Nucli Universitari Of Pedralbes

Barcelona, Spain

Nucli Universitari Of Pedralbes

Barcelona, Spain
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Verdaguer E.,University of Barcelona | Junyent F.,Nucli Universitari Of Pedralbes | Junyent F.,Rovira i Virgili University | Folch J.,Rovira i Virgili University | And 4 more authors.
Expert Opinion on Drug Discovery | Year: 2012

Introduction: The prevalence of age-related pathologies, such as cardiovascular disease, neurodegenerative disease and diabetes type II, has increased dramatically with the rising average age of populations. Antiaging molecules and appropriate animal models need to be developed to prevent and or delay alterations that occur during aging and are manifested as age-associated illnesses. Areas covered: This review covers the main experimental models used in aging research, from invertebrates up to nonhuman primates. The authors discuss studies of the biochemical pathways involved in dietary restriction, which has been associated with life span extension. The authors also describe the implications of sirtuin 1, insulin growth factor, mTOR (the mammalian target of rapamycin) and AMPK activation, which are well-characterized antiaging pathways. All these pathways are highly conserved from invertebrates to nonhuman primates. Although some invertebrate models are used to study the antiaging properties of drugs, mice models and nonhuman primates are more suitable, as the study of changes in memory loss is critical. The review highlights the conservation of the aging pathways between species. Expert opinion: Further studies on aging should focus on two ways: i) improving animal models, for example, the genetically heterogeneous mice and ii) drug research. It is almost impossible to evaluate clinically the efficacy of antiaging drugs. Moreover, caloric restriction currently constitutes the most effective antiaging pathway. Thus, the strategy is to study drugs for aging-associated diseases, such as diabetes, that also have antiaging effects. © 2012 Informa UK, Ltd.

Folch J.,Rovira i Virgili University | Junyent F.,Nucli Universitari Of Pedralbes | Junyent F.,Rovira i Virgili University | Verdaguer E.,University of Barcelona | And 5 more authors.
Neurotoxicity Research | Year: 2012

Currently, there is no effective treatment for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Thus, a major focus of neuroscience research is to examine the mechanisms involved in neuronal loss in order to identify potential drug targets. Recent results indicate that DNA damage and re-entry into the cell cycle may constitute a common pathway in apoptosis in neurological diseases. The role of the cell cycle in such disorders is supported by data on the brain of patients who showed an increase in cell-cycle protein expression. Indeed, studies performed in neuronal cell preparations indicate that oxidative stress could be the main mechanism responsible for cell cycle re-entry. DNA damage and repair after oxidative stress may activate the enzyme ataxia telangiectasia mutated, which is a cell-cycle regulator. Once the cell cycle is activated, the increase in the expression of transcription factor E2F-1 could induce neuronal apoptosis. Furthermore, the potential routes involved in E2F-1 induced apoptosis could be p53-dependent or p53-independent. Under this E2F-1 hypothesis of cell death, multiple mitochondria-dependent pathways may be activated, including caspase and caspase-independent signaling cascades. Finally, given that cyclin-dependent kinase inhibitory drugs have neuroprotective and anti-apoptotic effects in experimental models, their potential application for the treatment of neurological disorders should be taken into account. © 2011 Springer Science+Business Media, LLC.

Ortuno-Sahagun D.,University of Guadalajara | Gonzalez R.M.,Laboratory of Cellular and Molecular Neurobiology | Verdaguer E.,Nucli Universitari Of Pedralbes | Huerta V.C.,Laboratory of Cellular and Molecular Neurobiology | And 6 more authors.
Journal of Molecular Neuroscience | Year: 2014

Current knowledge concerning the molecular mechanisms of the cellular response to excitotoxic insults in neurodegenerative diseases is insufficient. Although glutamate (Glu) has been widely studied as the main excitatory neurotransmitter and principal excitotoxic agent, the neuroprotective response enacted by neurons is not yet completely understood. Some of the molecular participants have been revealed, but the signaling pathways involved in this protective response are just beginning to be identified. Here, we demonstrate in vivo that, in response to the cell damage and death induced by Glu excitotoxicity, neurons orchestrate a survival response through the extracellular signal-regulated kinase (ERK) signaling pathway by increasing ERK expression in the rat hippocampal (CA1) region, allowing increased neuronal survival. In addition, this protective response is specifically reversed by U0126, an ERK inhibitor, which promotes cell death only when it is administered together with Glu. Our findings demonstrate that the ERK signaling pathway has a neuroprotective role in the response to Glu-induced excitotoxicity in hippocampal neurons. Therefore, the ERK signaling pathway may be activated as a cellular response to excitotoxic injury to prevent damage and neural loss, representing a novel therapeutic target in the treatment of neurodegenerative diseases. © 2013 Springer Science+Business Media New York.

Torre A.V.D.L.,Nucli Universitari Of Pedralbes | Junyent F.,Nucli Universitari Of Pedralbes | Junyent F.,Rovira i Virgili University | Folch J.,Rovira i Virgili University | And 7 more authors.
Neurochemistry International | Year: 2011

In the present study we focused in the PI3K/Akt pathway which plays a key role in neuronal survival. Here we show that inhibition of PI3K/Akt by means of LY294002 induces apoptosis via a caspase-dependent and calpain-independent pathway in cerebellar granule neurons (CGNs). This finding was confirmed using zVAD-fmk, a widely caspase inhibitor that prevents apoptosis. For this purpose, we compared two models of apoptosis in CGNs, namely inhibition of PI3K/Akt, and serum potassium deprivation (S/K deprivation). In contrast to the S/K deprivation model, caspase-3 was not activated when PI3K is inhibited. Likewise, CDK5 activation was not involved in this apoptotic process, because calpain activation is responsible for the formation of CDK5/p25 neurotoxic form. However, S/K deprivation activated calpain, as it is shown by α-spectrin breakdown, and favoured the formation of CDK5/p25. Moreover, although PI3K/Akt inhibition enhanced pRbser780 phosphorylation, no increase in the expression of cell-cycle proteins, namely: cyclin D, cyclin E, CDK2 or CDK4, was detected. Furthermore, BrdU incorporation assay did not shown any increase in DNA synthesis. Likewise, PI3K/Akt inhibition increased GSK3β activity and c-Jun phosphorylation, which implicates these two pathways in this apoptotic route. Although previous reports suggest that apoptosis induced in CGNs by LY294002 and S/K deprivation causes PI3K inhibition and increases GSK3β activity and c-Jun phosphorylation activation, our results demonstrate substantial differences between them and point to a key role of GSK3β in the apoptosis induced in CGNs in the two models tested. © 2011 Elsevier B.V. All rights reserved.

Chang J.,Case Western Reserve University | Pallas M.,Nucli Universitari Of Pedralbes | Zhu X.,Case Western Reserve University | Kim H.-J.,Case Western Reserve University | And 6 more authors.
Advances in Alzheimer's Disease | Year: 2011

Current mouse models of Alzheimer's disease (AD) are restricted to the expression of AD-related pathology associated with specific mutations present in early-onset familial AD and thus represent <5% of AD cases. To date there are no mouse lines that model late-onset/age-related AD, the feature which accounts for the vast majority of cases. As such, based on current mutation-associated models, the chronology of events that lead to the disease in the aged population is difficult to establish. However, published data show that senescence-accelerated mouse (SAMP8), as a model of aging, display many features that are known to occur early in the pathogenesis of AD such as increased oxidative stress, amyloid-β alterations, and tau phosphorylation. Therefore, SAMP8 mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD and provide a more encompassing picture of human disease, a syndrome triggered by a combination of age-related events. Here, the neurochemical, neuropathological, and behavioral alterations, characterized in SAMP8 mice are critically reviewed and discussed in relation to the potential use of this mouse model in the study of AD pathogenesis. © 2011 The authors and IOS Press. All rights reserved.

Pizarro J.G.,Nucli Universitari Of Pedralbes | Verdaguer E.,University of Barcelona | Ancrenaz V.,Nucli Universitari Of Pedralbes | Junyent F.,Nucli Universitari Of Pedralbes | And 4 more authors.
Neurochemical Research | Year: 2011

Resveratrol prolongs lifespan and prevent cancer formation; however, the mechanisms are not understood. Here we evaluated the cell-cycle inhibition and apoptosis of resveratrol in B65 neuroblastoma cells, and we also studied the effects of resveratrol on the mammalian silent information regulator 2 (SIRT1). Results show that resveratrol reduces cell viability and causes apoptosis at 24 h of treatment. Resveratrol partially blocked cell proliferation, and significantly increased the fraction of cells arrested in the S phase. The role of SIRT1 in cell-cycle effects mediated by resveratrol was studied through changes in the expression of SIRT1 using western blot. Exposure to resveratrol decreased SIRT1 content, concomitant with an increase in the acetylated form of sirtuin substrates p53 and NFκ-β. Treatment of B65 neuroblastoma cells with resveratrol also reduced the content of the phosphorylated form of AKT. Exposure to the SIRT1 inhibitors nicotinamide and sirtinol altered neither cell viability nor the fraction of apoptotic cells. Furthermore, when cells were exposed simultaneously to resveratrol and nicotinamide or sirtinol, no changes were observed in the fraction of apoptotic cells. Our results show that a decrease in SIRT1 content, caused by exposure to resveratrol, does not appear to be involved in cell-cycle arrest or activation of apoptosis. © 2010 Springer Science+Business Media, LLC.

Bayod S.,Nucli Universitari Of Pedralbes | Menella I.,Nucli Universitari Of Pedralbes | Sanchez-Roige S.,Autonomous University of Barcelona | Lalanza J.F.,Autonomous University of Barcelona | And 4 more authors.
Brain Research | Year: 2014

An active lifestyle involving regular exercise reduces the deleterious effects of the aging process. At the cerebral level, both synaptic plasticity and neurogenesis are modulated by exercise, although the molecular mechanisms underlying these effects are not clearly understood. In the mature nervous system, the canonical Wnt (Wnt/β-catenin) signaling pathway is implicated in neuroprotection and synaptic plasticity. Here, we examined whether the Wnt pathway could be modulated in adult male rat hippocampus by long-term moderate exercise (treadmill running) or enrichment (handling/environmental stimulation). Sedentary animals showed higher protein levels of the Wnt antagonist, Dkk-1, the lowest levels being found in the exercised group. Although there was no evidence of any changes in activation of the LRP6 receptor, the total levels of LRP6 were higher in exercised and enriched animals. Analysis of some of the components implicated in the phosphorylation of β-catenin, which leads ultimately to its proteasomal degradation, revealed higher levels and activation of Axin1 and GSK-3α/β respectively in sedentary animals. However neither different phosphorylated forms nor total β-catenin protein levels differed between the experimental groups. Higher protein levels of Axin2 and the antiapoptotic protein, Bcl-2, were found with exercise and handling, whereas the proapototic, Bax, was unaffected. Thus, our results suggest activation of the Wnt pathway not only with moderate exercise, but also with the handling of the animals. © 2013 Elsevier B.V.

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