Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68.494
Filtrar
1.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500626

RESUMO

We investigated the protective effect and mechanisms of apigenin against cognitive impairments in a scopolamine-injected mouse model. Our results showed that intraperitoneal (i.p.) injection of scopolamine leads to learning and memory dysfunction, whereas the administration of apigenin (synthetic compound, 100 and 200 mg/kg/day) improved cognitive ability, which was confirmed by behavioral tests such as the T-maze test, novel objective recognition test, and Morris water maze test in mice. In addition, scopolamine-induced lipid peroxidation in the brain was attenuated by administration of apigenin. To further evaluate the protective mechanisms of apigenin on cognitive and memory function, Western blot analysis was carried out. Administration of apigenin decreased the B-cell lymphoma 2-associated X/B-cell lymphoma 2 (Bax/Bcl-2) ratio and suppressed caspase-3 and poly ADP ribose polymerase cleavage. Furthermore, apigenin down-regulated the ß-site amyloid precursor protein-cleaving enzyme, along with presenilin 1 (PS1) and PS2 protein levels. Apigenin-administered mice showed lower protein levels of a receptor for advanced glycation end-products, whereas insulin-degrading enzyme, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) expression were promoted by treatment with apigenin. Therefore, this study demonstrated that apigenin is an active substance that can improve cognitive and memory functions by regulating apoptosis, amyloidogenesis, and BDNF/TrkB signaling pathways.


Assuntos
Apigenina/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Neurônios/efeitos dos fármacos , Escopolamina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360675

RESUMO

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 µg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 µg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo , Sesquiterpenos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Técnicas de Cocultura , Escherichia coli , Humanos , Inflamação/induzido quimicamente , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substâncias Protetoras/farmacologia
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445634

RESUMO

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called "hunger" hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.


Assuntos
Corpo Estriado/patologia , Dieta Hiperlipídica/efeitos adversos , Grelina/metabolismo , Neurônios/patologia , Obesidade/patologia , Receptor CB2 de Canabinoide/metabolismo , Receptores de Grelina/metabolismo , Animais , Canabinoides/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Grelina/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB2 de Canabinoide/genética , Receptores de Grelina/genética , Transdução de Sinais , Regulação para Cima
4.
Molecules ; 26(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34361628

RESUMO

In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.


Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores , Acidente Vascular Cerebral/tratamento farmacológico , Tiazepinas , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Mitocôndrias , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Tiazepinas/síntese química , Tiazepinas/farmacologia
5.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361702

RESUMO

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.


Assuntos
Antioxidantes/síntese química , Inibidores da Colinesterase/síntese química , Cumarínicos/síntese química , Curcumina/análogos & derivados , Inibidores da Monoaminoxidase/síntese química , Fármacos Neuroprotetores/síntese química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Curcumina/farmacologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Córtex Motor/citologia , Córtex Motor/enzimologia , Nanopartículas/química , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fármacos Neuroprotetores/farmacologia , Picratos/antagonistas & inibidores , Cultura Primária de Células , Ratos , Relação Estrutura-Atividade
6.
Anesth Analg ; 133(3): 781-793, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34403389

RESUMO

BACKGROUND: Orexin, a neuropeptide derived from the perifornical area of the hypothalamus (PeFLH), promotes the recovery of propofol, isoflurane, and sevoflurane anesthesias, without influencing the induction time. However, whether the orexinergic system also plays a similar role in desflurane anesthesia, which is widely applied in clinical practice owing to its most rapid onset and offset time among all volatile anesthetics, has not yet been studied. In the present study, we explored the effect of the orexinergic system on the consciousness state induced by desflurane anesthesia. METHODS: The c-Fos staining was used to observe the activity changes of orexinergic neurons in the PeFLH and their efferent projection regions under desflurane anesthesia. Chemogenetic and optogenetic techniques were applied to compare the effect of PeFLH orexinergic neurons on the induction, emergence, and maintenance states between desflurane and isoflurane anesthesias. Orexinergic terminals in the paraventricular thalamic nucleus (PVT) were manipulated with pharmacologic, chemogenetic, and optogenetic techniques to assess the effect of orexinergic circuitry on desflurane anesthesia. RESULTS: Desflurane anesthesia inhibited the activity of orexinergic neurons in the PeFLH, as well as the neuronal activity in PVT, basal forebrain, dorsal raphe nucleus, and ventral tegmental area, as demonstrated by c-Fos staining. Activation of PeFLH orexinergic neurons prolonged the induction time and accelerated emergence from desflurane anesthesia but only influenced the emergence in isoflurane anesthesia, as demonstrated by chemogenetic and pharmacologic techniques. Meanwhile, optical activation of orexinergic neurons exhibited a long-lasting inhibitory effect on burst-suppression ratio (BSR) under desflurane anesthesia, and the effect may be contributed by the orexinergic PeFLH-PVT circuitry. The orexin-2 receptor (OX2R), but not orexin-1 receptor (OX1R), in the PVT, which had been inhibited most significantly by desflurane, mediated the proemergence effect of desflurane anesthesia. CONCLUSIONS: We discovered, for the first time, that orexinergic neurons in the PeFLH could not only influence the maintenance and emergence from isoflurane and desflurane anesthesias but also affect the induction under desflurane anesthesia. Furthermore, this specific effect is probably mediated by orexinergic PeFLH-PVT circuitry, especially OX2Rs in the PVT.


Assuntos
Período de Recuperação da Anestesia , Anestesia por Inalação , Anestésicos Inalatórios/farmacologia , Estado de Consciência/efeitos dos fármacos , Desflurano/farmacologia , Isoflurano/farmacologia , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Orexinas/farmacologia , Potenciais de Ação , Animais , Eletroencefalografia , Masculino , Núcleos da Linha Média do Tálamo/metabolismo , Neurônios/metabolismo , Optogenética , Receptores de Orexina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo
7.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443598

RESUMO

Apocynin (APO) is a known multi-enzymatic complexed compound, employed as a viable NADPH oxidase (NOX) inhibitor, extensively used in both traditional and modern-day therapeutic strategies to combat neuronal disorders. However, its therapeutic efficacy is limited by lower solubility and lesser bioavailability; thus, a suitable nanocarrier system to overcome such limitations is needed. The present study is designed to fabricate APO-loaded polymeric nanoparticles (APO-NPs) to enhance its therapeutic efficacy and sustainability in the biological system. The optimized APO NPs in the study exhibited 103.6 ± 6.8 nm and -13.7 ± 0.43 mV of particle size and zeta potential, respectively, along with further confirmation by TEM. In addition, the antioxidant (AO) abilities quantified by DPPH and nitric oxide scavenging assays exhibited comparatively higher AO potential of APO-NPs than APO alone. An in-vitro release profile displayed a linear diffusion pattern of zero order kinetics for APO from the NPs, followed by its cytotoxicity evaluation on the PC12 cell line, which revealed minimal toxicity with higher cell viability, even after treatment with a stress inducer (H2O2). The stability of APO-NPs after six months showed minimal AO decline in comparison to APO only, indicating that the designed nano-formulation enhanced therapeutic efficacy for modulating NOX-mediated ROS generation.


Assuntos
Acetofenonas/química , Acetofenonas/farmacologia , Peróxido de Hidrogênio/farmacologia , NADPH Oxidases/metabolismo , Nanopartículas/química , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos
8.
Eur J Endocrinol ; 185(4): R93-R101, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370694

RESUMO

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.


Assuntos
Hormônios Peptídicos/fisiologia , Animais , Regulação do Apetite/efeitos dos fármacos , Regulação do Apetite/genética , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/genética , Humanos , Hipertensão/genética , Hipertensão/terapia , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Obesidade/genética , Obesidade/terapia , Hormônios Peptídicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Somatostatina/química , Somatostatina/farmacologia , Somatostatina/fisiologia
9.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360854

RESUMO

Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine's actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.


Assuntos
Anestésicos/farmacologia , Antidepressivos/farmacologia , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Receptores de N-Metil-D-Aspartato/metabolismo
10.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445117

RESUMO

Neonicotinoids are a class of insecticides that exert their effect through a specific action on neuronal nicotinic acetylcholine receptors (nAChRs). The success of these insecticides is due to this mechanism of action, since they act as potent agonists of insect nAChRs, presenting low affinity for vertebrate nAChRs, which reduces potential toxic risk and increases safety for non-target species. However, although neonicotinoids are considered safe, their presence in the environment could increase the risk of exposure and toxicity. On the other hand, although neonicotinoids have low affinity for mammalian nAChRs, the large quantity, variety, and ubiquity of these receptors, combined with its diversity of functions, raises the question of what effects these insecticides can produce in non-target species. In the present systematic review, we investigate the available evidence on the biochemical and behavioral effects of neonicotinoids on the mammalian nervous system. In general, exposure to neonicotinoids at an early age alters the correct neuronal development, with decreases in neurogenesis and alterations in migration, and induces neuroinflammation. In adulthood, neonicotinoids induce neurobehavioral toxicity, these effects being associated with their modulating action on nAChRs, with consequent neurochemical alterations. These alterations include decreased expression of nAChRs, modifications in acetylcholinesterase activity, and significant changes in the function of the nigrostriatal dopaminergic system. All these effects can lead to the activation of a series of intracellular signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. Neonicotinoid-induced changes in nAChR function could be responsible for most of the effects observed in the different studies.


Assuntos
Mamíferos/metabolismo , Neonicotinoides/toxicidade , Receptores Nicotínicos/metabolismo , Animais , Humanos , Inseticidas/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
11.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445294

RESUMO

Coupling of cells to biomaterials is a prerequisite for most biomedical applications; e.g., neuroelectrodes can only stimulate brain tissue in vivo if the electric signal is transferred to neurons attached to the electrodes' surface. Besides, cell survival in vitro also depends on the interaction of cells with the underlying substrate materials; in vitro assays such as multielectrode arrays determine cellular behavior by electrical coupling to the adherent cells. In our study, we investigated the interaction of neurons and glial cells with different electrode materials such as TiN and nanocolumnar TiN surfaces in contrast to gold and ITO substrates. Employing single-cell force spectroscopy, we quantified short-term interaction forces between neuron-like cells (SH-SY5Y cells) and glial cells (U-87 MG cells) for the different materials and contact times. Additionally, results were compared to the spreading dynamics of cells for different culture times as a function of the underlying substrate. The adhesion behavior of glial cells was almost independent of the biomaterial and the maximum growth areas were already seen after one day; however, adhesion dynamics of neurons relied on culture material and time. Neurons spread much better on TiN and nanocolumnar TiN and also formed more neurites after three days in culture. Our designed nanocolumnar TiN offers the possibility for building miniaturized microelectrode arrays for impedance spectroscopy without losing detection sensitivity due to a lowered self-impedance of the electrode. Hence, our results show that this biomaterial promotes adhesion and spreading of neurons and glial cells, which are important for many biomedical applications in vitro and in vivo.


Assuntos
Interfaces Cérebro-Computador , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Titânio/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Matriz Extracelular/química , Ouro/química , Ouro/farmacologia , Humanos , Teste de Materiais , Nanoestruturas/química , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Compostos de Estanho/química , Compostos de Estanho/farmacologia , Titânio/química
12.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371875

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) have been recognized to cause neurobehavioral dysfunctions and disorder of cognition and behavioral patterns in childhood. Momordica charantia L. (MC) has been widely known for its nutraceutical and health-promoting properties. To date, the effect of MC for the prevention and handling of PAHs-induced neurotoxicity has not been reported. In the current study, the neuroprotective effects of MC and its underlying mechanisms were investigated in mouse hippocampal neuronal cell line (HT22); moreover, in silico analysis was performed with the phytochemicals MC to decipher their potential function as neuroprotectants. MC was demonstrated to possess neuroprotective effect by reducing reactive oxygen species' (ROS') production and down-regulating cyclin D1, p53, and p38 mitogen-activated protein kinase (MAPK) protein expressions, resulting in the inhibition of cell apoptosis and the normalization of cell cycle progression. Additionally, 28 phytochemicals of MC and their competence on inhibiting cytochrome P450 (CYP: CYP1A1, CYP1A2, and CYP1B1) functions were resolved. In silico analysis of vitamin E and stigmasterol revealed that their binding to either CYP1A1 or CYP1A2 was more efficient than the binding of each positive control (alizarin or purpurin). Together, MC is potentially an interesting neuroprotectant including vitamin E and stigmasterol as probable active components for the prevention for PAHs-induced neurotoxicity.


Assuntos
Hipocampo/efeitos dos fármacos , Momordica charantia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Estigmasterol/farmacologia , Vitamina E/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Momordica charantia/química , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Estigmasterol/isolamento & purificação , Vitamina E/isolamento & purificação
13.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371921

RESUMO

The study of different natural products can provide a wealth of bioactive compounds, and more interestingly, their combination can exert a new strategy for several neurodegenerative diseases with major public health importance, such as Alzheimer's disease (AD). Here, we investigated the synergistic neuroprotective effects of a mixed extract composed of docosahexaenoic acid, Ginkgo biloba, D-pinitol, and ursolic acid in several transgenic Caenorhabditis elegans (C. elegans) and a senescence-accelerated prone mice 8 (SAMP8) model. First, we found a significantly higher survival percentage in the C. elegans group treated with the natural product mixture compared to the single extract-treated groups. Likewise, we found a significantly increased lifespan in group of C. elegans treated with the natural product mixture compared to the other groups, suggesting synergistic effects. Remarkably, we determined a significant reduction in Aß plaque accumulation in the group of C. elegans treated with the natural product mixture compared to the other groups, confirming synergy. Finally, we demonstrated better cognitive performance in the group treated with the natural product mixture in both AD models (neuronal Aß C. elegans strain CL2355 and the SAMP8 mice model), confirming the molecular results and unraveling the synergist effects of this combination. Therefore, our results proved the potential of this new natural product mixture for AD therapeutic strategies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Produtos Biológicos/farmacologia , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Encéfalo/metabolismo , Encéfalo/patologia , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Longevidade , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide
14.
J Stroke Cerebrovasc Dis ; 30(9): 105987, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34273708

RESUMO

OBJECTIVES: The 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1H) is an effective novel drug for the treatment of ischemic cerebrovascular disease derived from Ginkgolide B, a traditional Chinese medicine, has been widely used in the treatment of cardiovascular and cerebrovascular diseases. However, whether XQ-1H exerts neuroprotective effect via regulating neuronal apoptosis and the underlying mechanism remain to be elucidated. MATERIALS AND METHODS: This study was aimed to investigate the neuroprotective effect of XQ-1H in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and the oxygen glucose deprivation/reoxygenation (OGD/R) induced neuronal apoptosis on pheochromocytoma (PC-12) cells. RESULTS: The results showed that administration of XQ-1H at different dosage (7.8, 15.6, 31.2 mg/kg) reduced the brain infarct and edema, attenuated the neuro-behavioral dysfunction, and improved cell morphology in brain tissue after MCAO/R in rats. Moreover, incubation with XQ-1H (1 µM, 3 µM, 10 µM, 50 µM, 100 µM) could increase the cell viability, and showed no toxic effect to PC-12 cells. XQ-1H at following 1 µM, 10 µM, 100 µM decreased the lactate dehydrogenase (LDH) activity and suppressed the cell apoptosis in PC-12 cells exposed to OGD/R. In addition, XQ-1H treatment could significantly inhibit caspase-3 activation both in vivo and in vitro, reciprocally modulate the expression of apoptosis related proteins, bcl-2, and bax via activating PI3K/Akt signaling pathway. For mechanism verification, LY294002, the inhibitor of PI3K/Akt pathway was introduced the expressions of bcl-2 and phosphorylated Akt were down-regulated, the expression of bax was up-regulated, indicating that XQ-1H could alleviate the cell apoptosis through activating the PI3K/Akt pathway. CONCLUSIONS: Our findings demonstrated that XQ-1H treatment could provide a neuroprotective effect against ischemic stroke induced by cerebral ischemia/reperfusion injury in vivo and in vitro through regulating neuronal survival and inhibiting apoptosis. The findings of the study confirmed that XQ-1H could be develop as a potential drug for treatment of cerebral ischemic stroke.


Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Ginkgolídeos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Lactonas/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
15.
Gene ; 799: 145811, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34224829

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in the eye of A30P fly PD model. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.


Assuntos
Carotenoides/farmacologia , Crocus/química , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/etiologia , Degeneração Retiniana/tratamento farmacológico , Vitamina A/análogos & derivados , Animais , Animais Geneticamente Modificados , Linhagem Celular , Modelos Animais de Doenças , Drosophila melanogaster/genética , Feminino , Humanos , Longevidade/efeitos dos fármacos , Masculino , Mutação , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Degeneração Retiniana/etiologia , Degeneração Retiniana/fisiopatologia , Vitamina A/farmacologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidade
16.
Molecules ; 26(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34299412

RESUMO

Gintonin is a kind of ginseng-derived glycolipoprotein that acts as an exogenous LPA receptor ligand. Gintonin has in vitro and in vivo neuroprotective effects; however, little is known about the cellular mechanisms underlying the neuroprotection. In the present study, we aimed to clarify how gintonin attenuates iodoacetic acid (IAA)-induced oxidative stress. The mouse hippocampal cell line HT22 was used. Gintonin treatment significantly attenuated IAA-induced reactive oxygen species (ROS) overproduction, ATP depletion, and cell death. However, treatment with Ki16425, an LPA1/3 receptor antagonist, suppressed the neuroprotective effects of gintonin. Gintonin elicited [Ca2⁺]i transients in HT22 cells. Gintonin-mediated [Ca2⁺]i transients through the LPA1 receptor-PLC-IP3 signaling pathway were coupled to increase both the expression and release of BDNF. The released BDNF activated the TrkB receptor. Induction of TrkB phosphorylation was further linked to Akt activation. Phosphorylated Akt reduced IAA-induced oxidative stress and increased cell survival. Our results indicate that gintonin attenuated IAA-induced oxidative stress in neuronal cells by activating the LPA1 receptor-BDNF-TrkB-Akt signaling pathway. One of the gintonin-mediated neuroprotective effects may be achieved via anti-oxidative stress in nervous systems.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Sobrevivência Celular , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais
17.
Methods Mol Biol ; 2352: 57-71, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34324180

RESUMO

Direct neuronal reprogramming is a promising strategy to generate various types of neurons that are, otherwise, inaccessible for researchers. However, the efficiency of neuronal conversion is highly dependent on the transcription factor used, the identity of the initial cells to convert, their species' background, and the neuronal subtype to which cells will convert. Regardless of these conditioning factors, the apoptotic regulator Bcl-2 acts as a pan-neuronal reprogramming enhancer. Bcl-2 mediates its effect in reprogramming by preventing an overshot of oxidative stress during the acquisition of a neuronal oxidative metabolism, thus reducing cell death by ferroptosis and facilitating the phenotypic conversion. In this chapter, we outline two methods to obtain either mouse or human neurons derived from postnatal astrocytes and skin fibroblasts, respectively. The overall reprogramming strategy is based on the co-expression of Bcl-2 and the transcription factor Neurog2 that produces mostly excitatory neurons. However, the method can be easily adapted to achieve alternative neuronal subtypes by using additional transcription factors, such as Isl1 for motor neurons. Therefore, our approaches provide solid but flexible platforms to obtain human and mouse induced neurons in vitro that can be applied to basic or translational research.


Assuntos
Astrócitos/citologia , Astrócitos/metabolismo , Técnicas de Reprogramação Celular , Reprogramação Celular/genética , Fibroblastos/citologia , Neurônios/citologia , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Astrócitos/efeitos dos fármacos , Técnicas de Cultura de Células , Linhagem Celular , Células Cultivadas , Reprogramação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Expressão Gênica , Vetores Genéticos/genética , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Retroviridae/genética , Transdução Genética , Transfecção
18.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299511

RESUMO

Nanostructuring nanocarbons with IrOx yields to material coatings with large charge capacities for neural electrostimulation, and large reproducibility in time, that carbons do not exhibit. This work shows the contributions of carbon and the different nanostructures present, as well as the impact of functionalizing graphene with oxygen and nitrogen, and the effects of including conducting polymers within the hybrid materials. Different mammalian neural growth models differentiate the roles of the substrate material in absence and in presence of applied electric fields and address optimal electrodes for the future clinical applications.


Assuntos
Carbono/química , Carbono/farmacologia , Irídio/química , Irídio/farmacologia , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Neurônios/efeitos dos fármacos , Animais , Terapia por Estimulação Elétrica/métodos , Eletrodos , Grafite/química , Humanos , Polímeros/química , Reprodutibilidade dos Testes
19.
Toxicol Lett ; 350: 171-184, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34280503

RESUMO

Recent studies have reported that melamine can accumulate in several regions of the brain including the medial prefrontal cortex (mPFC). Although melamine accumulation in the hippocampus has been verified to induce cognitive impairments, whether it can cause mPFC-dependent working memory deficits is still unknown. After chronic treatment with melamine (150 (Mel(150)) or 300 (Mel(300)) mg/kg), rats were tested during both delay nonmatching-to-sample spatial and odor discrimination tasks. Levels of AMPA receptor subunits in the mPFC were detected using western blotting. To further explore the mechanism at the cellular level, prefrontal activity was recorded during the odor discrimination. The working memory of Mel(150) rats was found to be significantly impaired in a 3-minute delay odor discrimination task (control: n = 6, Mel(150): n = 6; P < 0.05). Compared with the control group (n = 6), rats in the 300 mg/kg Mel(300)-treated group (n = 8) displayed working memory deficits in 60-second delay Y-maze task (P < 0.05), 1-minute and 3-minute delay odor discrimination tasks (both P < 0.05). The levels of AMPA receptor mGluR2/3 subunit were significantly decreased in rats of the Mel(150) (n = 7) and Mel(300) (n = 7) groups (both P < 0.05). Exposure to 150 (n = 7) or 300 mg/kg (n = 7) melamine resulted in significant inhibition of the regular-spiking neuron activity during the delay period of the memory test (both P < 0.05). Intraperitoneal (n = 7) and intra-mPFC (n = 6) infusions of GluR2/3 agonists, effectively enhanced the neural correlate (both P < 0.05) while rescuing cognitive deficits in Mel(300)-treated rats (both P < 0.05). Collectively, these findings suggested that melamine could induce prefrontal dysfunction and cause cognitive impairments.


Assuntos
Memória de Curto Prazo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Triazinas/toxicidade , Animais , Relação Dose-Resposta a Droga , Exposição Ambiental , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Animais , Ratos , Ratos Sprague-Dawley
20.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328201

RESUMO

Diabetes­associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2­deoxy­2­(3­methy1­3­nitrosoureido) D­glucopyranose; STZ] is one of the most well­established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study was to demonstrate that C8­B4 microglia transformed by the stimulus of repetitive low­dose lipopolysaccharide (LPSx3­microglia) prevent STZ­induced Neuro­2a neuronal cell death in vitro. The ELISA results showed that neurotrophin­4/5 (NT­4/5) secretion was promoted in LPSx3­microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3­microglia prevented STZ­induced neuronal cell death. In addition, reverse transcription­quantitative PCR showed that neurons treated with the culture supernatant of LPSx3­microglia promoted the gene expression of B­cell lymphoma­extra large and glucose­dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT­4/5, suppressed the neuroprotective effect of LPSx3­microglia. Taken together, the present study demonstrated that LPSx3­microglia prevent STZ­induced neuronal death and that NT­4/5 may be involved in the neuroprotective mechanism of LPSx3­microglia.


Assuntos
Morte Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Neurônios/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores dos Hormônios Gastrointestinais/genética , Estreptozocina/farmacologia , Proteína bcl-X/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...