Institute Investigacion Sanitaria Hospital Of La Princesa

Madrid, Spain

Institute Investigacion Sanitaria Hospital Of La Princesa

Madrid, Spain
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Cunha M.P.,Autonomous University of Madrid | Cunha M.P.,Federal University of Santa Catarina | Martin-de-Saavedra M.D.,Autonomous University of Madrid | Romero A.,Autonomous University of Madrid | And 8 more authors.
Neuroscience | Year: 2013

The guanidine-like compound creatine exerts bioenergetic, antiexcitotoxic, antioxidant and neuroprotective properties; however, the intracellular mechanisms responsible for these effects are still not well established. The purpose of this study was to investigate the protective effect of creatine against 6-hydroxydopamine (6-OHDA)-induced cell death in neuroblastoma SH-SY5Y cells and the possible intracellular signaling pathways involved in such effect. Exposure of SH-SY5Y cells to 100-300μM of 6-OHDA for 24h caused a significant concentration-dependent cell death measured as a diminution of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) reduction and as an increase in the extracellular release of lactate dehydrogenase. SH-SY5Y cells incubated for 24 or 48h with creatine (10-5000μM) was not cytotoxic. However, pre and co-treatment with creatine (0.3-1000μM) for 24h reduced 6-OHDA-induced toxicity. The protective effect afforded by creatine against 6-OHDA-induced toxicity was reversed by inhibitors of different protein kinases, i.e. phosphatidylinositol-3 kinase (PI3K) (LY294002), Ca2+/calmodulin-dependent protein kinase II (CaMKII) (KN-93), protein kinase A (H-89), mitogen-activated protein kinase kinase 1/2 (MEK1/2) (PD98059) and protein kinase C (PKC) (chelerythrine). Furthermore, creatine prevented the 6-OHDA-induced dephosphorylation of glycogen synthase kinase-3β (GSK-3β) at the serine 9 residue. In conclusion, the results of this study show that creatine can protect against 6-OHDA-induced toxicity and its protective mechanism is related to a signaling pathway that involves PI3K, PKC, PKA, CaMKII, MEK1/2 and GSK-3β. © 2013 IBRO.


Peiro C.,Autonomous University of Madrid | Peiro C.,Hospital Universitario La Paz | Lorenzo O.,Autonomous University of Madrid | Lorenzo O.,Institute Investigacion Sanitaria Fundacion Jimenez Diaz | And 5 more authors.
Frontiers in Pharmacology | Year: 2017

Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of β-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL-1β. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1β inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1β inhibitors as novel therapeutic tools for treating these patients. © 2017 Peiró, Lorenzo, Carraro and Sánchez-Ferrer.


Pastor J.,Institute Investigacion Sanitaria Hospital Of La Princesa | Sola R.G.,Institute Investigacion Sanitaria Hospital Of La Princesa | Ortega G.J.,Institute Investigacion Sanitaria Hospital Of La Princesa
Journal of Neuroscience Methods | Year: 2014

Background: The presence of spikes and sharp waves in recordings of epileptic patients contaminates background signal synchronization. When estimating functional connectivity between extended cortical areas, the influence of epileptic spikes in specific areas should be considered; however, this step is sometimes overlooked. We present a simple method for quantifying the influence of epileptic activity on background signal synchronization. Method: Standard synchronization measures were calculated for both pure correlated Gaussian signals and correlated Gaussian signals with different levels of epileptic spikes in order to determine the influence of epileptic activity on synchronization estimates. Results: Synchronization from invasive epileptic recordings (e.g., depth electrodes) displays a much higher bias due to epileptic activity than superficial electrodes. Moreover, statistical methods such as mutual information are more affected by spike presence than phase synchronization methods. The influence of spikes is far greater at low values of background synchronization. Conclusions: The information provided by this procedure makes it possible to differentiate true background synchronization from spike synchronization. Thus, our procedure serves as a guide for analyzing synchronization and functional connectivity calculations in epileptic recordings. © 2013 Elsevier B.V.


Sanz-Garcia A.,Institute Investigacion Sanitaria Hospital Of La Princesa | Vega-Zelaya L.,Institute Investigacion Sanitaria Hospital Of La Princesa | Vega-Zelaya L.,Hospital Universitario Of La Princesa | Pastor J.,Institute Investigacion Sanitaria Hospital Of La Princesa | And 5 more authors.
Entropy | Year: 2017

The postictal period is characterized by several neurological alterations, but its exact limits are clinically or even electroencephalographically hard to determine in most cases. We aim to provide quantitative functions or conditions with a clearly distinguishable behavior during the ictal-postictal transition. Spectral methods were used to analyze foramen ovale electrodes (FOE) recordings during the ictal/postictal transition in 31 seizures of 15 patients with strictly unilateral drug resistant temporal lobe epilepsy. In particular, density of links, spectral entropy, and relative spectral power were analyzed. Partial simple seizures are accompanied by an ipsilateral increase in the relative Delta power and a decrease in synchronization in a 66% and 91% of the cases, respectively, after seizures offset. Complex partial seizures showed a decrease in the spectral entropy in 94% of cases, both ipsilateral and contralateral sides (100% and 73%, respectively) mainly due to an increase of relative Delta activity. Seizure offset is defined as the moment at which the “seizure termination mechanisms” actually end, which is quantified in the spectral entropy value. We propose as a definition for the postictal start the time when the ipsilateral SE reaches the first global minimum. © 2017 by the authors.


Cunha M.P.,Federal University of Santa Catarina | Pazini F.L.,Federal University of Santa Catarina | Ludka F.K.,Federal University of Santa Catarina | Ludka F.K.,Contestado University | And 13 more authors.
Amino Acids | Year: 2015

The modulation of N-methyl-D-aspartate receptor (NMDAR) and l-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and l-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/l-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), d-serine (30 μg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 μg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 μg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NO x levels, an effect potentiated by l-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability. © 2014 Springer-Verlag Wien.


Caballero P.,Hospital Of La Princesa | Alonso R.,Lipid Clinic | Rosado P.,Hospital Of La Princesa | Fernandez-Friera L.,National Research Center Cardiovascular | And 3 more authors.
Atherosclerosis | Year: 2012

Objectives: To investigate the extent of subclinical atherosclerosis in asymptomatic familial hypercholesterolemia (FH) patients using non-invasive images techniques. Patients, methods and results: The atherosclerotic burden of 36 molecularly defined FH patients (18 males, 45.7 ± 10.9 years) without evidence of cardiovascular disease receiving lipid-lowering treatment and 19 (47.8 ± 11.3 years) controls was investigated. Descending thoracic aorta magnetic resonance imaging (MRI) was performed in a 1.5. T equipment with T1 and T2 sequences to characterize atherosclerotic plaques and to measure aortic wall volumen. Carotid intima-media thickness (cIMT) and presence of plaques were measured using B-mode carotid ultrasound.Mean aortic wall volumen, cIMT and atherosclerotic plaques in aorta were significantly higher in FH cases (P< 0.001). A significant correlation between aortic wall volume and cIMT was observed (P< 0.01). Aortic MRI detected plaques in 94% and carotid ultrasound in 14% of cases. Lipid-rich plaques were observed only in FH cases (33%) and were associated with family history of premature coronary artery disease (P< 0.05). Conclusions: Asymptomatic middle-aged FH patients have significantly higher atherosclerotic burden than controls. cIMT has shown a significant correlation with aortic wall volume and MRI allowed the detection of lipid-rich plaques in FH subjects that were associated with family history of premature coronary artery disease. © 2012 Elsevier Ireland Ltd.


Cunha M.P.,Autonomous University of Madrid | Cunha M.P.,Federal University of Santa Catarina | Martin-De-Saavedra M.D.,Autonomous University of Madrid | Martin-De-Saavedra M.D.,Northwestern University | And 10 more authors.
ASN Neuro | Year: 2015

Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mito chondrialdysfunction and cell death in rat striatal slices, used as an in vitro Parkinson’s model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3b (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine473) and GSK3b (Serine9). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons. © The Author(s) 2014.


Palmigiano A.,University of Buenos Aires | Pastor J.,Institute Investigacion Sanitaria Hospital Of La Princesa | de Sola R.G.,Institute Investigacion Sanitaria Hospital Of La Princesa | Ortega G.J.,Institute Investigacion Sanitaria Hospital Of La Princesa
PLoS ONE | Year: 2012

Purpose: Identification of critical areas in presurgical evaluations of patients with temporal lobe epilepsy is the most important step prior to resection. According to the "epileptic focus model", localization of seizure onset zones is the main task to be accomplished. Nevertheless, a significant minority of epileptic patients continue to experience seizures after surgery (even when the focus is correctly located), an observation that is difficult to explain under this approach. However, if attention is shifted from a specific cortical location toward the network properties themselves, then the epileptic network model does allow us to explain unsuccessful surgical outcomes. Methods: The intraoperative electrocorticography records of 20 patients with temporal lobe epilepsy were analyzed in search of interictal synchronization clusters. Synchronization was analyzed, and the stability of highly synchronized areas was quantified. Surrogate data were constructed and used to statistically validate the results. Our results show the existence of highly localized and stable synchronization areas in both the lateral and the mesial areas of the temporal lobe ipsilateral to the clinical seizures. Synchronization areas seem to play a central role in the capacity of the epileptic network to generate clinical seizures. Resection of stable synchronization areas is associated with elimination of seizures; nonresection of synchronization clusters is associated with the persistence of seizures after surgery. Discussion: We suggest that synchronization clusters and their stability play a central role in the epileptic network, favoring seizure onset and propagation. We further speculate that the stability distribution of these synchronization areas would differentiate normal from pathologic cases. © 2012 Palmigiano et al.


PubMed | Institute Investigacion Sanitaria Hospital Of La Princesa and CONICET
Type: | Journal: Journal of visualized experiments : JoVE | Year: 2017

Approximately 30% of epilepsy patients are refractory to antiepileptic drugs. In these cases, surgery is the only alternative to eliminate/control seizures. However, a significant minority of patients continues to exhibit post-operative seizures, even in those cases in which the suspected source of seizures has been correctly localized and resected. The protocol presented here combines a clinical procedure routinely employed during the pre-operative evaluation of temporal lobe epilepsy (TLE) patients with a novel technique for network analysis. The method allows for the evaluation of the temporal evolution of mesial network parameters. The bilateral insertion of foramen ovale electrodes (FOE) into the ambient cistern simultaneously records electrocortical activity at several mesial areas in the temporal lobe. Furthermore, network methodology applied to the recorded time series tracks the temporal evolution of the mesial networks both interictally and during the seizures. In this way, the presented protocol offers a unique way to visualize and quantify measures that considers the relationships between several mesial areas instead of a single area.


PubMed | Institute Investigacion Sanitaria Hospital Of La Princesa
Type: | Journal: Journal of neuroscience methods | Year: 2014

The presence of spikes and sharp waves in recordings of epileptic patients contaminates background signal synchronization. When estimating functional connectivity between extended cortical areas, the influence of epileptic spikes in specific areas should be considered; however, this step is sometimes overlooked. We present a simple method for quantifying the influence of epileptic activity on background signal synchronization.Standard synchronization measures were calculated for both pure correlated Gaussian signals and correlated Gaussian signals with different levels of epileptic spikes in order to determine the influence of epileptic activity on synchronization estimates.Synchronization from invasive epileptic recordings (e.g., depth electrodes) displays a much higher bias due to epileptic activity than superficial electrodes. Moreover, statistical methods such as mutual information are more affected by spike presence than phase synchronization methods. The influence of spikes is far greater at low values of background synchronization.The information provided by this procedure makes it possible to differentiate true background synchronization from spike synchronization. Thus, our procedure serves as a guide for analyzing synchronization and functional connectivity calculations in epileptic recordings.

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