Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress

Ansiedad Materna Prenatal, Desarrollo Psicológico Infantil y Reactividad del Eje HPA en Bebés de 2 a 3 Meses de Edad

Los bebés expuestos a altos niveles de ansiedad materna durante la etapa prenatal pueden desarrollar un eje HPA (hipotálamo pituitario adrenal) más reactivo, lo que supone vulnerabilidad a padecer psicopatologías. En este estudio prospectivo investigamos las relaciones entre la ansiedad prenatal maternal, el desarrollo psicológico infantil y la reactividad del eje HPA en bebés de 2 a 3 meses. Recogimos datos de cuarenta y seis díadas de madres y bebés. El análisis principal no reveló relaciones significativas entre las tres variables estudiadas, pero la variabilidad apuntó a que la ansiedad materna prenatal podría asociarse a efectos diferenciales en la reactividad del eje HPA en función del desarrollo psicológico infantil. Además, los resultados indicaron que las madres con ansiedad prenatal presentaban otros síntomas psicopatológicos, como sensibilidad interpersonal (p < .001) y obsesión-compulsión (p < .001). Esto es significativo para futuras investigaciones y a nivel clínico para promover intervenciones psicológicas durante la gestación

Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study

<p>Abstract</p> <p>Background</p> <p>The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS).</p> <p>Methods</p> <p>Vascular responses of pial vessels were analyzed by intravital microscopy and inflammatory parameters measured by qRT-PCR.</p> <p>Results</p> <p>CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS-induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD.</p> <p>Conclusions</p> <p>These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid.</p

Un modelo inédito de reproducibilidad sonora en musicoterapia pasiva. Enfoque metodológico con ratas Wistar en laboratorio clínico como paso previo para su aplicación con neonatos pretérmino

Este modelo muestra el proceso de grabación, análisis y reproducción digital de los ruidos emitidos por los dispositivos técnicos que, involucrados en la rehabilitación de neonatos pretérmino que se hallan en las incubadoras neonatales, provocan un entorno ambiental perjudicial para el desarrollo neurológico de éstos. Por otro lado, se elaboran, graban y mezclan digitalmente en estudio profesional, una suma de composiciones musicales que plantean beneficios sustanciales en dicho desarrollo como elemento de compensación o atenuación sonora. A su vez, se presenta un enfoque del conjunto de la reproducción sonora para verificar este doble objetivo una vez que los audios de sala y/o musicales producidos respetan el límite ético propuesto como criterio básico de exposición con ratas Wistar en la investigación de laboratorio planteada. La reproducción sonora de los audios obtenidos ofrece las máximas garantías, tras la validación y acreditación ENAC de los instrumentos de medida utilizados

The Role of the Dopamine System in Post-Stroke Mood Disorders in Newborn Rats

Post-stroke mood disorders (PSMD) affect disease prognosis in adults. Adult rodent models underlie the importance of the dopamine (DA) system in PSMD pathophysiology. There are no studies on PSMD after neonatal stroke. We induced neonatal stroke in 7-day-old (P7) rats by temporal left middle cerebral artery occlusion (MCAO). Performance in the tail suspension test (TST) at P14 and the forced swimming test (FST) and open field test (OFT) at P37 were studied to assess PSMD. DA neuron density in the ventral tegmental area, brain DA concentration and DA transporter (DAT) expression as well as D2 receptor (D2R) expression and G-protein functional coupling were also studied. MCAO animals revealed depressive-like symptoms at P14 associated with decreased DA concentration and reduced DA neuron population and DAT expression. At P37, MCAO rats showed hyperactive behavior associated with increased DA concentration, normalization of DA neuron density and decreased DAT expression. MCAO did not modify D2R expression but reduced D2R functionality at P37. MCAO-induced depressive-like symptoms were reversed by the DA reuptake inhibitor GBR-12909. In conclusion, MCAO in newborn rats induced depressive-like symptoms and hyperactive behavior in the medium and long term, respectively, that were associated with alterations in the DA system.This research was funded by the PI19/00927, PID2019-106404RB-I00 and RD21/0012/0023 projects, integrated in the Spanish Plan for R + D + I, AES 2017–2020; funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF) “A way to make Europe” (J.M.-O.) and the Irycis Chromatographic Services and Nervous System Markers Unit, UCS (2018/0135) (M.J.C.)

Regulation of Expression of Cannabinoid CB2 and Serotonin 5HT1A Receptor Complexes by Cannabinoids in Animal Models of Hypoxia and in Oxygen/Glucose-Deprived Neurons

Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB2 and serotonin 5HT1A receptors included. These two receptors may interact to form heteromers (CB2-5HT1A-Hets) that are also a target of CBD. Aims: We aimed to assess whether the expression and function of CB2-5HT1A-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen-deprived neurons. Methods: We developed a quantitation of signal transduction events in a heterologous system and in glucose/oxygen-deprived neurons. The expression of receptors was assessed by immuno-cyto and -histochemistry and, also, by using the only existing technique to visualize CB2-5HT1A-Hets fixed cultured cells and tissue sections (in situ proximity ligation PLA assay). Results: CBD and cannabigerol, which were used for comparative purposes, affected the structure of the heteromer, but in a qualitatively different way; CBD but not CBG increased the affinity of the CB2 and 5HT1A receptor-receptor interaction. Both cannabinoids regulated the effects of CB2 and 5HT1A receptor agonists. CBD was able to revert the upregulation of heteromers occurring when neurons were deprived of oxygen and glucose. CBD significantly reduced the increased expression of the CB2-5HT1A-Het in glucose/oxygen-deprived neurons. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of CB2-5HT1A-Hets. Conclusions: Benefits of CBD in the hypoxia of the neonate are mediated by acting on CB2-5HT1A-Hets and by reducing the aberrant expression of the receptor-receptor complex in hypoxic-ischemic conditions. These results reinforce the potential of CBD for the therapy of the hypoxia of the neonate

Efectos de un modelo experimental de preeclampsia sobre la reactividad vascular de ratas gestantes y de sus crías fetales y neonatales

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología y Terapéutica. Fecha de lectura: 25 de Enero de 199

Non-Contact, Simple Neonatal Monitoring by Photoplethysmography

This paper presents non-contact vital sign monitoring in neonates, based on image processing, where a standard color camera captures the plethysmographic signal and the heart and breathing rates are processed and estimated online. It is important that the measurements are taken in a non-invasive manner, which is imperceptible to the patient. Currently, many methods have been proposed for non-contact measurement. However, to the best of the authors&#8217; knowledge, it has not been possible to identify methods with low computational costs and a high tolerance to artifacts. With the aim of improving contactless measurement results, the proposed method based on the computer vision technique is enhanced to overcome the mentioned drawbacks. The camera is attached to an incubator in the Neonatal Intensive Care Unit and a single area in the neonate&#8217;s diaphragm is monitored. Several factors are considered in the stages of image acquisition, as well as in the plethysmographic signal formation, pre-filtering and filtering. The pre-filter step uses numerical analysis techniques to reduce the signal offset. The proposed method decouples the breath rate from the frequency of sinus arrhythmia. This separation makes it possible to analyze independently any cardiac and respiratory dysrhythmias. Nine newborns were monitored with our proposed method. A Bland-Altman analysis of the data shows a close correlation of the heart rates measured with the two approaches (correlation coefficient of 0.94 for heart rate (HR) and 0.86 for breath rate (BR)) with an uncertainty of 4.2 bpm for HR and 4.9 for BR (k = 1). The comparison of our method and another non-contact method considered as a standard independent component analysis (ICA) showed lower central processing unit (CPU) usage for our method (75% less CPU usage)

Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: Role of 5HT1A and CB2 receptors

et al.The mechanisms underlying the neuroprotective effects of cannabidiol (CBD) were studied in vivo using a hypoxic-ischemic (HI) brain injury model in newborn pigs. One- to two-day-old piglets were exposed to HI for 30 min by interrupting carotid blood flow and reducing the fraction of inspired oxygen to 10%. Thirty minutes after HI, the piglets were treated with vehicle (HV) or 1 mg/kg CBD, alone (HC) or in combination with 1 mg/kg of a CB2 receptor antagonist (AM630) or a serotonin 5HT1A receptor antagonist (WAY100635). HI decreased the number of viable neurons and affected the amplitude-integrated EEG background activity as well as different prognostic proton-magnetic-resonance-spectroscopy (H±-MRS)-detectable biomarkers (lactate/N-acetylaspartate and N-acetylaspartate/choline ratios). HI brain damage was also associated with increases in excitotoxicity (increased glutamate/N-acetylaspartate ratio), oxidative stress (decreased glutathione/creatine ratio and increased protein carbonylation) and inflammation (increased brain IL-1 levels). CBD administration after HI prevented all these alterations, although this CBD-mediated neuroprotection was reversed by co-administration of either WAY100635 or AM630, suggesting the involvement of CB2 and 5HT1A receptors. The involvement of CB2 receptors was not dependent on a CBD-mediated increase in endocannabinoids. Finally, bioluminescence resonance energy transfer studies indicated that CB2 and 5HT1A receptors may form heteromers in living HEK-293T cells. In conclusion, our findings demonstrate that CBD exerts robust neuroprotective effects in vivo in HI piglets, modulating excitotoxicity, oxidative stress and inflammation, and that both CB2 and 5HT 1A receptors are implicated in these effects. © 2013 Elsevier Ltd. All rights reserved.This work was supported by grants from the Spanish Fund for Health Research (FIS-PS09/01900 and PS09/00434), from Programa de Biomedicina, Comunidad de Madrid (S2010/BMD-2308), Ministerio de Educación (PR2009-0169), and from GW Pharma, Ltd (GWCRI09119).Peer Reviewe

Ajuste psicológico de padres e hijos prematuros españoles

To date there have been few studies in Spain and Latin America that address the psychological adjustment of premature infants. This paper examines the psychological adjustment of children and some factors relevant to it, in a sample of Spanish premature children. Participants: 29 minors (Mean age = 36.2 months, SD = 1.42) with a history of prematurity. 51.7% were girls. Instruments: A sociodemographic survey, the Strengths and Difficulties Questionnaire (SDQ) and the Parental Stress Scale (PSS) were used. Results: Between 71.4 and 82.1% of the children obtained scores considered normal in the SDQ, in 50% of them, their parents indicated the existence of some negative impact. There are no statistically significant relationships between the SDQ scales and the neonatal variables. Being Spanish, having higher education and being active was related to a better psychological adjustment in children. Parental stress was associated with a worse adjustment. Conclusions: The study of the strengths and psychological adjustment of parents and children in prematurity is of special importance to know, prevent and intervene on the well-being of this population.Hasta la fecha se han realizado escasas investigaciones en España y Latinoamérica que aborden el ajuste psicológico de los prematuros. El presente trabajo examina el ajuste psicológico infantil y algunos factores relevantes para el mismo, en una muestra de niños prematuros españoles. Participantes: 29 menores (Media de edad=36.2 meses, DT=1.42)con antecedentes de prematuridad. El 51.7% fueron niñas. Instrumentos: Se utilizó una encuesta sociodemográfica, el Strengths and Difficulties Questionnaire (SDQ) y la Escala de estrés parental (PSS). Resultados: Entre el 71.4 y el 82.1% de los menores obtuvieron puntuaciones consideradas normales en el SDQ, en el 50% de ellos, sus progenitores indicaron la existencia de algún impacto negativo. No se encuentran relaciones estadísticamente significativas entre las escalas del SDQ y las variables neonatales. Ser español, tener estudios superiores y encontrarse en activo se relacionó con un mejor ajuste psicológico infantil. El estrés parental se relacionó con un peor ajuste. Conclusiones: El estudio de las fortalezas y del ajuste psicológico de padres e hijos en prematuridad es de especial importancia para poder conocer, prevenir e intervenir sobre el bienestar de esta población