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1.
J Agric Food Chem ; 68(6): 1609-1620, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31957426

RESUMO

Oxidative stress is known to be a key factor in many neurodegenerative diseases. Inflammation also plays a relevant role in a myriad of pathologies such as diabetes and atherosclerosis. Polyphenols coming from dietary sources, such as pterostilbene, may be beneficial in this type of diseases. However, most of them are rapidly metabolized and excreted, yielding very low phenolic bioavailability what makes it difficult to find out which are the mechanisms responsible for the observed bioactivity. Herein, we evaluate the effects of pterostilbene and its metabolites against H2O2-induced cell damage in human neuroblastoma SH-SY5Y cells and against lipopolysaccharide (LPS)-challenged RAW 264.7 macrophages. Among the metabolites tested, 3-methyl-4'-glucuronate-resveratrol (also called 4'-glucuronate pinostilbene, PIN-GlcAc, 11) prevented neuronal death via attenuation of reactive oxygen species (ROS) levels and increased REDOX activity in neurons. This compound is also able to ameliorate LPS-mediated inflammation on macrophages via inhibition of IL-6 and NO production. Thus, polyphenol from dietary sources could be part of potential functional foods designed to ameliorate the onset and progression of certain neurodegenerative diseases via oxidative stress reduction.


Assuntos
Anti-Inflamatórios/farmacologia , Neuroblastoma/metabolismo , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio/toxicidade , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Neuroblastoma/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/metabolismo
2.
Mini Rev Med Chem ; 20(1): 66-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31556858

RESUMO

Plants from the genus Hypericum, one genus of the Hypericaceae family, have attracted a lot of attention for their potential pharmaceutical applications. Most of the studies in the literature focus on H. perforatum L. (common St. John's wort), whose complex spectrum of bioactive compounds makes this species one of the top herbal remedies and supplements in the world. It is also important to compare the studies on other Hypericum species, both from the phytochemical and biological point of view. The aim of this review was to provide an update of most recent studies about biological investigations of plants belonging to Hypericum genus. The metabolic profiles of Hypericum spp. were also discussed in order to present a spectrum of secondary metabolites not previously identified in this genus.


Assuntos
Hypericum/metabolismo , Metaboloma , Extratos Vegetais/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Antidepressivos/química , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas/métodos , Humanos , Hypericum/química , Metabolômica/métodos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Metabolismo Secundário
3.
Nihon Yakurigaku Zasshi ; 154(3): 133-137, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527363

RESUMO

Hydrogen sulfide (H2S) has been focused as a biological mediator, which modulates signal transduction and protects cells and tissues from oxidative stress. H2S is also expected as a neuroprotectant because it has a neuroprotective activity. Endogenous H2S is mainly generated from L-cysteine. However, it is difficult to use L-cysteine as a neuroprotectant because of its neurotoxicity. In 2013, a novel biogenesis pathway of H2S from D-cysteine has been identified. In this pathway, D-amino acid oxidase (DAO) converts D-cysteine to 3-mercaptopyruvate (3MP), followed by the generation of H2S from 3MP by 3-mercaptopyrvate sulfurtransferase. DAO is especially abundant in cerebellum among various brain regions and mediates efficient generation of H2S from D-cysteine in the cerebellar tissues. In addition, D-cysteine has more potent neuroprotective activity in cerebellar primary neurons than L-cysteine. Cerebella Purkinje cells (PCs) are characterized by the highly-branched dendrites and are important for cerebellar functions. The dendritic shrinkage and degeneration of PCs are frequently observed in patients and model mice of cerebellar ataxias. We revealed that D-cysteine enhanced dendritic development of primary cultured PCs, but L-cysteine impaired the dendritic development. This effect of D-cysteine was inhibited by DAO inhibitors and reproduced by 3MP and a H2S donor, suggesting that this enhancement of dendritic development is caused by the production of H2S from D-cysteine. Taken together, D-cysteine would be available as a neuroprotectant against cerebellar ataxias, which are accompanied with dendritic shrinkage of cerebellar PCs.


Assuntos
Cisteína/metabolismo , Sulfeto de Hidrogênio/metabolismo , Neurônios/citologia , Fármacos Neuroprotetores/metabolismo , Animais , Células Cultivadas , D-Aminoácido Oxidase/antagonistas & inibidores , D-Aminoácido Oxidase/metabolismo , Humanos , Camundongos , Neurogênese , Estresse Oxidativo , Células de Purkinje/citologia
4.
Med Sci Monit ; 25: 5776-5784, 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31376345

RESUMO

BACKGROUND The purpose of this study was to investigate the role and mechanism of steroid receptor coactivator-interacting protein (SIP) in an astrocyte model of 1-methyl-4-phenylpyridinium (MPP⁺)-induced Parkinson's disease. MATERIAL AND METHODS To perform our study, a Parkinson's disease cell model was established by treating the rat glioblastoma cell line C6 with MPP⁺. SIP was overexpressed in C6 cells using SIP-plasmid. Cell viability and apoptosis were analyzed using MTT assay and flow cytometer respectively. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1ß levels were detected using enzyme linked immunosorbent assay and quantitative reverse transcription PCR. Besides, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production, and superoxide dismutase (SOD) enzyme activity were determined in the present study. For protein and mRNA detection, western blot assay, and qRT-PCR were performed respectively. RESULTS SIP was decreased in MPP⁺-induced C6 cells. SIP overexpression relieved MPP⁺-induced cytotoxicity of C6 cells, displayed as increased cell viability and reduced cell apoptosis and reduced LDH release. Besides, SIP inhibited MPP⁺-induced inflammatory response and oxidative stress, evidenced by decreased levels of inflammatory factors (TNF-alpha and IL-1ß), reduced ROS generation and enhanced SOD activity. Moreover, MPP⁺-induced nuclear factor-kappaB activation was inhibited by SIP overexpression. CONCLUSIONS SIP was downregulated in Parkinson's disease and it played a protective role in the development Parkinson's disease, thus may be a promising target for Parkinson's disease treatment.


Assuntos
Astrócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , 1-Metil-4-fenilpiridínio/farmacologia , Animais , Apoptose/efeitos dos fármacos , Astrócitos/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Biológicos , Fármacos Neuroprotetores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Esteroides/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Biomed Pharmacother ; 117: 109117, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226635

RESUMO

BACKGROUND: Ischemic stroke is significantly affected by the dysfunction of the miRNA network. Recent research has described that disordered expression of miR-130a is associated with ischemic stroke. Here, we aimed to investigate the possible mechanism of the miR-130a-mediated neuroprotection that follows ischemia-reperfusion (I/R) injury. METHOD: This study was comprised of two models: oxygen-glucose deprivation/Reperfusion (OGDR) and middle cerebral artery occlusion (MCAO). RT-PCR and immunoblotting were used to examine gene expression levels, and MTT assay and flow cytometric analysis were used to examine cell states. We also used 2, 3, 5-triphenyltetrazolium chloride (TTC) staining to assess the cerebral infarct volume. Then, we employed bioinformatics analysis and luciferase reporter assay to identify and validate the target molecule of miR-130a, PTEN. RESULTS: Our findings indicated that miR-130a expression was lower in PC12 cells after OGDR (oxygen-glucose deprivation/reperfusion) and in rats after MCAO (middle cerebral artery occlusion). Moreover, ectopic-expression of miR-130a can significantly improve cell survival rate and reduce cell apoptosis and ROS production in PC12 cells after OGDR. In addition, re-expression of miR-130a yielded an obvious reduction in MCAO-induced infarct volume and neurological deficits in rats. Bioinformatics analysis revealed that PTEN was a miR-130a target and could overturn the effect of miR-130a on cerebral ischemia, both in vivo and in vitro. Therefore, we set out to further investigate the PTEN-affected PI3K/AKT pathway and found that upregulation of miR-130a activated the PI3K/AKT pathway. CONCLUSIONS: Our data demonstrated that miR-130a prevented cerebral I/R damage by mediating the PTEN/PI3K/AKT axis. These preliminarily findings furthered our understanding of this mechanism and identified new potential therapeutic targets for ischemic stroke.


Assuntos
Isquemia Encefálica/genética , MicroRNAs/metabolismo , Fármacos Neuroprotetores/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acidente Vascular Cerebral/genética , Animais , Sequência de Bases , Sítios de Ligação , Isquemia Encefálica/complicações , Masculino , MicroRNAs/genética , Células PC12 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Acidente Vascular Cerebral/complicações
6.
Food Chem ; 297: 124975, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31253324

RESUMO

This study aimed to evaluate the formation of tryptophan derivatives in the kynurenine pathway during wort fermentation using a multi-response kinetic model and an empirical modified logistic model. Saccharomyces cerevisiae NCYC 88 (ale yeast) and S. pastorianus NCYC 203 (lager yeast) were used to understand the effect of fermentation type on tryptophan derivatives. According to the modified logistic model, tryptophan concentration was critical for the maximum production rate of kynurenic acid, a neuroprotective compound. The results indicated that utilization of tryptophan and kynurenic acid formation were faster in wort fermented with S. cerevisiae than with S. pastorianus. The reaction rate constants implied that the kynurenic acid formation stage was minor compared to other enzymatic reactions leading to NAD+ synthesis. Multi-response kinetic modeling of kynurenine pathway provided insights into tryptophan derivative formation, which can facilitate improved beer fermentation processing.


Assuntos
Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Fármacos Neuroprotetores/metabolismo , Preparações de Plantas/química , Saccharomyces/metabolismo , Triticum/química , Triptofano/análogos & derivados , Cerveja/análise , Vias Biossintéticas , Fermentação , Cinética , Modelos Logísticos , Saccharomyces cerevisiae/metabolismo
7.
Eur J Med Chem ; 178: 243-258, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185414

RESUMO

To address the multifactorial nature of Alzheimer's Disease (AD), a multi-target-directed ligand approach was herein developed. As a follow-up of our previous studies, a small library of newly designed 2-arylbenzofuran derivatives was evaluated towards cholinesterases and cannabinoid receptors. The two most promising compounds, 8 and 10, were then assessed for their neuroprotective activity and for their ability to modulate the microglial phenotype. Compound 8 emerged as able to fight AD from several directions: it restored the cholinergic system by inhibiting butyrylcholinesterase, showed neuroprotective activity against Aß1-42 oligomers, was a potent and selective CB2 ligand and had immunomodulatory effects, switching microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. Derivative 10 was a potent CB2 inverse agonist with promising immunomodulatory properties and could be considered as a tool for investigating the role of CB2 receptors and for developing potential immunomodulating drugs addressing the endocannabinoid system.


Assuntos
Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CHO , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Cricetulus , Desenho de Drogas , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
8.
Eur J Med Chem ; 177: 414-424, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158754

RESUMO

Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 µM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-ß (Aß) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aß1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.


Assuntos
Azepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Azepinas/síntese química , Azepinas/química , Azepinas/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Relação Dose-Resposta a Droga , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Neuropharmacology ; 155: 31-43, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31103617

RESUMO

Ghrelin is an orexigenic hormone that also plays an important role in mood disorders. Our previous studies demonstrated that ghrelin administration could protect against depression-like behaviors of chronic unpredictable mild stress (CUMS) in rodents. However, the mechanism related to the effect of ghrelin on CUMS mice has yet to be revealed. This article shows that ghrelin (5 nmol/kg/day for 2 weeks, i.p.) decreased depression-like behaviors induced by CUMS and increased hippocampal integrity (neurogenesis and spine density) measured via Ki67, 5-bromo-2-deoxyuridine (BrdU), doublecortin (DCX) labeling and Golgi-cox staining, which were decreased under CUMS. The behavioral phenotypes of Growth hormone secretagogue receptor (Ghsr)-null and wild type (WT) mice were evaluated under no stress condition and after CUMS exposure to determine the effect of Ghsr knockout on the behavioral phenotypes and stress susceptibility of mice. Ghsr-null mice exhibited depression-like behaviors under no stress condition. CUMS induced similar depression- and anxiety-like behavioral manifestations in both Ghsr-null and WT mice. A similar pattern of behavioral changes was observed after hippocampal GHSR knockdown. Additionally, both Ghsr knockout as well as CUMS exhibited deleterious effects on neurogenesis and spine density in the dentate gyrus (DG). Besides, CCK8 assay and 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assay showed that ghrelin has a proliferative effect on primary cultured hippocampal neural stem cells (NSCs) and this proliferation was blocked by D-Lys3-GHRP-6 (DLS, the antagonist of GHSR, 100 µM) pretreatment. Ghrelin-induced proliferation is associated with the inhibition of G1 arrest, and this inhibition was blocked by LY294002 (specific inhibitor of PI3K, 20 µM). Furthermore, the in vivo data displayed that LY294002 (50 nmol, i.c.v.) can significantly block the antidepressant-like action of exogenous ghrelin treatment. All these results suggest that ghrelin/GHSR signaling maintains the integrity of hippocampus and has an inherent neuroprotective effect whether facing stress or not.


Assuntos
Grelina/deficiência , Hipocampo/metabolismo , Neurogênese/fisiologia , Fármacos Neuroprotetores/metabolismo , Receptores de Grelina/deficiência , Estresse Psicológico/metabolismo , Animais , Células Cultivadas , Cromonas/farmacologia , Doença Crônica , Grelina/genética , Hipocampo/citologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfolinas/farmacologia , Neurogênese/efeitos dos fármacos , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/genética , Estresse Psicológico/prevenção & controle , Estresse Psicológico/psicologia
10.
Exp Mol Pathol ; 109: 16-24, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31067440

RESUMO

Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Recently, microRNAs (miRNAs) were emerging as important mediators in dopaminergic neuron biology. This study determined miR-410 expression in the 6-hydroxydopamine (6-OHDA)-induced in vitro cellular model of PD and explored the mechanistic role of miR-410 in the modulation of neuronal cell viability and apoptosis. Our data showed that 6-OHDA concentration-dependently suppressed neuronal cell viability and miR-410 expression in SH-SY5Y and PC12 cells. Overexpression of miR-410 partially restored the effects of 6-OHDA on neuronal cell viability, apoptosis, capsase-3 activity as well as reactive oxygen species (ROS) production. On the other hand, inhibition of miR-410 decreased neuronal cell viability and increased apoptotic rates, capase-3 activity as well as ROS production. Furthermore, the potential targets of miR-410 were predicted by TargetScan tool, and we verified that phosphatase and tensin homolog (PTEN) was a target of miR-410 as confirmed by the dual-luciferase reporter assay. MiR-410 overexpression attenuated PTEN expression and mediated the effects in the 6-OHDA-treated cells via targeting PTEN in SH-SY5Y and PC12 cells. Furthermore, 6-OHDA treatment suppressed the protein expression of phosphorylated AKT and phosphorylated mTOR, which was partially attenuated by miR-410 overexpression in SH-SY5Y and PC12 cells. MiR-410 overexpression increased phosphorylated AKT and phosphorylated mTOR protein expression, and this effect was attenuated by PTEN overexpression in both SH-SY5Y and PC12 cells. Collectively, this is the first study to demonstrate the neuroprotective effects of miR-410 in a 6-OHDA-induced cellular model of PD, and our data implied that miR-410 exerted its neuroprotective effects via regulating PTEN/AKT/mTOR signaling axis. The present study may suggest new paradigm to study the pathology of PD.


Assuntos
MicroRNAs/genética , PTEN Fosfo-Hidrolase/metabolismo , Transtornos Parkinsonianos/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Fármacos Neuroprotetores/metabolismo , Oxidopamina/toxicidade , Células PC12 , PTEN Fosfo-Hidrolase/genética , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
11.
Acta Biochim Biophys Sin (Shanghai) ; 51(6): 627-637, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31056648

RESUMO

Class B G-protein coupled receptors (GPCR) PAC1-R is a neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP)-preferring receptor that mediates the effective neuroprotective activity. Based on our previous data showing that doxycycline and minocycline work as the positive allosteric modulator (PAM) of PAC1-R, we used computer molecular docking and isothermal titration calorimetry assay to further determine the bindings of doxycycline/minocycline's derivatives including tetracycline/tigecycline with the N-terminal extracellular domain of PAC1-R (PAC1-EC1). Then the cAMP assay combined with the PAC1-R natural agonist PACAP27 was used to confirm the possible PAM roles of the small-molecule antibiotics. The results showed that tetracycline/tigecycline had significant lower affinity to PAC1-EC1 than doxycycline/minocycline, which was consistent with their non-positive allosteric modulation activity on PAC1-R. Furthermore, by comparing the key residues contributing to the PAM binding with the predicted allosteric site in PAC1-EC1, we characterized four motifs contributing to PAM binding in PAC1-EC1. The site-directed mutation results showed that ASN60 played the most important role in the PAM binding of the small-molecule antibiotics, while ASP116 played a sensitive marginal role in the PAM binding. These results not only help to explain the clinical and experimental neuroprotective effects of doxycycline/minocycline, but also help to characterize the PAM binding site in PAC1-EC1, which will promote the screening and characterization of novel small-molecule PAMs targeting PAC1-EC1 with drug development potency in nerve system disease.


Assuntos
Doxiciclina/metabolismo , Minociclina/metabolismo , Simulação de Acoplamento Molecular , Receptores de Neuropeptídeos/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Sequência de Aminoácidos , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Sítios de Ligação/genética , Células CHO , Cricetinae , Cricetulus , Doxiciclina/química , Doxiciclina/farmacologia , Humanos , Minociclina/química , Minociclina/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/genética , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/agonistas , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/química , Homologia de Sequência de Aminoácidos
12.
Neurotox Res ; 36(2): 411-423, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069754

RESUMO

Creatine is a nitrogenous organic acid that plays a central role as an energy buffer in high energy demanding systems, including the muscular and the central nervous system. It can be acquired from diet or synthesized endogenously, and its main destination is the system creatine/phosphocreatine that strengthens cellular energetics via a temporal and spatial energy buffer that can restore cellular ATP without a reliance on oxygen. This compound has been proposed to possess secondary roles, such as direct and indirect antioxidant, immunomodulatory agent, and possible neuromodulator. However, these effects may be associated with its bioenergetic role in the mitochondria. Given the fundamental roles that creatine plays in the CNS, several preclinical and clinical studies have tested the potential that creatine has to treat degenerative disorders. However, although in vitro and in vivo animal models are highly encouraging, most clinical trials fail to reproduce positive results suggesting that the prophylactic use for neuroprotection in at-risk populations or patients is the most promising field. Nonetheless, the only clearly positive data of the creatine supplementation in human beings are related to the (rare) creatine deficiency syndromes. It seems critical that future studies must establish the best dosage regime to increase brain creatine in a way that can relate to animal studies, provide new ways for creatine to reach the brain, and seek larger experimental groups with biomarkers for prediction of efficacy.


Assuntos
Encéfalo/metabolismo , Creatina/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/metabolismo , Animais , Encéfalo/patologia , Creatina/uso terapêutico , Metabolismo Energético/fisiologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fármacos Neuroprotetores/uso terapêutico
13.
Eur J Med Chem ; 174: 87-115, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029947

RESUMO

Given their therapeutic activity, natural products have been used in traditional medicines throughout the centuries. The growing interest of the scientific community in phytopharmaceuticals, and more recently in marine products, has resulted in a significant number of research efforts towards understanding their effect in the treatment of neurodegenerative diseases, such as Alzheimer's (AD), Parkinson (PD) and Huntington (HD). Several studies have shown that many of the primary and secondary metabolites of plants, marine organisms and others, have high affinities for various brain receptors and may play a crucial role in the treatment of diseases affecting the central nervous system (CNS) in mammalians. Actually, such compounds may act on the brain receptors either by agonism, antagonism, allosteric modulation or other type of activity aimed at enhancing a certain effect. The current manuscript comprehensively reviews the state of the art on the interactions between natural compounds and brain receptors. This information is of foremost importance when it is intended to investigate and develop cutting-edge drugs, more effective and with alternative mechanisms of action to the conventional drugs presently used for the treatment of neurodegenerative diseases. Thus, we reviewed the effect of 173 natural products on neurotransmitter receptors, diabetes related receptors, neurotrophic factor related receptors, immune system related receptors, oxidative stress related receptors, transcription factors regulating gene expression related receptors and blood-brain barrier receptors.


Assuntos
Produtos Biológicos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fármacos Neuroprotetores/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/toxicidade , Humanos , Ligantes , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/toxicidade , Receptores de Superfície Celular/química
14.
Int J Mol Med ; 43(6): 2523-2531, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017264

RESUMO

Docosahexaenoic acid (DHA) is an omega­3 polyunsaturated fatty acid, derived mainly from fish oil. It is well known that DHA is present in high concentrations in nervous tissue and plays an important role in brain development and neuroprotection. However, the molecular mechanisms underlying its role remain to be fully elucidated. In this study, to enhance our understanding of the pathophysiological role of DHA, we investigated the possible neuroprotective mechanisms of action of DHA against hydrogen peroxide (H2O2)­induced oxidative damage in a rat pheochromocytoma cell line (PC12). Specifically, we evaluated the viability, oxidation potential, and the expression and production of antioxidant/cytoprotective enzymes, and eventual apoptosis. We found that pre­treatment with DHA (24 h) protected the cells from H2O2­induced oxidative damage. In particular, pre­treatment with DHA: i) Antagonized the consistent decrease in viability observed following exposure to H2O2 for 24 h; ii) reduced the high levels of intracellular reactive oxygen species (ROS) associated with H2O2­induced oxidative stress; iii) increased the intracellular levels of enzymatic antioxidants [superoxide dismutase (SOD) and glutathione peroxidase (GSH­Px)] both under basal conditions and following H2O2 exposure; iv) augmented the intracellular levels of reduced glutathione (GSH) and ascorbic acid, while it reduced the malondialdehyde (MDA) levels under conditions of oxidative stress; v) upregulated the expression of nuclear factor (erythroid­derived 2)­like 2 (NFE2L2) and its downstream target protein, heme­oxygenase­1 (HO­1); and vi) induced an anti­apoptotic effect by decreasing Bax and increasing Bcl2 expression. These findings provide evidence suggesting that DHA is able to prevent H2O2­induced oxidative damage to PC12 cells, which is attributed to its antioxidant and anti­apoptotic effects via the regulation NFE2L2/HO­1 signaling. Therefore, DHA may play protective role in neurodegenerative diseases associated with oxidative stress.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/metabolismo , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Fármacos Neuroprotetores/metabolismo , Células PC12 , Ratos , Superóxido Dismutase/metabolismo
15.
Life Sci ; 227: 137-144, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31005550

RESUMO

AIMS: Incidence of stroke increases in postmenopausal women with dangerous consequences. In this study we used zeranol to protect ovariectomized (OVX) rats against cerebral I/R damage and our target is to identify the mechanism of its protection, in addition to investigating whether this mechanism inhibits inflammation (by preventing glial cell activation) and apoptosis. MAIN METHODS: First 18 ovariectomized rats were allocated into 3 groups: I/R group, zeranol+ I/R group and U0126, MEK1/2 inhibitor + zeranol+ I/R group. After 24 h reperfusion, protein expression of total extracellular signal-regulated protein kinase (t-ERK1/2), phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2), Bcl-2, and Bax were quantified. Second 36 female rats were allocated into 3 groups: sham group, I/R group (after ovariectomy by 7 weeks, rats exposed to cerebral I/R) and zeranol group (after ovariectomy by 2 weeks, rats received zeranol for 5 weeks). After 24 h of reperfusion, the following parameters were measured; total nitrate/nitrite, interleukin-10, myeloperoxidase, caspase-3, and finally immunohistochemistry analysis of glial fibrillary acidic protein, cyclooxygenase-2 in cortex and hippocampus (CA1) regions were performed. KEY FINDINGS: U-0126 administration reversed the neuroprotective effect induced by zeranol through decreasing ratio of p-ERK1/2:ERK1/2 and Bcl-2/Bax in brain tissue. Activation of ERK signaling pathway by zeranol caused reduction in brain apoptosis and inflammation. SIGNIFICANCE: Zeranol showed protective effect in OVX rats that were exposed to cerebral I/R by activation of ERK signaling pathway which was blocked by U0126. This protective effect in turns led to decrease inflammation and apoptosis.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Zeranol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Infarto Cerebral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Hipocampo/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ovariectomia , Ratos , Ratos Wistar , Reperfusão , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Zeranol/metabolismo
16.
Protein Pept Lett ; 26(7): 471-478, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30942142

RESUMO

Nerve agents have been used extensively in chemical warfare in the past. However, recent use of Novichok agents have reignited the debate on the threat posed by Organophosphorus Nerve Agents (OPNAs). The currently available therapy for OPNA toxicity is only symptomatic and is potentially ineffective in neutralizing OPNAs. Hence, there is a dire need to develop a prophylactic therapy for counteracting OPNA toxicity. In this regard, human paraoxonase 1 has emerged as the enzyme of choice. In this review, we have focussed upon the recent and past events of OPNA use, their mechanism of action and toxicity. Further, we have emphasized upon the potential of enzyme based therapy and the various advances in the development of paraoxonase 1 as a countermeasure for OPNA poisoning. Finally, we have elaborated the shortcomings of paraoxonase 1 and the work that needs to be undertaken in order to develop human paraoxonase 1 as a prophylactic against OPNA poisoning.


Assuntos
Arildialquilfosfatase/metabolismo , Arildialquilfosfatase/uso terapêutico , Agentes Neurotóxicos/envenenamento , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Intoxicação por Organofosfatos/terapia , Animais , Arildialquilfosfatase/toxicidade , Humanos , Fármacos Neuroprotetores/toxicidade , Intoxicação por Organofosfatos/prevenção & controle , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/toxicidade
17.
Innate Immun ; 25(4): 255-264, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30935267

RESUMO

The correlation of serum and synovial fluid (SF) pituitary adenylate cyclase-activating polypeptide (PACAP) levels with disease progression of primary knee osteoarthritis (OA) was explored. Radiographic severity of OA was determined by Kellgren-Lawrence (K-L) grades. PACAP levels were measured by ELISA before treatment, and 4 and 8 wk following hyaluronic acid (HA) injection. Levels of IL-1ß and MMP-3 were also detected. The numeric pain scale (NPS), revised Oxford Knee Score (OKS), and American Knee Society Score (AKSS) were employed to evaluate to symptomatic severity. Receiver-operating-characteristic (ROC) curve analysis was carried out to compare the diagnostic value of PACAP, IL-1ß, and MMP-3 for the K-L grade. PACAP concentrations in SF but not serum were significantly lower in OA patients compared with controls. SF PACAP levels were negatively associated with K-L grades and higher NPS as well as worse AKSS and OKS. Further analysis demonstrated that PACAP concentration in SF was negatively correlated with expressions of IL-1ß as well as MMP-3 and may act as a marker for radiographic progression along with MMP-3. Last, we found SF PACAP levels exhibited an incremental trend after HA injection. These findings confirmed the crucial role of PACAP deficiency in the development of primary knee OA.


Assuntos
Cartilagem Articular/diagnóstico por imagem , Fármacos Neuroprotetores/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Líquido Sinovial/metabolismo , Sinoviócitos/metabolismo , Progressão da Doença , Feminino , Humanos , Ácido Hialurônico/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite do Joelho
18.
Eur J Med Chem ; 169: 185-199, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877973

RESUMO

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related neurodegenerative disorders, affecting several millions of aged people globally. Among these disorders, AD is more severe, affecting about 7% of individuals aged 65 and above. AD is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while PD is primarily a movement disorder illness having three major kinesia or movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. AD is characterized by deposition of extracellular beta-amyloid (Aß) proteins and intracellular neurofibrillary tangles (NFT), composed of hyperphosphorylated tau proteins in the neurons located particularly in hippocampus and cerebral cortex regions of brain, resulting the neuronal loss, while PD is characterized by deposition of intraneuronal aggregates of mostly composed of alpha-synuclein gene as Lewy bodies (LB) in the striatal region, known as substantia nigra pars compacta (SNpc) of brain, leading to the death of dopaminergic neurons. These are known as pathological hallmarks of these diseases. However, in some overlapping cases, known as Alzheimer with Parkinson disease or vice versa, alpha-synuclein deposition in AD and tau deposition in PD patients are found. Oxidative stress-induced glial cells activation, neuroinflammation and mitochondrial dysfunction lead to various molecular events in brain neurons causing neuronal cell death in these neurodegenerative disorders. Currently used drugs for treatment of AD and PD only reduce the symptoms of these diseases, but unable to stop the process of neurodegeneration. Therefore, innovation of new synthetic drugs or discovery of natural drugs for the treatment of AD and PD, is a challenging task of basic science and clinical medicine. Plant iridoids such as catalpol and its 10-O-trans-p-coumaroyl derivative, geniposide, harpagoside, and loganin, and seco-iridoids, oleuropein and its aglycone and oleocanthal have been found to exhibit significant neuroprotective effect and the property of slowing down the process of neurogedeneration in AD and PD. These plant metabolites have been shown to ameliorate AD by increasing the expression of insulin degrading enzyme (IDE), neprilysin (NEP), PPAR-γ, and α-secretase, and decreasing the expression of ß-secretase (BACE-1) to reduce the levels of Aß oligomers (AßO) deposition in brain neurons. These plant metabolites reduced the expression of GSK-3ß and its receptor gene, PTEN to reduce hyperphosphorylation of tau proteins and neurofibrillary tangles (NFTs) formation. These metabolites improved the expressions of neuroprotective proteins, Bcl-2 via activations of growth-related protein-1 receptor (GLP-1R), PKC, MEK, MAPK/PI3K, and AMPK, and suppressed the expressions of pro-apoptotic proteins, Bax and caspase-3. Furthermore, these plant metabolites improved the lysosomal autophagy process by increasing the expression levels of Beclin-1, LC3II and cathepsin B genes for clearance of Aß and NFT, and increased the expression of transporter proteins, P-glycoprotein (P-gp) and low density lipoprotein receptor-related protein-1 (LRP-1) for the clearance of Aß load from brain across the blood-brain barrier (BBB) as well as increased the expression of PPAR-γ and ApoE proteins for clearance of Aß in ApoE mediated pathway from brain. Moreover, these plant metabolites reduced the cognitive impairment by increasing the expression of synaptic proteins, BDNF, PSD-95, SNAP-25, SYP and GAP-43 for improvement of learning and memory functions in AD. While among these iridoids, catalpol, 10-O-trans-p-coumaroylcatalpol, geniposide and harpagoside, in PD improved the expressions of GDNF and Bcl-2 proteins and TH-positive neurons by increasing the levels of antioxidant enzymes, SOD and GSH-PX and down-regulating insulin/IGF signalling via activation of MEK protein. Moreover, catalpol and its p-coumaroyl derivative in mutant nematode C. elegans model, up-regulated the expression of DAF-16, a FOXO family transcription factor and SKN-1 genes for improvement of lifespan and resistance against oxidative- and other stresses of mutated worms. Furthermore, geniposide increased the expression of autophagy-related LAMP-2A-protein for clearance of LB from dopaminergic neurons in PD brain via improving lysosomal autophagy process. The present review summarizes the neuroprotective activities and molecular mechanisms of these iridoids and secoiridoids, in prevention and/or treatment of both AD and PD. This review will be helpful to find out the research gap on these plant metabolites in this field to use them as potential drugs against these disorders.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Iridoides/uso terapêutico , Magnoliopsida/química , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Animais , Humanos , Iridoides/química , Iridoides/metabolismo , Magnoliopsida/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo
19.
Mol Brain ; 12(1): 23, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909971

RESUMO

It is now generally accepted that the extra-skeleton functionalities of bone are multifaceted. Its endocrine functions came first to light when it was realized that osteoblasts, the bone forming cells, maintain energy homeostasis by improving glucose metabolism, insulin sensitivity and energy expenditure through osteocalcin, a multipurpose osteokine secreted by osteoblasts. Recently, the emerging knowledge on the functional aspects of this osteokine expanded to properties including adult and maternal regulation of cognitive functions. Therapeutic potential of this osteokine has also been recently reported in experimental Parkinson's disease models. This review highlights such findings on the functions of osteocalcin in the brain and emphasizes on exploring and analyzing much more in-depth basic and clinical studies.


Assuntos
Encéfalo/metabolismo , Cognição/fisiologia , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/fisiopatologia , Osteocalcina/metabolismo , Transdução de Sinais , Animais , Humanos , Doença dos Neurônios Motores/terapia , Fármacos Neuroprotetores/metabolismo
20.
J Agric Food Chem ; 67(7): 1831-1838, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30742443

RESUMO

Roots of Glehnia littoralis have been used to heal stroke as a traditional medicine. Even though many studies on this plant have been conducted, the secondary metabolites produced by its endophytes and their bioactivities have not been investigated thus far. Therefore, a new meroditerpenoid named sartorypyrone E (1) and eight known compounds (2-9) were isolated from extracts of cultured Neosartorya fischeri JS0553, an endophyte of G. littoralis. The isolated metabolites were identified using spectroscopic methods and chemical reaction, based on a comparison to literature data. Relative and absolute stereochemistries of compound 1 were also elucidated. To identify the protective effects of isolated compounds (1-9) in HT22 cells against glutamate-induced cytotoxicity, we assessed inhibition of cell death, intracellular reactive oxygen species (ROS) accumulation, and calcium ion (Ca2+) influx. Among the isolates, compound 8, identified as fischerin, showed significant neuroprotective activity on glutamate-mediated HT22 cell death through inhibition of ROS, Ca2+ influx, and phosphorylation of mitogen-activated protein kinase, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38. The results suggested that the metabolites produced by the endophyte N. fischeri JS0553 might be related to the neuroprotective activity of its host plant, G. littoralis.


Assuntos
Apiaceae/microbiologia , Neosartorya/metabolismo , Fármacos Neuroprotetores/metabolismo , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Transformada , Ácido Glutâmico/toxicidade , Hipocampo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Naftalenos/isolamento & purificação , Naftalenos/farmacologia , Neosartorya/isolamento & purificação , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Piridonas/isolamento & purificação , Piridonas/farmacologia , Pironas/metabolismo , Pironas/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores
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