AAV-mediated expression of secreted and transmembrane αKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice.

Senescence represents a stage in life associated with elevated incidence of morbidity and increased risk of mortality due to the accumulation of molecular alterations and tissue dysfunction, promoting a decrease in the organism's protective systems. Thus, aging presents molecular and biological hallmarks, which include chronic inflammation, epigenetic alterations, neuronal dysfunction, and worsening of physical status. In this context, we explored the AAV9-mediated expression of the two main isoforms of the aging-protective factor Klotho (KL) as a strategy to prevent these general age-related features using the senescence-accelerated mouse prone 8 (SAMP8) model. Both secreted and transmembrane KL isoforms improved cognitive performance, physical state parameters, and different molecular variables associated with aging. Epigenetic landscape was recovered for the analyzed global markers DNA methylation (5-mC), hydroxymethylation (5-hmC), and restoration occurred in the acetylation levels of H3 and H4. Gene expression of pro- and anti-inflammatory mediators in central nervous system such as TNF-α and IL-10, respectively, had improved levels, which were comparable to the senescence-accelerated-mouse resistant 1 (SAMR1) healthy control. Additionally, this improvement in neuroinflammation was supported by changes in the histological markers Iba1, GFAP, and SA ß-gal. Furthermore, bone tissue structural variables, especially altered during senescence, recovered in SAMP8 mice to SAMR1 control values after treatment with both KL isoforms. This work presents evidence of the beneficial pleiotropic role of Klotho as an anti-aging therapy as well as new specific functions of the KL isoforms for the epigenetic regulation and aged bone structure alteration in an aging mouse model.

Consenso de la Asociación Española de Urología sobre el uso de mallas en la cirugía del prolapso de órganos pélvicos / Consensus statement of the Spanish Association Of Urology on the use of meshes in pelvic organ prolapse

INTRODUCCIÓN: Recientemente la Food and Drug Administration ha prohibido el uso de mallas transvaginales para el tratamiento quirúrgico de los prolapsos de órganos pélvicos (POP) en Estados Unidos. Esto ha suscitado una repercusión a escala mundial en el manejo de la patología del suelo pélvico por parte de los diferentes especialistas. OBJETIVO: Lograr un consenso sobre el uso de mallas en el tratamiento quirúrgico de los POP. ADQUISICIÓN DE DATOS/EVIDENCIA: Se organizó un Comité de expertos de la Asociación Española de Urología (AEU) para una revisión de la literatura y analizar la seguridad y eficacia del uso de mallas de polipropileno en la cirugía de los POP. RESULTADOS/EVIDENCIA DE LA LITERATURA: La evidencia refleja que el uso de mallas, comparado con el uso de tejidos nativos, ofrece una mejor eficacia a expensas de nuevas complicaciones y una mayor tasa de revisiones quirúrgicas, siendo estas menores en manos de cirujanos expertos. CONCLUSIONES: La cirugía del POP debe ser realizada por cirujanos con experiencia, adecuadamente formados y en centros de referencia. El paciente debe recibir una información correcta acerca de las diferentes opciones de tratamiento. Las mallas transvaginales solo deben indicarse en casos complejos y en recidivas tras cirugía del POP. PROPUESTA AEU: Creación de una guía clínica y de un registro nacional para la evaluación a largo plazo. Elaboración de un Consentimiento Informado a disposición de todos los profesionales y pacientes, así como un plan de formación específico para conseguir una mejor capacitación en la cirugía compleja del suelo pélvico

INTRODUCTION: Recently the Food and Drug Administration has banned the use of transvaginal meshes for the surgical treatment of pelvic organ prolapse (POP) in the United States. This has caused a worldwide impact on the management of pelvic floor pathology by different specialists. OBJECTIVE: To achieve a consensus on the use of meshes in the surgical treatment of POPs. ACQUISITION OF DATA/EVIDENCE: A Committee of experts of the Spanish Association of Urology (AEU) was organized to review the literature and analyze the safety and efficacy of the use of polypropylene meshes in POP surgery. RESULTS/EVIDENCE FROM THE LITERATURE: The evidence reflects that the use of meshes, compared to the use of native tissues, offers better efficacy at the expense of new complications and a higher rate of surgical reviews, these being minor in the hands of expert surgeons. CONCLUSIONS: POP surgery must be performed by experienced surgeons, properly trained and in referral centers. The patient should receive correct information about the different treatment options. Transvaginal meshes should only be indicated in complex cases and in recurrences after POP surgery. AEU PROPOSAL: Creation of a clinical guideline and a national registry for long-term evaluation. Preparation of an Informed Consent available to all professionals and patients, as well as a specific training plan to achieve better training in complex pelvic floor surgery

Consensus statement of the Spanish Association Of Urology on the use of meshes in pelvic organ prolapse. / Consenso de la Asociación Española de Urología sobre el uso de mallas en la cirugía del prolapso de órganos pélvicos.

INTRODUCTION: Recently the Food and Drug Administration has banned the use of transvaginal meshes for the surgical treatment of pelvic organ prolapse (POP) in the United States. This has caused a worldwide impact on the management of pelvic floor pathology by different specialists. OBJECTIVE: To achieve a consensus on the use of meshes in the surgical treatment of POPs. ACQUISITION OF DATA/EVIDENCE: A Committee of experts of the Spanish Association of Urology (AEU) was organized to review the literature and analyze the safety and efficacy of the use of polypropylene meshes in POP surgery. RESULTS/EVIDENCE FROM THE LITERATURE: The evidence reflects that the use of meshes, compared to the use of native tissues, offers better efficacy at the expense of new complications and a higher rate of surgical reviews, these being minor in the hands of expert surgeons. CONCLUSIONS: POP surgery must be performed by experienced surgeons, properly trained and in referral centers. The patient should receive correct information about the different treatment options. Transvaginal meshes should only be indicated in complex cases and in recurrences after POP surgery. AEU PROPOSAL: Creation of a clinical guideline and a national registry for long-term evaluation. Preparation of an Informed Consent available to all professionals and patients, as well as a specific training plan to achieve better training in complex pelvic floor surgery.

Resveratrol Modulates and Reverses the Age-Related Effect on Adenosine-Mediated Signalling in SAMP8 Mice.

Resveratrol (RSV) is a natural compound present in berries, grapes and red wine that has shown some neuroprotective properties, but the mechanism by which RSV exhibits its protective role is not very well understood yet. Little is known about the effect of RSV on adenosinergic system, a system regulated in an age-dependent manner in SAMP8 mice, widely considered as an Alzheimer's model. Therefore, the aim of the present work was to assess whether RSV intake was able to modulate the adenosine-mediated signalling in SAMP8 mice. Data showed herein clearly demonstrate the ability of RSV to modulate adenosine receptor gene expression as well as transduction pathway mediated by receptors expressed on plasma membrane. Interestingly, this polyphenol was able to reverse the age-related loss of adenosine A1 receptors and its corresponding signalling pathway. Moreover, adenosine A2A receptors were not modulated by aging or RSV, but A2A-mediated signalling was completely desensitized after RSV treatment compared to untreated mice. Enzymes involved on adenosine metabolism, such as 5'-nucleotidase and adenosine deaminase, were found to be reduced after RSV treatment, but adenosine levels remained unchanged. Nevertheless, an age-related decrease on 5'-nucleotidase activity and adenosine and related metabolite levels was observed. In conclusion, our data show that RSV modulates adenosine-mediated signalling, strongly suggesting that the role of RSV via adenosine receptor signalling and its modulation of neurotransmission in neurodegenerative diseases should be considered as new therapeutic target for RSV neuroprotective effect.

Resveratrol modulates response against acute inflammatory stimuli in aged mouse brain.

With upcoming age, the capability to fight against harmful stimuli decreases and the organism becomes more susceptible to infections and diseases. Here, the objective was to demonstrate the effect of dietary resveratrol in aged mice in potentiating brain defenses against LipoPolySaccharide (LPS). Acute LPS injection induced a strong proinflammatory effect in 24-months-old C57/BL6 mice hippocampi, increasing InterLeukin (Il)-6, Tumor Necrosis Factor-alpha (Tnf-α), Il-1ß, and C-X-C motif chemokine (Cxcl10) gene expression levels. Resveratrol induced higher expression in those cytokines regarding to LPS. Oxidative Stress (OS) markers showed not significant changes after LPS or resveratrol, although for resveratrol treated groups a slight increment in most of the parameters studies was observed, reaching signification for NF-kB protein levels and iNOS expression. However, Endoplasmic Reticulum (ER) stress markers demonstrated significant changes in resveratrol-treated mice after LPS treatment, specifically in eIF2α, BIP, and ATF4. Moreover, as described, resveratrol is able to inhibit the mechanistic Target of Rapamycin (mTOR) pathway and this effect could be linked to (eIF2α) phosphorylation and the increase in the expression of the previously mentioned proinflammatory genes as a response to LPS treatment in aged animals. In conclusion, resveratrol treatment induced a different cellular response in aged animals when they encountered acute inflammatory stimuli.

Resveratrol Protects SAMP8 Brain Under Metabolic Stress: Focus on Mitochondrial Function and Wnt Pathway.

Metabolic stress induced by high-fat (HF) diet leads to cognitive dysfunction and aging, but the physiological mechanisms are not fully understood. Senescence-accelerated prone mouse (SAMP8) models were conducted under metabolic stress conditions by feeding HF for 15 weeks, and the preventive effect of resveratrol was studied. This dietary strategy demonstrates cognitive impairment in SAMP8-HF and significant preventive effect by resveratrol-treated animals. Hippocampal changes in the proteins involved in mitochondrial dynamics optic atrophy-1 protein (OPA1) and mitofusin 2 (MFN2) comprised a differential feature found in SAMP8-HF that was prevented by resveratrol. Electronic microscopy showed a larger mitochondria in SAMP8-HF + resveratrol (SAMP8-HF + RV) than in SAMP8-HF, indicating increases in fusion processes in resveratrol-treated mice. According to the mitochondrial morphology, significant increases in the I-NDUFB8, II-SDNB, III-UQCRC2, and V-ATPase complexes, in addition to that of voltage-dependent anion channel 1 (VDAC1)/porin, were found in resveratrol-treated animals with regard to SAMP8-HF, reaching control-animal levels. Moreover, tumor necrosis factor alpha (TNF-α) and interleukin (IL-6) were increased after HF, and resveratrol prevents its increase. Moreover, we found that the HF diet affected the Wnt pathway, as demonstrated by ß-catenin inactivation and modification in the expression of several components of this pathway. Resveratrol induced strong activation of ß-catenin. The metabolic stress rendered in the cognitive and cellular pathways altered in SAMP8 focus on different targets in order to act on preventing cognitive impairment in neurodegeneration, and resveratrol can offer therapeutic possibilities for preventive strategies in aging or neurodegenerative conditions.

Environmental Enrichment Improves Behavior, Cognition, and Brain Functional Markers in Young Senescence-Accelerated Prone Mice (SAMP8).

The environment in which organisms live can greatly influence their development. Consequently, environmental enrichment (EE) is progressively recognized as an important component in the improvement of brain function and development. It has been demonstrated that rodents raised under EE conditions exhibit favorable neuroanatomical effects that improve their learning, spatial memory, and behavioral performance. Here, by using senescence-accelerated prone mice (SAMP8) and these as a model of adverse genetic conditions for brain development, we determined the effect of EE by raising these mice during early life under favorable conditions. We found a better generalized performance of SAMP8 under EE in the results of four behavioral and learning tests. In addition, we demonstrated broad molecular correlation in the hippocampus by an increase in NeuN and Ki67 expression, as well as an increase in the expression of neurotrophic factors, such as pleiotrophin (PTN) and brain-derived neurotrophic factor (BDNF), with a parallel decrease in neurodegenerative markers such as GSK3, amyloid-beta precursor protein, and phosphorylated beta-catenin, and a reduction of SBDP120, Bax, GFAP, and interleukin-6 (IL-6), resulting in a neuroprotective panorama. Globally, it can be concluded that EE applied to SAMP8 at young ages resulted in epigenetic regulatory mechanisms that give rise to significant beneficial effects at the molecular, cellular, and behavioral levels during brain development, particularly in the hippocampus.

Adipokine pathways are altered in hippocampus of an experimental mouse model of Alzheimer's disease.

A growing body of evidence suggests that ß-amyloid peptides (Aß) are unlikely to be the only factor involved in Alzheimer's disease (AD) aetiology. In fact, a strong correlation has been established between AD patients and patients with type 2 diabetes and/or cholesterol metabolism alterations. In addition, a link between adipose tissue metabolism, leptin signalling in particular, and AD has also been demonstrated. In the present study we analyzed the expression of molecules related to metabolism, with the main focus on leptin and prolactin signalling pathways in an APPswe/PS1dE9 (APP/PS1) transgenic mice model, at 3 and 6 months of age, compared to wild-type controls. We have chosen to study 3 months-old APP/PS1 animals at an age when neither the cognitive deficits nor significant Aß plaques in the brain are present, and to compare them to the 6 months-old mice, which exhibit elevated levels of Aß in the hippocampus and memory loss. A significant reduction in both mRNA and protein levels of the prolactin receptor (PRL-R) was detected in the hippocampi of 3 months old APP/PS1 mice, with a decrease in the levels of the leptin receptor (OB-R) first becoming evident at 6 months of age. We proceeded to study the expression of the intracellular signalling molecules downstream of these receptors, including stat (1-5), sos1, kras and socs (1-3). Our data suggest a downregulation in some of these molecules such as stat-5b and socs (1-3), in 3 months-old APP/PS1 brains. Likewise, at the same age, we detected a significant reduction in mRNA levels of lrp1 and cyp46a1, both of which are involved in cholesterol homeostasis. Taken together, these results demonstrate a significative impairment in adipokine receptors signalling and cholesterol regulation pathways in the hippocampus of APP/PS1 mice at an early age, prior to the Aß plaque formation.

Valores de referencia para el cuestionario CAVIPRES-30, un cuestionario global sobre la calidad de vida relacionada con la salud de pacientes con cáncer de próstata / Reference values for the CAVIPRES-30 questionnaire, a global questionnaire on the health-related quality of life of patients with prostate cancer

Objetivo: Definir y establecer los valores de referencia del cuestionario CAVIPRES-30, un cuestionario de la calidad de vida relacionada con la salud específica para pacientes con cáncer de próstata. Material y métodos: El cuestionario CAVIPRES-30 fue administrado a 2.630 hombres con cáncer de próstata incluidos por 238 urólogos del sistema de sanidad español. Se llevaron a cabo análisis descriptivos de los datos sociodemográficos y clínicos, y análisis multivariados para corroborar que las variables estratificadas se asociaban de forma independiente y estadísticamente significativa a la puntuación global del cuestionario. Resultados: Las variables de tiempo desde el diagnóstico de la enfermedad, tanto si el paciente tenía pareja estable como si no, y si estaba o no recibiendo tratamiento sintomático, se asociaron de forma independiente y estadísticamente significativa (p < 0,001) a la puntuación global del cuestionario. La tabla de valores de referencia del cuestionario CAVIPRES-30 contiene diferentes tipos de información sobre el perfil de cada paciente: tamaño muestral, estadísticas descriptivas con respecto a la puntuación global y el valor de alfa de Cronbach (entre 0,791 y 0,875); los valores del cuestionario están reportados en deciles. Conclusiones: Los resultados de este estudio aportan nuevas evidencias con respecto a la idoneidad y utilidad del cuestionario CAVIPRES-30 como instrumento para evaluar individualmente la calidad de vida del cáncer de próstata

Objective: Define and establish the reference values of the CAVIPRES-30 questionnaire, a health related quality of life questionnaire specific for prostate cancer patients. Materials and methods: The CAVIPRES-30 was administered to 2630 males with prostate cancer included by 238 Urologist belonging to the Spanish National Healthcare System. Descriptive analysis on socio-demographic and clinical data was performed, and multivariate analyses were used to corroborate that stratification variables were statistically significantly and independently associated to the overall score of the questionnaire. Results: The variables, time since diagnosis of the illness, whether the patient had a stable partner or not, and whether he was undergoing symptomatic treatment or not were statistically, significantly, and independently associated (p < 0.001) to the overall score of the questionnaire. The reference values table of the CAVIPRES-30 questionnaire is made up of different kinds of information of each patient profile: sample size, descriptive statistics with regard to the overall score, Cronbach's alpha value (between 0.791 and 0.875) and the questionnaire's values are reported by deciles. Conclusions: The results of this study provide new proof as to the suitability and usefulness of the CAVIPRES-30 questionnaire as an instrument for assessing individually the quality of life of prostate cancer patients

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 cortex.

Reference values for the CAVIPRES-30 questionnaire, a global questionnaire on the health-related quality of life of patients with prostate cancer.

OBJECTIVE: Define and establish the reference values of the CAVIPRES-30 Questionnaire, a health related quality of life questionnaire specific for prostate cancer patients. MATERIAL AND METHODS: The CAVIPRES-30 was administered to 2,630 males with prostate cancer included by 238 Urologist belonging to the Spanish National Healthcare System. Descriptive analysis on socio-demographic and clinical data were performed, and multivariate analyses were used to corroborate that stratification variables were statistically significantly and independently associated to the overall score of the questionnaire. RESULTS: The variables Time since diagnosis of the illness, whether the patient had a Stable partner or not, if he was, or not, undergoing Symptomatic treatment were statistically significantly and independently associated (P < .001) to the overall score of the questionnaire. The reference values table of the CAVIPRES-30 questionnaire is made up of different kinds of information of each patient profile: sample size, descriptive statistics with regard to the overall score, Cronbach's alpha value (between .791 and .875) and the questionnaire's values are reported by deciles. CONCLUSIONS: The results of this study contribute new proof as to the suitability and usefulness of the CAVIPRES-30 questionnaire as an instrument for assessing individually the quality of life of prostate cancer.

Melatonin suppresses nitric oxide production in glial cultures by pro-inflammatory cytokines through p38 MAPK inhibition.

Melatonin has been shown to down-regulate inflammatory responses and provide neuroprotection. However, the mechanisms underlying the anti-inflammatory properties of melatonin are poorly understood. In the present work, we studied the modulatory effect of melatonin against pro-inflammatory cytokines in glial cell cultures. Treatment with pro-inflammatory cytokines mainly tumor necrosis factor-alpha, interleukin 1-beta, and interferon-gamma induces an increase in inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. Pre-treatment with melatonin produced an inhibitory effect on iNOS expression and NO production. The biochemical studies revealed that cytokine treatment favors the activation of several pathways, such as mitogen-activated protein kinases (MAPKs), STAT1, and STAT3; however, the anti-inflammatory effect of melatonin was accompanied only by a decrease in p38 MAPK activity. Likewise, SB203580 a p38 kinase inhibitor inhibits NO production. These data indicate that the anti-inflammatory action of melatonin in glial cells after stimulation with pro-inflammatory cytokines may be in part, attributable to p38 inhibition which down-regulates iNOS expression and NO production.

Wnt pathway regulation by long-term moderate exercise in rat hippocampus.

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/ß-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 ß-catenin, which leads ultimately to its proteasomal degradation, revealed higher levels and activation of Axin1 and GSK-3α/ß respectively in sedentary animals. However neither different phosphorylated forms nor total ß-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.

Depression-like behavior is dependent on age in male SAMP8 mice.

Aging is associated with an increased risk of depression in humans. To elucidate the underlying mechanisms of depression and its dependence on aging, here we study signs of depression in male SAMP8 mice. For this purpose, we used the forced swimming test (FST). The total floating time in the FST was greater in SAMP8 than in SAMR1 mice at 9 months of age; however, this difference was not observed in 12-month-old mice, when both strains are considered elderly. Of the two strains, only the SAMP8 animals responded to imipramine treatment. We also applied the dexamethasone suppression test (DST) and studied changes in the dopamine and serotonin (5-HT) uptake systems, the 5-HT2a/2c receptor density in the cortex, and levels of TPH2. The DST showed a significant difference between SAMR1 and SAMP8 mice at old age. SAMP8 exhibits an increase in 5-HT transporter density, with slight changes in 5-HT2a/2c receptor density. In conclusion, SAMP8 mice presented depression-like behavior that is dependent on senescence process, because it differs from SAMR1, senescence resistant strain.

Long-term physical exercise induces changes in sirtuin 1 pathway and oxidative parameters in adult rat tissues.

The protein deacetylase, sirtuin 1, is suggested as a master regulator of exercise-induced beneficial effects. Sirtuin 1 modulates mitochondrial biogenesis, primarily via its ability to deacetylate and activate proliferator-activated receptor-γ coactivator-1α (PGC-1α), interacting with AMPK kinase. Redox cell status can also influence this regulatory axis and together they form an important convergence point in hormesis during the aging process. Here, we tested whether treadmill training (36weeks), as a paradigm of long-term moderate exercise, modifies the AMPK-sirtuin 1-PGC-1α axis and redox balance in rat gastrocnemius muscle, liver and heart. Physical activity induced increases in sirtuin 1 protein levels in all the aged rat tissues studied, as well as total PGC-1α levels. However, no changes in AMPK activation or significant differences in mitochondrial biogenesis (by measuring electron transport chain protein content) were found after exercise training. Parallel to these changes, we observed an improvement of oxidative stress defenses, mainly in muscle, with modification of the antioxidant enzyme machinery resulting in a reduction in lipid peroxidation and protein carbonylation. Thus, we demonstrate that moderate long-term exercise promotes tissue adaptations, increasing muscle, liver and heart sirtuin 1 protein content and activity and increasing PGC-1α protein expression. However, AMPK activation or mitochondrial biogenesis is not modified, but it cannot be discarded that its participation in the adaptive mechanism which prevents the development of the deleterious effects of age.

Lack of Jun-N-terminal kinase 3 (JNK3) does not protect against neurodegeneration induced by 3-nitropropionic acid.

AIMS: 3-Nitropropionic acid (3-NP) is a toxin that replicates most of the clinical and pathophysiological symptoms of Huntington's disease, inducing neurodegeneration in the striatum due to the inhibition of mitochondrial succinate dehydrogenase. Different pathways have been implicated in the cell death induced by 3-NP in rodents. One of them is the Jun-N-terminal kinase (JNK) pathway, which may play a role in the neurodegenerative process in different diseases. Moreover, the lack of one isoform of JNK (JNK3) has been associated with neuroprotection in different experimental models of neurodegeneration. Therefore, in the present study the role of JNK3 in the experimental Huntington's model induced by 3-NP administration was evaluated. METHODS: 3-NP was intraperitoneally administered once a day for 3 days to wild-type and Jnk3-null mice. Coronal brain sections were used to determine cell death and astrogliosis in striatum. Western blots were performed to determine the involvement of different pathways in both wild-type and Jnk3-null mice. RESULTS: Although JNK activation was observed following 3-NP administration, the results indicate that the lack of JNK3 does not confer neuroprotection against 3-NP toxicity. Thus, other pathways must be involved in the neurodegeneration induced in this model. One of the possible pathways towards 3-NP-induced apoptosis could involve the calpains, as their activity was increased in wild-type and Jnk3-null mice. CONCLUSION: Although JNK3 is a key protein involved in cell death in different neurodegenerative diseases, the present study demonstrates that the lack of JNK3 does not confer neuroprotection against 3-NP-induced neuronal death.

Long-term treadmill exercise induces neuroprotective molecular changes in rat brain.

Exercise enhances general health. However, its effects on neurodegeneration are controversial, and the molecular pathways in the brain involved in this enhancement are poorly understood. Here, we examined the effect of long-term moderate treadmill training on adult male rat cortex and hippocampus to identify the cellular mechanisms behind the effects of exercise. We compared three animal groups: exercised (30 min/day, 12 m/min, 5 days/wk, 36 wk), handled but nonexercised (treadmill handling procedure, 0 m/min), and sedentary (nonhandled and nonexercised). Moderate long-term exercise induced an increase in IGF-1 levels and also in energy parameters, such as PGC-1α and the OXPHOS system. Moreover, the sirtuin 1 pathway was activated in both the exercised and nonexercised groups but not in sedentary rats. This induction could be a consequence of exercise as well as the handling procedure. To determine whether the long-term moderate treadmill training had neuroprotective effects, we studied tau hyperphosphorylation and GSK3ß activation. Our results showed reduced levels of phospho-tau and GSK3ß activation mainly in the hippocampus of the exercised animals. In conclusion, in our rodent model, exercise improved several major brain parameters, especially in the hippocampus. These improvements induced the upregulation of sirtuin 1, a protein that extends life, the stimulation of mitochondrial biogenesis, the activation of AMPK, and the prevention of signs of neurodegeneration. These findings are consistent with other reports showing that physical exercise has positive effects on hormesis.

HIF-1α expression in the hippocampus and peripheral macrophages after glutamate-induced excitotoxicity.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a master transcription factor that regulates the response to hypoxia and ischemia and induces the expression of various genes, including vascular endothelial growth factor (VEGF) and erythropoietin (EPO). This study shows the systemic response of increased HIF-1α, EPO, and VEGF mRNA and protein. In addition, VEGF expression was increased in neurons and over-expressed in glial cells in a model of neuroexcitotoxicity in the hippocampus, in which rats were neonatally exposed to high glutamate concentrations. Simultaneous increases in HIF-1α, EPO and VEGF mRNA in peritoneal macrophages were also observed. Our study is consistent with the hypothesis that these genes exert a protective effect in response to neurotoxicity.

[Effects of melatonin in the brain of the senescence-accelerated mice-prone 8 (SAMP8) model]. / Efectos de la melatonina en el cerebro de ratones con senescencia acelerada SAMP8.

Senescence-accelerated mice (SAM) represent an aging model establish by selective inbreeding of the AKR/J strain. SAMP8 is a suitable model to study the genetics or proteics fundamental mechanisms of aging, in physiological or pathological conditions, because SAMP8 develop neuropathological markers also found in neurodegenerative diseases like Alzheimer. Melatonin is known as sleep hormone because its action controlling the sleep/awake circadian rhythm. Moreover, melatonin has antioxidant properties and may have an important anti-aging role. The chronic treatment with melatonin in the SAMP8 model was able to reduce oxidative stress and the neurodegenerative calpain/Cdk5 pathway and primed phosphorylation of GSK3beta and tau hiperphosphorylation markers of cerebral aging and neurodegeneration in SAMP8 brains, indicating the neuroprotective and anti-aging effect of melatonin.