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1.
Food Chem ; 339: 127849, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858383

RESUMO

Anthocyanin-rich purple highland barley has attracted great attention recently due to its health benefits in humans. The composition of the purified anthocyanin extract (PAE) from purple highland barley bran (PHBB) was characterized by liquid chromatography-mass spectrometry (LC-MS) with a high acylated anthocyanin profile. PAE exhibited high antioxidant activity and potential neuroprotective effects on cobalt chloride (CoCl2)-induced hypoxic damage in PC12 cells by maintaining cell viability, restoring cell morphology, inhibiting lactic dehydrogenase (LDH) leakage, reducing reactive oxygen species (ROS) levels, enhancing antioxidant enzyme activities, inhibiting cell apoptosis, and attenuating cell cycle arrest. Treatment cells (PC12 and U2OS) with PAE activated autophagy, indicating that autophagy possibly acted as a survival mechanism against CoCl2-induced injury. This study demonstrated that PAE from the PHBB was a high-quality natural functional food colorant and potentially could be used as a preventive agent for brain dysfunction caused by hypoxic damage.


Assuntos
Antocianinas/análise , Antioxidantes/química , Hordeum/química , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cobalto/toxicidade , Hordeum/metabolismo , Humanos , Espectrometria de Massas , Fármacos Neuroprotetores/farmacologia , Células PC12 , Extratos Vegetais/análise , Extratos Vegetais/farmacologia , Ratos , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo
2.
Science ; 370(6513)2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33033186

RESUMO

Excitotoxicity induced by NMDA receptors (NMDARs) is thought to be intimately linked to high intracellular calcium load. Unexpectedly, NMDAR-mediated toxicity can be eliminated without affecting NMDAR-induced calcium signals. Instead, excitotoxicity requires physical coupling of NMDARs to TRPM4. This interaction is mediated by intracellular domains located in the near-membrane portions of the receptors. Structure-based computational drug screening using the interaction interface of TRPM4 in complex with NMDARs identified small molecules that spare NMDAR-induced calcium signaling but disrupt the NMDAR/TRPM4 complex. These interaction interface inhibitors strongly reduce NMDA-triggered toxicity and mitochondrial dysfunction, abolish cyclic adenosine monophosphate-responsive element-binding protein (CREB) shutoff, boost gene induction, and reduce neuronal loss in mouse models of stroke and retinal degeneration. Recombinant or small-molecule NMDAR/TRPM4 interface inhibitors may mitigate currently untreatable human neurodegenerative diseases.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Descoberta de Drogas , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Sinalização do Cálcio , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Doenças Neurodegenerativas/tratamento farmacológico , Domínios Proteicos , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/uso terapêutico , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Canais de Cátion TRPM/genética , Ativação Transcricional
3.
PLoS One ; 15(9): e0223815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32997672

RESUMO

Allium roseum is an important medicinal and aromatic plant, specific to the North African flora and a rich source of important nutrients and bioactive molecules including flavonoids and organosulfur compounds whose biological activities and pharmacological properties are well known. In the present study, the inhibition of amyloid beta protein toxicity by the ethanolic extract of this plant is investigated for the first time. Preliminary biochemical analyses identified kæmpferol and luteolin-7-o-glucoside as the more abundant phenolic compounds. The effects of A. roseum extract (ARE) on aggregation and aggregate cytotoxicity of amyloid beta-42 (Aß42), whose brain aggregates are a hallmark of Alzheimer's disease, were investigated by biophysical (ThT assay, Dynamic light scattering and transmission electron microscopy) and cellular assays (cytotoxicity, aggregate immunolocalization, ROS measurement and intracellular Ca2+ imaging). The biophysical data suggest that ARE affects the structure of the Aß42 peptide, inhibits its polymerization, and interferes with the path of fibrillogenesis. The data with cultured cells shows that ARE reduces Aß42 aggregate toxicity by inhibiting aggregate binding to the cell membrane and by decreasing both oxidative stress and intracellular Ca2+. Accordingly, ARE could act as a neuroprotective factor against Aß aggregate toxicity in Alzheimer's disease.


Assuntos
Allium/química , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Extratos Vegetais/farmacologia , Agregação Patológica de Proteínas/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Cálcio/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Citosol/metabolismo , Avaliação Pré-Clínica de Medicamentos , Difusão Dinâmica da Luz , Etanol/química , Humanos , Microscopia Eletrônica de Transmissão , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Agregação Patológica de Proteínas/patologia , Espécies Reativas de Oxigênio/metabolismo
4.
Int J Nanomedicine ; 15: 5977-5989, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32904394

RESUMO

Purpose: Baicalin (BA) has a good neuroprotective effect, but it is eliminated quickly in the body and does not easily reach the brain. In this experiment, borneol (BO) was used as an auxiliary drug to prepare borneol-baicalin-liposomes (BO-BA-LP) to prolong the efficacy time of BA, synergistically synergize, introduce drugs into the brain, and better exert the therapeutic effect on cerebral ischemia-reperfusion (I/R) injury. Methods: Through single-factor inspection and response surface optimization analysis, obtained the best preparation process of BO-BA-LP and characterized by various analytical techniques. Validated the long-term effectiveness of BA-BO-LP through pharmacokinetic studies and conducted pharmacodynamic studies on the middle cerebral artery occlusion (MCAO) rat model to verify the therapeutic effect of BO-BA-LP on cerebral I/R injury. Results: The optimum preparation conditions of BO-BA-LP were as follows: the dosage of BO was 9.55 mg, the ratio of phospholipid to drug was 4.02:1, the ratio of phospholipid to cholesterol was 7.25:1, the entrapment efficiency (EE) was 41.49%, and the drug loading (DL) was 4.29%. The particle size range of the liposomes was 167.1 nm, and the polydispersity index (PDI) range was 0.113. The results of pharmacokinetic experiments showed that the combination of BA and BO liposomes effectively improved the pharmacokinetic parameters of BA and prolonged the half-life of BA. Pharmacodynamic studies have found that, compared with BA-LP, BO-BA-LP can significantly improve neurological deficits, cerebral infarction volume, and brain pathological states on MCAO rats. Conclusion: These results demonstrated that BO-BA-LP can improve the circulation of drugs in the blood, and the addition of BO can enhance the therapeutic effect of BA and effectively improve cerebral I/R.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Canfanos/farmacologia , Flavonoides/farmacologia , Lipossomos/química , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Canfanos/administração & dosagem , Canfanos/farmacocinética , Sinergismo Farmacológico , Flavonoides/administração & dosagem , Flavonoides/química , Flavonoides/farmacocinética , Meia-Vida , Infarto da Artéria Cerebral Média , Lipossomos/farmacocinética , Lipossomos/farmacologia , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Fosfolipídeos/química , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
5.
EBioMedicine ; 59: 102980, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862101

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. METHODS: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. FINDING: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds. INTERPRETATION: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). FUNDING: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Compostos Organosselênicos/uso terapêutico , Superóxido Dismutase-1/metabolismo , Esclerose Amiotrófica Lateral/mortalidade , Esclerose Amiotrófica Lateral/patologia , Animais , Azóis/química , Azóis/metabolismo , Azóis/uso terapêutico , Betacoronavirus/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Dimerização , Modelos Animais de Doenças , Estabilidade Enzimática , Camundongos , Camundongos Transgênicos , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Compostos Organosselênicos/química , Compostos Organosselênicos/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Superóxido Dismutase-1/genética , Taxa de Sobrevida , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo
6.
Food Chem ; 333: 127456, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663750

RESUMO

Bioprospecting for seaweed-derived multimodal acting products have earned increasing attention in the fight against diseases of multifactorial origin, such as neurodegenerative conditions. This is a pioneer study on the in vitro screening of neuroactive properties of phlorotannin-targeted extracts from edible Fucus species. Phlorotannin extracts exhibited multifunctional antioxidant properties, which were suggested to be responsible for counteracting glutamate toxicity in neuronal human-derived SH-SY5Y cells. They also inhibited the activity of enzymes (cholinesterases, monoaminoxidases A and B, and tyrosinase) linked to a set of events that contribute to the onset/progression of neurodegeneration. In general, the bioactivities were correlated with the total phlorotannin content and phloroglucinol tetramers were suggested to be behind the observed effects. The capacity of the phlorotannin extracts to interact with multiple in vitro targets underpinning neurodegeneration points to the potential interest of the selected seaweed species for development of new added-value products and promising neuroactive agents.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Fucus/química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Alimentos , Ácido Glutâmico/toxicidade , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Floroglucinol/química , Floroglucinol/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Análise de Componente Principal , Alga Marinha/química
7.
J Med Chem ; 63(13): 6909-6923, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32545964

RESUMO

Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke. These neuroprognostic agents are inflammation-targeted gadolinium compounds conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs). Our results demonstrated that gadolinium-based MRI contrast agents conjugated with NSAIDs suppressed the increase in cyclooxygenase-2 (COX-2) levels, ameliorated glial activation, and neuron damage that are phenotypic for stroke by mitigating neuroinflammation, which prevented reperfusion injury. In addition, this study showed that the neuroprognostic agents are promising T1 molecular MRI contrast agents for detecting precise reperfusion injury locations at the molecular level. Our results build on this new concept of neuroprognostics as a novel management strategy for ischemia-reperfusion injury, combining neuroprotection and molecular diagnostics.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Gadolínio/química , Imagem por Ressonância Magnética , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/prevenção & controle , Acidente Vascular Cerebral/complicações , Animais , Anti-Inflamatórios não Esteroides/química , Meios de Contraste/química , Ciclo-Oxigenase 2/química , Masculino , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Conformação Proteica , Ratos , Ratos Sprague-Dawley
8.
Food Chem ; 329: 127168, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512395

RESUMO

A polyphenols-rich extract was obtained from polyvinylpolypyrrolidone (PVPP) winery residue, and its neuroprotective effects and ability to modulate the kinetics of type 2 diabetes-relevant enzymes were characterized. The PVPP-white wine extract is a mixture of polyphenols (840.08 ± 161.25 µg/mg, dry weight) dominated by proanthocyanidins and hydroxycinnamic acids, affording strong antioxidant activity, as detected by the protection of membrane lipids against oxidation and superoxide radical anion scavenging activity. Regarding type 2 diabetes framework, the extract inhibits α-glucosidase (Ki = 166.9 µg/mL) and aldose reductase (Ki = 127.5 µg/mL) through non-competitive mechanisms. Despite the modest ability to inhibit rat brain acetylcholinesterase, it protects neuronal SH-SY5Y cells against oxidative damage promoted by glutamate, decreasing reactive oxygen species generation and preserving cell redox state. Thus, PVPP-white wine extract has potential to support the development of functional foods and/or nutraceuticals aiming neuroprotection and glucose homeostasis regulation, with high relevance in Alzheimers disease and type 2 diabetes interlink.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Povidona/análogos & derivados , Vinho , Acetilcolinesterase , Aldeído Redutase/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Proteínas Ligadas por GPI/antagonistas & inibidores , Ácido Glutâmico/toxicidade , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/prevenção & controle , Oxirredução , Extratos Vegetais/química , Polifenóis/análise , Polifenóis/farmacologia , Povidona/química , Proantocianidinas/química , Proantocianidinas/farmacologia , Ratos , Vinho/análise
9.
Int J Nanomedicine ; 15: 2841-2858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425521

RESUMO

Introduction: Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against Aß oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting. Methods: Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice. Results: In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology. Conclusion: Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Cumarínicos/farmacologia , Lipossomos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacocinética , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Polietilenoglicóis/química , Presenilina-1/genética , Ratos Sprague-Dawley , Distribuição Tecidual , Transferrina/química
10.
Chemistry ; 26(32): 7299-7308, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32358806

RESUMO

Alzheimer's disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)-1 and (S)-1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC-ECD coupling. (R)-1 and (S)-1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)-enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short- and long-term memory at low dosages.


Assuntos
Eriodictyon/química , Flavanonas/química , Flavonoides/química , Luteolina/química , Fármacos Neuroprotetores/química , Animais , Cromatografia Líquida de Alta Pressão , Camundongos , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Estereoisomerismo
11.
J Nanobiotechnology ; 18(1): 61, 2020 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-32306970

RESUMO

Primary intracerebral hemorrhage (ICH) is a leading cause of long-term disability and death worldwide. Drug delivery vehicles to treat ICH are less than satisfactory because of their short circulation lives, lack of specific targeting to the hemorrhagic site, and poor control of drug release. To exploit the fact that metal ions such as Fe2+ are more abundant in peri-hematomal tissue than in healthy tissue because of red blood cell lysis, we developed a metal ion-responsive nanocarrier based on a phosphonated calix[4]arene derivative in order to deliver the neuroprotective agent dauricine (DRC) specifically to sites of primary and secondary brain injury. The potential of the dauricine-loaded nanocarriers for ICH therapy was systematically evaluated in vitro and in mouse models of autologous whole blood double infusion. The nanocarriers significantly reduced brain water content, restored blood-brain barrier integrity and attenuated neurological deficits by inhibiting the activation of glial cells, infiltration by neutrophils as well as production of pro-inflammatory factors (IL-1ß, IL-6, TNF-α) and matrix-metalloprotease-9. These results suggest that our dauricine-loaded nanocarriers can improve neurological outcomes in an animal model of ICH by reducing inflammatory injury and inhibiting apoptosis and ferroptosis.


Assuntos
Benzilisoquinolinas/química , Calixarenos/química , Hemorragia Cerebral/patologia , Portadores de Fármacos/química , Metais/química , Nanoestruturas/química , Fármacos Neuroprotetores/química , Fenóis/química , Tetra-Hidroisoquinolinas/química , Animais , Benzilisoquinolinas/administração & dosagem , Benzilisoquinolinas/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Interleucina-1beta/metabolismo , Íons/química , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Organofosfonatos/química , Espécies Reativas de Oxigênio/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/farmacologia
12.
Arch Biochem Biophys ; 689: 108382, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32343976

RESUMO

Nicotine is a psychoactive alkaloid of tobacco, which is ingested during cigarettes or electronic cigarette smoking. Extensive consumption of nicotine induced oxidative stress. Accordingly, it is implicated in many pathophysiology brain disorders and triggers neurodegeneration. In this study, we investigated the protective role of Spirulina platensis-lipopolysaccharides (S.LPS) and the low dose-ionizing radiation (LD-IR) against the induced neurotoxicity in the rats' brain due to the prolonged administration of high nicotine levels. Rats treated with nicotine for two months showed alterations in the oxidative stress markers (malondialdehyde (MDA), reduced glutathione (GSH) and oxidized glutathione disulfide (GSSG)), antioxidant enzymes (superoxide dismutase (SOD), catalase (Cat), glutathione enzymes (GPx and GST)) as well as several pro-inflammatory markers (Tumor Necrosis Factor-alpha (TNF-α), Interleukin-17 (IL-17), and Nuclear Factor-kappa B (NF-κB)), and induced apoptosis through Caspase-3 activity. Nicotine also upregulated the mRNA gene expression of cytochrome P450 enzymes (CYP2B1 and CYP2E1), Cyclin-dependent kinase 5 (CDK5), Toll-Like Receptor 4 (TLR4), and phospho-Tau (p-Tau) protein expression. Besides, it downregulated the alpha-7 nicotinic receptor (α7nAChR) mRNA gene expression accompanied by a decline in the calcium (Ca2+) level. S.LPS exhibited antioxidant, anti-inflammatory, anti-apoptotic and neuroprotective activities, which counteracting the detrimental effects of chronic nicotine administration. LD-IR demonstrated comparable effects to S.LPS. Exposure of rats to LD-IR enhanced the neuroprotective effects of S.LPS against nicotine toxicity. The light microscopic examination of the brain tissues was in agreement with the biochemical investigations. These findings display that S.LPS and LD-IR mitigated the oxidative stress and the impairment of rats' brain induced by nicotine, due to regulation of the mRNA gene expression of cytochrome P450 enzymes (CYP2B1 and CYP2E1) and the signaling pathway of Tau protein phosphorylation.


Assuntos
Encéfalo/efeitos dos fármacos , Estimulantes Ganglionares/efeitos adversos , Lipopolissacarídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Nicotina/efeitos adversos , Spirulina , Animais , Antioxidantes/química , Antioxidantes/uso terapêutico , Encéfalo/patologia , Encéfalo/efeitos da radiação , Lipopolissacarídeos/química , Masculino , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Radiação Ionizante , Radioterapia , Ratos , Ratos Wistar , Agentes de Cessação do Hábito de Fumar/efeitos adversos , Spirulina/química
13.
Arch Biochem Biophys ; 686: 108364, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315653

RESUMO

Fucoxanthin (Fx), a major carotenoid found in brown seaweed, is known to show a unique and wide variety of biological activities. Upon absorption, Fx is metabolized to fucoxanthinol and amarouciaxanthin, and these metabolites mainly accumulate in visceral white adipose tissue (WAT). As seen in other carotenoids, Fx can quench singlet oxygen and scavenge a wide range of free radicals. The antioxidant activity is related to the neuroprotective, photoprotective, and hepatoprotective effects of Fx. Fx is also reported to show anti-cancer activity through the regulation of several biomolecules and signaling pathways that are involved in either cell cycle arrest, apoptosis, or metastasis suppression. Among the biological activities of Fx, anti-obesity is the most well-studied and most promising effect. This effect is primarily based on the upregulation of thermogenesis by uncoupling protein 1 expression and the increase in the metabolic rate induced by mitochondrial activation. In addition, Fx shows anti-diabetic effects by improving insulin resistance and promoting glucose utilization in skeletal muscle.


Assuntos
Suplementos Nutricionais/análise , Alga Marinha/química , Xantofilas/química , Xantofilas/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Descoberta de Drogas , Radicais Livres/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Resistência à Insulina , Fígado/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Depuradores/metabolismo , Oxigênio Singlete/metabolismo , Proteína Desacopladora 1/química , Proteína Desacopladora 1/metabolismo , Xantofilas/efeitos adversos , beta Caroteno/análogos & derivados , beta Caroteno/química
14.
Biochem Pharmacol ; 177: 113977, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32298691

RESUMO

Citicoline or CDP-choline is a drug, made up by a cytidine 5'-diphosphate moiety and choline, which upon adsorption is rapidly hydrolyzed into cytidine 5'-diphosphate and choline, easily bypassing the blood-brain barrier. Once in the brain, these metabolites are used to re-synthesize citicoline in neurons and in the other cell histo-types which uptake them. Citicoline administration finds broad therapeutic application in the treatment of glaucoma as well as other retinal disorders by virtue of its safety profile and neuro-protective and neuroenhancer activity, which significantly improves the visual function. Further, though supported by limited clinical studies, this molecule finds therapeutic application in neurodegenerative disease, delaying the cognitive decline in Alzheimer's Disease (AD) and Parkinson's Disease (PD) subjects. In this work we show that citicoline greatly affects the proteolytic activity of the 20S proteasome on synthetic and natural substrates, functioning as a bimodal allosteric modulator, likely binding at multiple sites. In silico binding simulations identify several potential binding sites for citicoline on 20S proteasome, and their topology envisages the possibility that, by occupying some of these pockets, citicoline may induce a conformational shift of the 20S proteasome, allowing to sketch a working hypothesis for the structural basis of its function as allosteric modulator. In addition, we show that over the same concentration range citicoline affects the distribution of assembled proteasome populations and turn-over of ubiquitinated proteins in SH-SY5Y and SK-N-BE human neuroblastoma cells, suggesting its potential role as a regulator of proteostasis in nervous cells.


Assuntos
Citidina Difosfato Colina/química , Fármacos Neuroprotetores/química , Nootrópicos/química , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/química , Regulação Alostérica , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Citidina Difosfato Colina/farmacologia , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteostase/efeitos dos fármacos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Termodinâmica , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
15.
Eur J Med Chem ; 194: 112242, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32248004

RESUMO

N-Methyl-d-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC50 values in a Ca2+ entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.


Assuntos
Lactamas/farmacologia , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Barreira Hematoencefálica/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Lactamas/síntese química , Lactamas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Doenças do Sistema Nervoso/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
16.
Sci Rep ; 10(1): 6654, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313035

RESUMO

Microglia act as the protective immune cell of the brain. By surveying the tissue to identify and rectify problems, they function to maintain the health of brain cells. The prion protein N-terminal cleavage fragment, N1, has demonstrated neuroprotective activities in vitro and in vivo. This study aimed to elucidate whether N1 could modulate microglial function and, if so, determine the consequences for the surrounding tissue. Using a mixed neuronal lineage and microglia co-culture system, we showed that N1 stimulation changed overall morphology and metabolism, suggesting enhanced cellular viability. Furthermore, N1 induced an increase in Cxcl10 secretion in the co-cultures. Recombinant Cxcl10, administered exogenously, mediated the changes in the mixed neuronal lineage culture morphology and metabolism in the absence of microglia, but no effect of Cxcl10 was observed on microglia cultured on their own. Direct cell-to-cell contact was required for N1 to influence microglia in the co-cultures, and this was linked with restructuring of microglial membrane composition to include a higher GM1 content at interaction sites with surrounding cells. Our findings show that N1 can play a regulatory role in microglial function in the context of an inter-connected network of cells by changing both cellular interaction sites and cytokine secretion.


Assuntos
Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas Priônicas/farmacologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Técnicas de Cocultura , Gangliosídeo G(M1)/metabolismo , Expressão Gênica/efeitos dos fármacos , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Knockout , Microglia/citologia , Microglia/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Cultura Primária de Células , Proteínas Priônicas/química , Proteínas Priônicas/metabolismo , Príons/química , Príons/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Análise de Célula Única
17.
Oxid Med Cell Longev ; 2020: 6431459, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184918

RESUMO

Oxidative stress has been recognized as the contributor to diabetic peripheral neuropathy (DPN). Antioxidant strategies have been most widely explored; nevertheless, whether antioxidants alone prevent DPN still remains inconclusive. In the present study, we established an in vitro DPN cell model for drug screening using Schwann RSC96 cells under high glucose (HG) stimulation, and we found that salvianolic acid A (SalA) mitigated HG-induced injury evidenced by cell viability and myelination. Mechanistically, SalA exhibited strong antioxidative effects by inhibiting 1,1-diphenyl-2-picrylhydrazyl (DPPH) and reducing reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) content, as well as upregulating antioxidative enzyme mRNA expression. In addition, SalA significantly extenuated neuroinflammation with downregulated inflammatory factor mRNA expression. Furthermore, SalA improved the mitochondrial function of HG-injured Schwann cells by scavenging mitochondrial ROS, decreasing mitochondrial membrane potential (MMP), and enhancing ATP production, as well as upregulating oxidative phosphorylation gene expression. More importantly, we identified nuclear factor-E2-related factor 2 (Nrf2) as the upstream regulator which mediated protective effects of SalA on DPN. SalA directly bound to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) and thus disrupted the interaction of Nrf2 and Keap1 predicted by LibDock of Discovery Studio. Additionally, SalA significantly inhibited Nrf2 promoter activity and downregulated Nrf2 mRNA expression but without affecting Nrf2 protein expression. Interestingly, SalA upregulated the nuclear Nrf2 expression and promoted Nrf2 nuclear translocation by high content screening assay, which was confirmed to be involved in its antiglucotoxicity effect by the knockdown of Nrf2 in RSC96 cells. In KK-Ay mice, we demonstrated that SalA could effectively improve the abnormal glucose and lipid metabolism and significantly protect against DPN by increasing the mechanical withdrawal threshold and sciatic nerve conduction velocity and restoring the ultrastructural impairment of the injured sciatic nerve induced by diabetes. Hence, SalA protected against DPN by antioxidative stress, attenuating neuroinflammation, and improving mitochondrial function via Nrf2. SalA may be prospective therapeutics for treating DPN.


Assuntos
Ácidos Cafeicos/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Lactatos/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Linhagem Celular , Neuropatias Diabéticas/patologia , Glucose/toxicidade , Inflamação/patologia , Lactatos/química , Lactatos/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura
18.
Sci Adv ; 6(12): eaay9751, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32206718

RESUMO

Rational design of potent antioxidative agent with high biocompatibility is urgently needed to treat ischemic reperfusion-induced ROS-mediated cerebrovascular and neural injury during ischemia strokes. Here, we demonstrate an in situ synthetic strategy of bioactive zeolitic imidazolate framework-8-capped ceria nanoparticles (CeO2@ZIF-8 NPs) to achieve enhanced catalytic and antioxidative activities and improved stroke therapeutic efficacy. This nanosystem exhibits prolonged blood circulation time, reduced clearance rate, improved BBB penetration ability, and enhanced brain accumulation, where it effectively inhibits the lipid peroxidation in brain tissues in middle cerebral artery occlusion mice and reduces the oxidative damage and apoptosis of neurons in brain tissue. CeO2@ZIF-8 also suppresses inflammation- and immune response-induced injury by suppressing the activation of astrocytes and secretion of proinflammatory cytokines, thus achieving satisfactory prevention and treatment in neuroprotective therapy. This study also sheds light on the neuroprotective action mechanisms of ZIF-8-capped nanomedicine against reperfusion-induced injury in ischemic stroke.


Assuntos
Imidazóis/farmacologia , Estruturas Metalorgânicas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Nanomedicina Teranóstica , Zeolitas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Técnicas de Química Sintética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Imidazóis/química , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/ultraestrutura , Camundongos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Zeolitas/química
19.
Sci Rep ; 10(1): 3748, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111938

RESUMO

Cognitive impairments such as dementia are common in later life, and have been suggested to occur via a range of mechanisms, including oxidative stress, age-related changes to cellular metabolism, and a loss of phospholipids (PLs) from neuronal membranes. PLs are a class of amphipathic lipids that form plasma membrane lipid bilayers, and that occur at high concentrations in neuronal membranes. Our previous study suggested that a porcine liver decomposition product (PLDP) produced via protease treatment may improve cognitive function at older ages, by acting as a rich source of PLs and lysophospholipids (LPLs); however, its specific composition remains unclear. Thus, the present study used a novel liquid chromatography electrospray ionization tandem mass spectrometric (LC-MS/MS) protocol to identify the major PLs and LPLs in PLDP. Furthermore, it assessed the effect of identified LPLs on microglial activation in vitro, including cell shape, proliferation, and cell morphology. The results of the conducted analyses showed that PLDP and PLDP-derived LPLs concentration-dependently modulate microglial activation in vitro. In particular, lysophosphatidylcholine (LPC) concentration-dependently promotes cell morphology, likely via effects mediated by the enzyme autotaxin (ATX), since inhibiting ATX also promoted cell morphology, while conversely, increasing ATX production (via treatment with high levels of LPC) abolished this effect. These findings suggest that LPC is likely neuroprotective, and thus, support the importance of further research to assess its use as a therapeutic target to treat age-related cognitive impairments, including dementia.


Assuntos
Fígado/química , Lisofosfatidilcolinas/farmacologia , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Animais , Humanos , Lisofosfatidilcolinas/química , Fármacos Neuroprotetores/química , Suínos
20.
Int J Mol Sci ; 21(6)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197305

RESUMO

Alpinia oxyphylla Miq. (i.e., A. oxyphylla), a traditional Chinese medicine, can exert neuroprotective effects in ameliorating mild cognitive impairment and improving the pathological hallmarks of Alzheimer's disease (AD). Here, 50 active compounds and 164 putative targets were collected and identified with 251 clinically tested AD-associated target proteins using network pharmacology approaches. Based on the Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichments, the compound-target-pathway-disease/protein-protein interaction network constructions, and the network topological analysis, we concluded that A. oxyphylla may have neuroprotective effects by regulating neurotransmitter function, as well as brain plasticity in neuronal networks. Moreover, closely-related AD proteins, including the amyloid-beta precursor protein, the estrogen receptor 1, acetylcholinesterase, and nitric oxide synthase 2, were selected as the bottleneck nodes of network for further verification by molecular docking. Our analytical results demonstrated that terpene, as the main compound of A. oxyphylla extract, exerts neuroprotective effects, providing new insights into the development of a natural therapy for the prevention and treatment of AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Bases de Dados Factuais , Fármacos Neuroprotetores/farmacologia , Alpinia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Humanos , Fármacos Neuroprotetores/química , Fitoterapia
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