RESUMO
Alzheimer's disease is the most common neurodegenerative disease, and its treatment is lacking. In this work, we tested Amylovis-201, a naphthalene-derived compound, as a possible therapeutic candidate for the treatment of AD. For this purpose, we performed three experiments. In the first and third experiment, animals received a bilateral administration of streptozotocin and, starting 24 h after injection, a daily dose of Amylovis-201 (orally), for 17 days or for the whole time of the experiment respectively (28 days), after which learning and memory, as well as the number of hippocampal dentate gyrus cells, were assessed. In the second experiment, healthy animals received a single dose of Amylovis-201, 10 min or 5 h after the learning section to assess whether this substance could promote specific mechanisms involved in memory trace formation. Our data show that, administration of a single dose of Amylovis-201, 10 min after the end of training, but not at 5 h, produces a prolongation in memory duration, probably because it modulates specific mechanisms involved in memory trace consolidation. Furthermore, daily administration of Amylovis-201 to animals with bilateral intracerebroventricular injection of STZ produces a reduction in the loss of the hippocampus dentate gyrus cells and an improvement in spatial memory, probably because Amylovis-201 can interact with some of the protein kinases of the insulin signaling cascade, also involved in neural plasticity, and thereby halt or reverse some of the effects of STZ. Taking to account these results, Amylovis-201 is a good candidate for the therapeutic treatment of AD.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Animais , Estreptozocina/farmacologia , Doenças Neurodegenerativas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Memória Espacial , Transtornos da Memória/metabolismo , Aprendizagem em LabirintoRESUMO
The aggregation of ß-amyloid peptides is associated to neurodegeneration in Alzheimer's disease (AD) patients. Consequently, the inhibition of both oligomerization and fibrillation of ß-amyloid peptides is considered a plausible therapeutic approach for AD. Herein, the synthesis of new naphthalene derivatives and their evaluation as anti-ß-amyloidogenic agents are presented. Molecular dynamic simulations predicted the formation of thermodynamically stable complexes between the compounds, the Aß1-42 peptide and fibrils. In human microglia cells, these compounds inhibited the aggregation of Aß1-42 peptide. The lead compound 8 showed a high affinity to amyloid plaques in mice brain ex vivo assays and an adequate log Poct/PBS value. Compound 8 also improved the cognitive function and decreased hippocampal ß-amyloid burden in the brain of 3xTg-AD female mice. Altogether, our results suggest that 8 could be a novel therapeutic agent for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Naftalenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/metabolismo , Agregação Patológica de Proteínas/metabolismo , Relação Estrutura-Atividade , TermodinâmicaRESUMO
The complexity of the ischemic cascade is based on the integrated crosstalk of every cell type in the neurovascular unit. Depending on the features of the ischemic insult, several cell death mechanisms are triggered, such as apoptosis, necroptosis, ferroptosis/oxytosis, ETosis or pyroptosis, leading to reactive astrogliosis. However, emerging evidence demonstrates a dual role for the immune system in stroke pathophysiology, where it exerts both detrimental and also beneficial functions. In this review, we discuss the relevance of several cell death modalities and the dual role of the immune system in stroke pathophysiology. We also provide an overview of some emerging immunomodulatory therapeutic strategies, amongst which saponins, which are promising candidates that exert multiple pharmacological effects.
RESUMO
Two spirosteroid analogues were synthesized and evaluated for their in vitro neuroprotective activities in PC12 cells, against glutamate-induced excitotoxicity and mitochondrial damage in glucose deprivation conditions, as well as their anti-inflammatory potential in LPS/IFNγ-stimulated microglia primary cultures. We also evaluated the in vitro anti-excitotoxic and anti-inflammatory activities of natural and endogenous steroids. Our results show that the plant-derived steroid solasodine decreased PC12 glutamate-induced excitotoxicity, but not the cell death induced by mitochondrial damage and glucose deprivation. Among the two synthetic spirosteroid analogues, only the (25R)-5α-spirostan-3,6-one (S15) protected PC12 against ischemia-related in vitro models and inhibited NO production, as well as the release of IL-1ß by stimulated primary microglia. These findings provide further insights into the role of specific modifications of the A and B rings of sapogenins for their neuroprotective potential.
Assuntos
Anti-Inflamatórios , Microglia/metabolismo , Fármacos Neuroprotetores , Compostos de Espiro , Esteroides , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Morte Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Feminino , Interleucina-1beta/biossíntese , Microglia/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/biossíntese , Células PC12 , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Esteroides/síntese química , Esteroides/química , Esteroides/farmacologiaRESUMO
Introducción: la diosgenina y sus derivados se han descrito como potentes inhibidores de la proliferación en varias líneas tumorales. Sin embargo otras moléculas relacionadas estructuralmente con dichos derivados, se han reportado como candidatos terapéuticos y otras de ellas se incluyen en alimentos de consumo humano. Objetivo: el presente trabajo evalúa el efecto sobre la viabilidad celular de una nueva serie de espiroesteroides sintéticos derivados de la diosgenina, en células tipo neurales PC12. Métodos: la viabilidad de los cultivos de PC12 se determinó mediante el ensayo de MTT y se calcularon descriptores moleculares teóricos como la lipofilicidad (logP virtual) y la superficie de área polar (SAP), con el objetivo de establecer relaciones estructura-actividad. Resultados: nuestros resultados demuestran que solo el acido taurodesoxicólico disminuye de manera significativa la viabilidad celular. Más aun, dicha molécula presenta valores menores y mayores de logP virtual y SAP, respectivamente, respecto al resto de los esteroides de la serie. Conclusiones: los resultados anteriores avalan el estudio del acido taurodesoxicólico como potencial inhibidor de la proliferación celular y al resto de las moléculas de la serie como candidatos neuroprotectores a evaluar en esta misma línea celular y dosis de tratamiento
Introduction: diosgenin and its derivatives have been described as potent anti-proliferative compounds in several tumor cell lines. However, other structurally-related compounds are reported to exert neuroprotective activity and are also included in food for human consumption. Objective: to evaluate the effect of a novel series of diogesin-derived synthetic spirosteroids on cellular viability of neuron-like PC12 cell line. Methods: cellular viability was determined by the MTT assay along with some theorical molecular descriptors, such as lipophilicity and polar surface area, in order to establish the structure-activity relationships. Results: the results demonstrated that only taurodeoxycholic acid significantly decrease PC12 cell culture viability. Moreover, this molecule presents lower virtual logP values and higher polar surface area values than the rest of spirosteroid series. Conclusions: those results endorse future studies of taurodeoxycholic acid as a potential anti-tumor candidate and of the rest of the molecules in this series as potential neuroprotective agents to be evaluated in this PC12 cell line and similar therapeutic dose
Assuntos
Sobrevivência Celular , Citotoxicidade Imunológica , Diosgenina/análogos & derivados , Ácido TaurodesoxicólicoRESUMO
Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with several reported pharmacological actions. We have assessed the protective action of GA on iron-induced neuronal cell damage by employing the PC12 cell line and primary culture of rat cortical neurons (PCRCN). A strong protection by GA, assessed by the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbox-anilide (XTT) assay, was revealed, with IC(50) values <1 µM. GA also inhibited Fe(3+)-ascorbate reduction, iron-induced oxidative degradation of 2-deoxiribose, and iron-induced lipid peroxidation in rat brain homogenate, as well as stimulated oxygen consumption by Fe(2+) autoxidation. Absorption spectra and cyclic voltammograms of GA-Fe(2+)/Fe(3+) complexes suggest the formation of a transient charge transfer complex between Fe(2+) and GA, accelerating Fe(2+) oxidation. The more stable Fe(3+) complex with GA would be unable to participate in Fenton-Haber Weiss-type reactions and the propagation phase of lipid peroxidation. The results show a potential of GA against neuronal diseases associated with iron-induced oxidative stress.