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Cerebral ischemia constitutes the most frequent type of cerebrovascular disease. The reduction of blood supply to the brain initiates the ischemic cascade starting from ionic imbalance to subsequent glutamate excitotoxicity, neuroinflammation and oxidative stress, eventually causing neuronal death. Previously, the authors have demonstrated the in vitro cytoprotective and antioxidant effects of a new arylidene malonate derivative, KM-34, against oxidizing agents like hydrogen peroxide, glutamate or Fe3+/ascorbate. Here, we examined for the first time the neuroprotective effect of KM-34 on ischemia/reperfusion models. In vitro, treatment with 10 and 50 μM KM-34 reduced the cellular death (propidium iodide incorporation) induced by oxygen glucose deprivation (OGD) in rat organotypic hippocampal slices cultures. In vivo, stroke was induced in male Wistar rats through middle cerebral artery occlusion (MCAO), followed by 23 h of reperfusion. KM-34 was orally administered 105 min after MCAO onset. We noticed that 1 mg/kg KM-34 reduced infarct volume and neurological score, and increased the latency to fall in the Hanging Wire test compared to vehicle-treated ischemic animals. While ischemic and sham-operated groups showed similar horizontal locomotor activity, vertical counts decreased after MCAO, suggesting that vertical movements are more sensitive to the ischemic injury. Treatment with KM-34 also alleviated the mitochondrial impairment (ROS generation, swelling and membrane potential dissipation) induced by transient MCAO but not significant alterations were found in oxidative stress parameters. Overall, the study provides preclinical evidences confirming the neuroprotective effects of a novel synthetic molecule and paved the way for future investigations regarding its therapeutic potential against brain ischemia/reperfusion injury.

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., Highlights • Several cell death mechanisms coexist in stroke pathophysiology. • Neurons are more vulnerable to necroptosis than glial cells. • Inhibitors of receptor-interacting protein kinases and of ferroptosis induce neuroprotection. • Saponins exert modulatory effects on inflammation and neuronal cell death in stroke.

The preparation of colloidal gold nanoparticles (AuNPs) capped with β-cyclodextrin-epichlorohydrin polymer (AuNP@βCDP) was achieved by the reduction of gold(III) with trisodium citrate in the presence of the polymer (βCDP), both in different proportions. The gold nanoparticles showed a mean diameter of 4.8 nm with a narrow size distribution (±0.8 nm). The βCD polymer conferred a high water solubility and stability to the nanoparticles, even at high concentrations. The use of βCDP as a capping agent allowed the redispersion of precipitated nanoparticles without altering their size and optical properties. The stability of the AuNP@βCDP was evaluated in human blood serum. The nanoparticles retained 100% of their stability during 14 days of exposure to physiological fluid. An absence of cytotoxicity in SHSY5Y culture cells was observed at concentrations less than 0.1 mg mL−1.

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.

Stroke represents one of the first causes of mortality and morbidity worldwide. We evaluated the therapeutic potential of a novel semi-synthetic spirosteroid sapogenin derivative "S15" in a transient middle cerebral artery occlusion (tMCAO) focal ischemia model in rat. S15-treated rats had significantly reduced infarct volumes and improved neurological functions at 24 h post-reperfusion, compared with ischemia. Corresponding gene expression changes in brain were characterized by mRNA sequencing and gPCR approaches. Next, we applied geneset, pathway and transcription factor motif enrichment analysis to identify relevant signaling networks responsible for neuronal damage upon ischemia-reperfusion or neuroprotection upon pretreatment with S15. As expected, ischemia-reperfusion brain damage strongly modulates transcriptional programs associated with immune responses, increased differentiation of immune cells as well as reduced (cat)ion transport and synaptic activity. Interestingly, S15-dependent neuroprotection regulates inflammation-associated genes involved in phagosome specific resolution of tissue damage, chemotaxis and anti-inflammatory alternative activation of microglia. Altogether our transcriptome wide RNA sequencing and integrated pathway analysis provides new clues in the neuroprotective properties of a novel spirosteroid S15 or neuronal damage in rat brains subjected to ischemia, which opens new perspectives for successful treatment of stroke. (C) 2017 Published by Elsevier Inc.

Reactive oxygen species (ROS) are important mediators in a number of neurodegenerative diseases and molecules capable of scavenging ROS may be a feasible strategy for protecting neuronal cells. We previously demonstrated a powerful iron-chelating action of Guttiferone-A (GA), a naturally occurring polyphenol, on oxidative stress injuries initiated by iron overload. Here we addressed the neuroprotective potential of GA in hydrogen peroxide and glutamate-induced injury on rat's primary culture of cortical neurons and PC12 cells, respectively, and antioxidant properties concerning scavenging and anti-lipoperoxidative activities in cell-free models. The decrease in cell viability induced by each of the toxins, assessed by [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay, was significantly attenuated by GA. In addition, GA was found to be a potent antioxidant, as shown by (i) inhibition of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical reduction (EC50=20.0 μM), (ii) prevention against chemically or electrochemically generated superoxide radicals, (iii) inhibition of spontaneous brain lipid peroxidation and (iv) interference with the Fenton reaction. These results indicate that GA exerts neuroprotective effects against H2O2 or glutamate toxicity and its antioxidant activity, demonstrated in vitro, could be at least partly involved. They also suggest a promising potential for GA as a therapeutic agent against neurodegenerative diseases involving ROS and oxidative damage.

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 IC50 values

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.