Maternal Resveratrol Supplementation Prevents Cognitive Decline in Senescent Mice Offspring

A variety of environmental factors contribute significantly to age-related cognitive decline and memory impairment in Alzheimer's Disease (AD) and other neurodegenerative diseases. Nutrition can alter epigenetics, improving health outcomes, which can be transmitted across generations; this process is called epigenetic inheritance. We investigate the beneficial effects of maternal resveratrol supplementation in the direct exposed F1 generation and the transgenerational F2 generation. The offspring was generated from females Senescence Accelerated Mouse-Prone (SAMP8) fed a resveratrol-enriched diet for two months prior to mating. Object novel recognition and Morris Water Maze (MWM) demonstrated improvements in cognition in the 6-month-old F1 and F2 generations from resveratrol fed mothers. A significant increase in global DNA methylation with a decrease in hydroxymethylation in F1 and F2 were found. Accordingly, Dnmt3a/b and Tet2 gene expression changed. Methylation levels of Nrf2 and NF-kβ genes promoters raised in offspring, inducing changes in target genes expression, as well as hydrogen peroxide levels. Offspring that resulted from a resveratrol fed mother showed increase AMPKα activation, mTOR inhibition, and an increase in Pgc-1α gene expression and Beclin-1 protein levels. Endoplasmic reticulum stress sensors were found changed both in F1 and F2 generations. Overall, our results demonstrated that maternal resveratrol supplementation could prevent cognitive impairment in the SAMP8 mice offspring through epigenetic changes and cell signaling pathways. Keywords: cognitive decline; epigenetics; epigenetic inheritance; methylation; Nrf2; NF-κB; oxidative stress; inflammation; resveratrol; SAMP

Amyloid and tau pathology of familial Alzheimer's disease APP/PS1 mouse model in a senescence phenotype background (SAMP8)

The amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern at early ages, whereas senescence-accelerated mouse prone 8 (SAMP8) has a remarkable early senescence phenotype with pathological similarities to AD. The aim of this study was the investigation and characterization of cognitive and neuropathological AD markers in a novel mouse model that combines the characteristics of the APP/PS1 transgenic mouse model with a senescence-accelerated background of SAMP8 mice. Initially, significant differences were found regarding amyloid plaque formation and cognitive abnormalities. Bearing these facts in mind, we determined a general characterization of the main AD brain molecular markers, such as alterations in amyloid pathway, neuroinflammation, and hyperphosphorylation of tau in these mice along their lifetimes. Results from this analysis revealed that APP/PS1 in SAMP8 background mice showed alterations in the pathways studied in comparison with SAMP8 and APP/PS1, demonstrating that a senescence-accelerated background exacerbated the amyloid pathology and maintained the cognitive dysfunction present in APP/PS1 mice. Changes in tau pathology, including the activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 β (GSK3β), differs, but not in a parallel manner, with amyloid disturbances

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice

Alzheimer's disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo e cacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (H2O2), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade

Macroautophagic process was differentially modulated by long-term moderate exercise in rat brain and peripheral tissues

The autophagic process is a lysosomal degradation pathway, which is activated during stress conditions, such as starvation or exercise. Regular exercise has beneficial effects on human health, including neuroprotection. However, the cellular mechanisms underlying these effects are incompletely understood. Endurance and a single bout of exercise induce autophagy not only in brain but also in peripheral tissues. However, little is known whether autophagy could be modulated in brain and peripheral tissues by long-term moderate exercise. Here, we examined the effects on macroautophagy process of long-term moderate treadmill training (36 weeks) in adult rats both in brain (hippocampus and cerebral cortex) and peripheral tissues (skeletal muscle, liver and heart). We assessed mTOR activation and the autophagic proteins Beclin 1, p62, LC3B (LC3B-II/LC3B-I ratio) and the lysosomal protein LAMP1, as well as the ubiquitinated proteins. Our results showed in the cortex of exercised rats an inactivation of mTOR, greater autophagy flux (increased LC3-II/LC3-I ratio and reduced p62) besides increased LAMP1. Related with these effects a reduction in the ubiquitinated proteins was observed. No significant changes in the autophagic pathway were found either in hippocampus or in skeletal and cardiac muscle by exercise. Only in the liver of exercised rats mTOR phosphorylation and p62 levels increased, which could be related with beneficial metabolic effects in this organ induced by exercise. Thus, our findings suggest that long-term moderate exercise induces autophagy specifically in the corte

Preferències dels estudiants en relació al tema d’estudi del TFG de Farmàcia (UB)

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524El TFG del grau de farmàcia UB es porta a terme en el marc d’un àmbit docent principal i integra coneixements de com a mínim, dos àmbits docents addicionals atès la seva funció integradora. En el moment de definir les directrius i organització de l’assignatura, es van establir a la Facultat de Farmàcia 27 àmbits docents. Tanmateix, les característiques del TFG quan a tipus de projectes o estudis es van establir inicialment en base a tres opcions..

Grup d'Innovació Docent en Farmacologia (GIDOF)

Podeu consultar la Setena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/4335

Efecte de l'MK-801 i altres lligams PCP I Sigma sobre l'activitat noradrenèrgic

Tesi de Llicenciatura per a la obtenció del Grau de Farmàcia. Facultat de Farmàcia. Universitat de Barcelona. Director: Escubedo Rafa, Elena, Mercè Pallàs i Llibería. 1996.Un deis objectius més importants per a la fannacologia actual és el coneixement profünd deis mecanismes que mitjancen les malalties del sistema nervios central (SNC), tant degeneratives com psiquiátriques. Aquest coneixement portaría al desenvolupament de farmacs suficientment selectius per guarir aqüestes malalties sense causar efectes indesitjables. De la gran quantitat d’estudis realitzats al respecte fins a l’actualitat, sembla ser que la neurotransmissió per aminoácids excitadors (AAE), encapfalada peí glutamat, té un paper important en Faparició de malalties de tipus neurodegeneratiu. Concretament, entre els subtipus de receptors glutamatérgics que es coneixen són els del subtipus NMDA (N-metilD-aspartat) els que es consideren, per una sobreactivació deis mateixos, responsables de moltes d’aquestes patologies. A partir d’aquesta hipótesi, es desenvoluparen molécules antagonistes del receptor NMDA, tant de tipus competitiu com no competitiu, és a dir, bloquejants del canal iónic associat al receptor i que mitjancen el seu efecte. Aquests farmacs tindrien un efecte neuroprotector. Entre els antagonistes no competitius existents trobem substancies com l’MK-801, la fenciclidina o “pols d’ ángel” (PCP), d’aquí que també s’anomeni a aquests llocs d’unió llocs del PCP, o del dizocilpí (MK-801)

Estudi de la degeneració transneuronal en models de malalties que afecten als ganglis basals

[cat] L'objectiu general d'aquest treball és aprofundir en l'estudi de la fisiopatologia de les malalties degeneratives, un dels objectius principals per a la farmacologia actual degut a l'increment de la seva incidència en les últimes dècades. Mitjançant la utilització de models experimentals d 'aquestes patologies s'han plantejat diferents objectius més concrets: A.- Induir la malaltia de Parkinson experimental a través de la injecció de l'MPP+ en la substància negra de rata. A1.-Estudiar la resposta glial en el nucli estriat després de La degeneració anterograda de les neurones dopaminèrgiques causada per la injecció de l'MPP+ en la substància negra. Implicació en el mecanisme de mort neuronal i de regeneració. B.- Induir la malaltia de Huntington experimental a través de la injecció d'aminoàcids excitadors en el nucli estriat de rata. B1.-Caracteritzar la resposta endògena tròfica a l'excitotoxicitat, valorant els canvis en l 'expressió del BDNF i l'NT-3 així com la dels seus receptors, TrkB i TrkC, en l'escorça cerebral després de la injecció de diferents agonistes del receptor del glutamat en el nucli estriat. B2.-Estudiar la regulació endògena dels nivells de BDNF en Ja substància negra de rata després de la lesió estriatal induïda per l'àcid kaínic, així com la possible implicació d'aquesta neurotrofina en la supervivència de les neurones de la substància negra front la lesió excitotòxica en el nucli estriat. 3. Estudiar el possible efecte neuroprotector de les neurotrofines BDNF, NT-3 iNT-4/5, sobre les diferents poblacions neuronals de projecció del nucli estriat, en el model excitotòxic de l'àcid quinolínic. Es van implantar en l 'estriat de rata adulta línies cel·lulars establertes que secreten alts nivells de BDNF, NT-3 i NT-4/5 recombinant abans de la injecció de l'aminoàcid excitador

Heme Oxygenase-1 and Brain Oxysterols Metabolism Are Linked to Egr-1 Expression in Aged Mice Cortex, but Not in Hippocampus

Throughout life, stress stimuli act upon the brain leading to morphological and functional changes in advanced age, when it is likely to develop neurodegenerative disorders. There is an increasing need to unveil the molecular mechanisms underlying aging, in a world where populations are getting older. Egr-1 (early growth response 1), a transcriptional factor involved in cell survival, proliferation and differentiation - with a role also in memory, cognition and synaptic plasticity, can be implicated in the molecular mechanism of the aging process. Moreover, Heme Oxygenase-1a (HO), a 32 kDa heat-shock protein that converts heme to iron, carbon monoxide and biliverdin, is a key enzyme with neuroprotective properties. Several in vitro and in vivo studies reported that HO-1 could regulate the metabolism of oxysterols, oxidation products of cholesterol that include markers of oxidative stress. Recently, a link between Egr-1 and HO-1 has been demonstrated in mouse lung cells exposed to cigarette smoke. In view of these data, we wanted to investigate whether Egr-1 can be implicated also in the oxysterol metabolism during brain aging. Our results show that Egr-1 expression is differently expressed in the cortex and hippocampus of old mice, as well as the oxysterol profile between these two brain areas. In particular, we show that the cortex experiences in an age-dependent fashion increasing levels of the Egr-1 protein, and that these correlate with the level of HO-1 expression and oxysterol abundance. Such a situation was not observed in the hippocampus. These results are further strenghtened by our observations made with Egr-1 KO mice, confirming our hypothesis concerning the influence of Egr-1 on oxysterol production and accumulation via regulation of the expression of HO-1 in the cortex, but not the hippocampus, of old mice. It is important to notice that most of the oxysterols involved in this process are those usually stimulated by oxidative stress, which would then represent the triggering factor for this mechanism. Keywords: Egr-1, aging brain, oxysterols, HO-1, oxidative stress, cortex, hippocampu

Macroautophagic process was differentially modulated by long-term moderate exercise in rat brain and peripheral tissues

The autophagic process is a lysosomal degradation pathway, which is activated during stress conditions, such as starvation or exercise. Regular exercise has beneficial effects on human health, including neuroprotection. However, the cellular mechanisms underlying these effects are incompletely understood. Endurance and a single bout of exercise induce autophagy not only in brain but also in peripheral tissues. However, little is known whether autophagy could be modulated in brain and peripheral tissues by long-term moderate exercise. Here, we examined the effects on macroautophagy process of long-term moderate treadmill training (36 weeks) in adult rats both in brain (hippocampus and cerebral cortex) and peripheral tissues (skeletal muscle, liver and heart). We assessed mTOR activation and the autophagic proteins Beclin 1, p62, LC3B (LC3B-II/LC3B-I ratio) and the lysosomal protein LAMP1, as well as the ubiquitinated proteins. Our results showed in the cortex of exercised rats an inactivation of mTOR, greater autophagy flux (increased LC3-II/LC3-I ratio and reduced p62) besides increased LAMP1. Related with these effects a reduction in the ubiquitinated proteins was observed. No significant changes in the autophagic pathway were found either in hippocampus or in skeletal and cardiac muscle by exercise. Only in the liver of exercised rats mTOR phosphorylation and p62 levels increased, which could be related with beneficial metabolic effects in this organ induced by exercise. Thus, our findings suggest that long-term moderate exercise induces autophagy specifically in the corte