cannabinoid system is necessary for the induction of hyperlocomotor phenotype in mice with developmentally induced hypothyroidism.


Assuntos
Hipotireoidismo/metabolismo , Atividade Motora/fisiologia , Receptor CB1 de Canabinoide/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Agonistas de Receptores de Canabinoides/farmacologia , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Dronabinol/análogos & derivados , Dronabinol/farmacologia , Haloperidol/farmacologia , Imidazóis , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Percloratos , Fenótipo , Compostos de Potássio , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/genética , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
19.
J Neuroinflammation ; 13(1): 276, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27769255

RESUMO

BACKGROUND: The CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor implicated in the control of proliferation, differentiation, and inflammatory processes mainly in adipose tissue and liver; although more recent results have revealed an important role for this transcription factor in the brain. Previous studies from our laboratory indicated that CCAAT/enhancer-binding protein ß is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. More recently, we have shown that the complement component 3 gene (C3) is a downstream target of CCAAT/enhancer-binding protein ß and it could be a mediator of the proinflammatory effects of this transcription factor in neural cells. METHODS: Adult male Wistar rats (8-12 weeks old) were used throughout the study. C/EBPß+/+ and C/EBPß-/- mice were generated from heterozygous breeding pairs. Animals were injected or not with kainic acid, brains removed, and brain slices containing the hippocampus analyzed for the expression of both CCAAT/enhancer-binding protein ß and C3. RESULTS: In the present work, we have further extended these studies and show that CCAAT/enhancer-binding protein ß and C3 co-express in the CA1 and CA3 regions of the hippocampus after an excitotoxic injury. Studies using CCAAT/enhancer-binding protein ß knockout mice demonstrate a marked reduction in C3 expression after kainic acid injection in these animals, suggesting that indeed this protein is regulated by C/EBPß in the hippocampus in vivo. CONCLUSIONS: Altogether these results suggest that CCAAT/enhancer-binding protein ß could regulate brain disorders, in which excitotoxic and inflammatory processes are involved, at least in part through the direct regulation of C3.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Complemento C3/genética , Agonistas de Aminoácidos Excitatórios/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo , Ácido Caínico/toxicidade , Degeneração Neural/induzido quimicamente , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Antígeno CD11b/metabolismo , Complemento C3/metabolismo , Modelos Animais de Doenças , Fluoresceínas/metabolismo , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Degeneração Neural/patologia , Neuroglia/metabolismo , Neuroglia/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
20.
Future Med Chem ; 8(11): 1191-207, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27402296

RESUMO

BACKGROUND: Neurogenic agents emerge as innovative drugs for the treatment of Alzheimer's disease (AD), whose pathological complexity suggests strengthening research in the multi-target directed ligands strategy. RESULTS: By combining the lipoic acid structure with N-benzylpiperidine or N,N-dibenzyl(N-methyl)amine fragments, new multi-target directed ligands were obtained that act at three relevant targets in AD: σ-1 receptor (σ1R), ß-secretase-1 (BACE1) and acetylcholinesterase (AChE). Moreover, they show potent neurogenic properties, good antioxidant capacity and favorable CNS permeability. Molecular modeling studies on AChE, σ1R and BACE1 highlight relevant drug-protein interactions that may contribute to the development of new disease-modifying drugs. CONCLUSION: New lipoic-based σ1 agonists endowed with neurogenic, antioxidant, cholinergic and amyloid ß-peptide-reducing properties have been discovered for the potential treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Lipídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores sigma/agonistas , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Ácido Aspártico Endopeptidases/metabolismo , Inibidores Enzimáticos/química , Humanos , Lipídeos/química , Estrutura Molecular , Fármacos Neuroprotetores/química
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