Estudio de los efectos del URB597 en un modelo preclínico de la enfermedad de Huntington en ratas

El sistema endocannabinoide (SEC) participa activamente en una gran cantidad de procesos fisiológicos en el Sistema Nervioso Central. A la fecha se ha establecido su participación en la regulación del receptor N-metil-D-aspartato (NMDAr) glutamatérgico a través del control modulatorio en los receptores cannabinoides (CBr). De esta forma, el agonista endógeno de estos receptores, el ácido quinolínico (QUIN), puede actuar como excitotoxina a través de la sobreactivación selectiva de los NMDAr, participando por tanto en el inicio y desarrollo de desórdenes neurológicos. Con este antecedente, en este trabajo evaluamos si la inhibición farmacológica de hidrolasa de amidas de ácidos grasos (FAAH) inducida por el URB597, y el consecuente incremento en los niveles endógenos de anandamida, puede prevenir el daño excitotóxico inducido por QUIN. El URB597 (0.3 mg/kg/día por 7 días, administrado antes, durante y después de una lesión estriatal) ejerció efectos protectores en las alteraciones motoras (conducta asimétrica) y bioquímicas (peroxidación lipídica y carbonilación de proteínas) inducidas por el QUIN en el modelo de rata. Asimismo, el URB597 preservó la integridad estructural en el estriado, y previno la pérdida neuronal (evaluada por localización de proteína asociada a microtúbulos 2, y glutamato descarboxilasa) inducida por QUIN (1 µL intraestriatal, 240 nmol/µL), y modificó los patrones tempranos de localización de CB1r y la subunidad NR1 del NMDAr. En conjunto, estos hallazgos fundamentan que la manipulación del SEC desempeña un papel neuroprotector frente a los insultos excitotóxicos en el Sistema Nervioso Central.The endocannabinoid system (ECS) actively participates in several physiological processes within the Central Nervous System. It has been involved in the regulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr). The endogenous ligand of such receptors, the quinolinic acid (QUIN), can act as an excitotoxin through the selective overactivation of NMDAr, leading to the onset and development of neurological disorders. In this work we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day for 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats. URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 µL intrastriatal, 240 nmol/µL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1). Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the Central Nervous System

Comparing the Neuroprotective Effects of Caffeic Acid in Rat Cortical Slices and Caenorhabditis elegans: Involvement of Nrf2 and SKN-1 Signaling Pathways.

Caffeic acid (CA) is a hydroxycinnamic acid derivative and polyphenol with antioxidant and anti-inflammatory activities. The neuroprotective properties of CA still need detailed characterization in different biological models. Here, the antioxidant and neuroprotective effects of CA were compared in in vitro and in vivo neurotoxic models. Biochemical outcomes of cell dysfunction, oxidative damage, and transcriptional regulation were assessed in rat cortical slices, whereas endpoints of physiological stress and motor alterations were characterized in Caenorhabditis elegans (C. elegans). In rat cortical slices, CA (100 μM) prevented, in a differential manner, the loss of reductive capacity, the cell damage, and the oxidative damage induced by the excitotoxin quinolinic acid (QUIN, 100 μM), the pro-oxidant ferrous sulfate (FeSO4, 25 μM), and the dopaminergic toxin 6-hydroxydopamine (6-OHDA, 100 μM). CA also restored the levels of nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE; a master antioxidant regulatory pathway) binding activity affected by the three toxins. In wild-type (N2) of C. elegans, but not in the skn-1 KO mutant strain (worms lacking the orthologue of mammalian Nrf2), CA (25 mM) attenuated the loss of survival induced by QUIN (100 mM), FeSO4 (15 mM), and 6-OHDA (25 mM). Motor alterations induced by the three toxic models in N2 and skn-1 KO strains were prevented by CA in a differential manner. Our results suggest that (1) CA affords partial protection against different toxic insults in mammalian brain tissue and in C. elegans specimens; (2) the Nrf2/ARE binding activity participates in the protective mechanisms evoked by CA in the mammalian cortical tissue; (3) the presence of the orthologous skn-1 pathway is required in the worms for CA to exert protective effects; and (4) CA exerts antioxidant and neuroprotective effects through homologous mechanisms in different species

International Nosocomial Infection Control Consortiu (INICC) report, data summary of 43 countries for 2007-2012. Device-associated module

We report the results of an International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2007-December 2012 in 503 intensive care units (ICUs) in Latin America, Asia, Africa, and Europe. During the 6-year study using the Centers for Disease Control and Prevention's (CDC) U.S. National Healthcare Safety Network (NHSN) definitions for device-associated health care–associated infection (DA-HAI), we collected prospective data from 605,310 patients hospitalized in the INICC's ICUs for an aggregate of 3,338,396 days. Although device utilization in the INICC's ICUs was similar to that reported from ICUs in the U.S. in the CDC's NHSN, rates of device-associated nosocomial infection were higher in the ICUs of the INICC hospitals: the pooled rate of central line–associated bloodstream infection in the INICC's ICUs, 4.9 per 1,000 central line days, is nearly 5-fold higher than the 0.9 per 1,000 central line days reported from comparable U.S. ICUs. The overall rate of ventilator-associated pneumonia was also higher (16.8 vs 1.1 per 1,000 ventilator days) as was the rate of catheter-associated urinary tract infection (5.5 vs 1.3 per 1,000 catheter days). Frequencies of resistance of Pseudomonas isolates to amikacin (42.8% vs 10%) and imipenem (42.4% vs 26.1%) and Klebsiella pneumoniae isolates to ceftazidime (71.2% vs 28.8%) and imipenem (19.6% vs 12.8%) were also higher in the INICC's ICUs compared with the ICUs of the CDC's NHSN