Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse

Neuroinflammation is a complex process involved in the physiopathology of many central nervous system diseases, including addiction. Alcohol abuse is characterized by induction of peripheral inflammation and neuroinflammation, which hallmark is the activation of innate immunity toll-like receptors 4 (TLR4). In the last years, lipid transmitters have generated attention as modulators of parts of the addictive process. Specifically, the bioactive lipid oleoylethanolamide (OEA), which is an endogenous acylethanolamide, has shown a beneficial profile for alcohol abuse. Preclinical studies have shown that OEA is a potent anti-inflammatory and antioxidant compound that exerts neuroprotective effects in alcohol abuse. Exogenous administration of OEA blocks the alcohol-induced TLR4-mediated pro-inflammatory cascade, reducing the release of proinflammatory cytokines and chemokines, oxidative and nitrosative stress, and ultimately, preventing the neural damage in frontal cortex of rodents. The mechanisms of action of OEA are discussed in this review, including a protective action in the intestinal barrier. Additionally, OEA blocks cue-induced reinstatement of alcohol-seeking behavior and reduces the severity of withdrawal symptoms in animals, together with the modulation of alcohol-induced depression-like behavior and other negative motivational states associated with the abstinence, such as the anhedonia. Finally, exposure to alcohol induces OEA release in blood and brain of rodents. Clinical evidences will be highlighted, including the OEA release and the correlation of plasma OEA levels with TLR4-dependent peripheral inflammatory markers in alcohol abusers. In base of these evidences we hypothesize that the endogenous release of OEA could be a homeostatic signal to counteract the toxic action of alcohol and we propose the exploration of OEA-based pharmacotherapies to treat alcohol-use disorders

Dual effects of noradrenaline on astroglial production of chemokines and pro-inflammatory mediators

BACKGROUND: Noradrenaline (NA) is known to limit neuroinflammation. However, the previously described induction by NA of a chemokine involved in the progression of immune/inflammatory processes, such as chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein-1 (MCP-1), apparently contradicts NA anti-inflammatory actions. In the current study we analyzed NA regulation of astroglial chemokine (C-X3-C motif) ligand 1 (CX3CL1), also known as fractalkine, another chemokine to which both neuroprotective and neurodegenerative actions have been attributed. In addition, NA effects on other chemokines and pro-inflammatory mediators were also analyzed. METHODS: Primary astrocyte-enriched cultures were obtained from neonatal Wistar rats. These cells were incubated for different time durations with combinations of NA and lipopolysaccharide (LPS). The expression and synthesis of different proteins was measured by RT-PCR and enzyme-linked immunosorbent assay (ELISA) or enzyme immunoassays. Data were analyzed by one-way analysis of variance (ANOVA), followed by Newman-Keuls multiple comparison tests. RESULTS: The data presented here show that in control conditions, NA induces the production of CX3CL1 in rat cultured astrocytes, but in the presence of an inflammatory stimulus, such as LPS, NA has the opposite effect inhibiting CX3CL1 production. This inversion of NA effect was also observed for MCP-1. Based on the observation of this dual action, NA regulation of different chemokines and pro-inflammatory cytokines was also analyzed, observing that in most cases NA exerts an inhibitory effect in the presence of LPS. One characteristic exception was the induction of cyclooxygenase-2 (COX-2), where a summative effect was detected for both LPS and NA. CONCLUSION: These data suggest that NA effects on astrocytes can adapt to the presence of an inflammatory agent reducing the production of certain cytokines, while in basal conditions NA may have the opposite effect and help to maintain moderate levels of these cytokines

Tablets for access to electronic resources and for use as teaching support in the university library: A case study

The experience of the Library of the Faculty of Law of the Universidad Autónoma de Madrid (UAM) is presented, where patrons use tablets to access books that have been acquired in electronic format. In recent years, there has been an increasing number of titles that are being distributed in paper with an electronic copy attached (duo). These are characterized by the indivisibility of the pack and the increase in their price. This system encourages both the individual and private use of the copies by using a code associated with the user’s profile. The creation of a specific system based on the use of a tablet in order to provide the user public access to these copies is described. The system duplicates the number of copies available to users. In addition to access to e-books, a selection of electronic resources and programs previously offered by the University has been included in the tablets. The tablets are also configured for teaching uses, both for seminars and exams

Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression

<p>Abstract</p> <p>Background</p> <p>There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4) has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS) from Gram-negative bacteria may play a role in the pathophysiology of major depression.</p> <p>Methods</p> <p>Adult male Sprague-Dawley rats were subjected to chronic mild stress (CMS) or CMS+intestinal antibiotic decontamination (CMS+ATB) protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test.</p> <p>Results</p> <p>CMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL)-1β, COX-2, PGE₂and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ₂in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ₂, however this did not affect depressive-like behavior induced by CMS.</p> <p>Conclusions</p> <p>Our results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression.</p

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Background: Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive. Methods: This work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design. Results: No significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (- 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression. Conclusion: Data indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.This work was supported by the Instituto de Salud Carlos III and Spanish Ministry of Economy, Industry and Competitiveness (MINECO) through the Plan Estatal de I+D+i 2013-2016 (FIS-PI13/01102 and SAF2016-75500-R to JCL), the Agencia Estatal de Investigacion (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2017-83053-R to JRC), the Basque Government (IT-616-13), CIBERSAM and the EDR Funds. JRC and BGB are Ramon y Cajal fellows (MINECO)

Cardiovascular risk in early psychosis. Relationship with inflammation and clinical features 6 months after diagnosis

Background: We aimed to investigate the state of cardiovascular risk/protection factors in early psychosis patients. Methods: A total 119 subjects were recruited during the first year after their first episode of psychosis. Eighty-five of these subjects were followed during the next 6 months. Cardiovascular risk/protection factors were measured in plasma and co-variated by sociodemographic/clinical characteristics. Multiple linear regression models detected the change of each biological marker from baseline to follow-up in relation to clinical scales, antipsychotic medication, and pro-/antiinflammatory mediators. Results: Glycosylated hemoglobin is a state biomarker in first episode of psychosis follow-up patients and inversely correlated to the Global Assessment of Functioning scale. We found opposite alterations in the levels of VCAM-1 and E-selectin in first episode of psychosis baseline conditions compared with control that were absent in the first episode of psychosis follow-up group. Adiponectin levels decreased in a continuum in both pathological time points studied. E-Selectin plasma levels were inversely related to total antipsychotic equivalents and adiponectin levels inversely co-related to the Global Assessment of Functioning scale. Finally, adiponectin levels were directly related to antiinflammatory nuclear receptor PPARγ expression in first episode of psychosis baseline conditions and to proinflammatory nuclear factor nuclear factor κB activity in follow-up conditions, respectively. Conclusions: Our results support the need for integrating cardiovascular healthcare very early after the first episode of psychosis

Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors.

BACKGROUND: Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events. OBJECTIVES: This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals. METHODS: Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 ± 4.1 years, 50.3% women). CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol ≥40 mg/dl. A subgroup with optimal CVRFs (n = 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasound-detected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used. RESULTS: Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [×10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels. CONCLUSIONS: Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318)

The Role of the Oral Microbiota Related to Periodontal Diseases in Anxiety, Mood and Trauma- and Stress-Related Disorders

The prevalence of anxiety, mood and trauma- and stress-related disorders are on the rise; however, efforts to develop new and effective treatment strategies have had limited success. To identify novel therapeutic targets, a comprehensive understanding of the disease etiology is needed, especially in the context of the holobiont, i.e., the superorganism consisting of a human and its microbiotas. Much emphasis has been placed on the role of the gut microbiota in the development, exacerbation, and persistence of psychiatric disorders; however, data for the oral microbiota are limited. The oral cavity houses the second most diverse microbial community in the body, with over 700 bacterial species that colonize the soft and hard tissues. Periodontal diseases encompass a group of infectious and inflammatory diseases that affect the periodontium. Among them, periodontitis is defined as a chronic, multi-bacterial infection that elicits low-grade systemic inflammation via the release of pro-inflammatory cytokines, as well as local invasion and long-distance translocation of periodontal pathogens. Periodontitis can also induce or exacerbate other chronic systemic inflammatory diseases such as atherosclerosis and diabetes and can lead to adverse pregnancy outcomes. Recently, periodontal pathogens have been implicated in the etiology and pathophysiology of neuropsychiatric disorders (such as depression and schizophrenia), especially as dysregulation of the immune system also plays an integral role in the etiology and pathophysiology of these disorders. This review will discuss the role of the oral microbiota associated with periodontal diseases in anxiety, mood and trauma- and stress-related disorders. Epidemiological data of periodontal diseases in individuals with these disorders will be presented, followed by a discussion of the microbiological and immunological links between the oral microbiota and the central nervous system. Pre-clinical and clinical findings on the oral microbiota related to periodontal diseases in anxiety, mood and trauma- and stress-related phenotypes will be reviewed, followed by a discussion on the bi-directionality of the oral-brain axis. Lastly, we will focus on the oral microbiota associated with periodontal diseases as a target for future therapeutic interventions to alleviate symptoms of these debilitating psychiatric disorders. &nbsp;</p

Empleo de la gamificación como nueva herramienta docente en la asignatura de Intervención en adicciones dentro del grado de Terapia Ocupacional

El principal objetivo de este proyecto ha sido el de mejorar los resultados académicos de los alumnos así como aumentar su interés por la asignatura, su asistencia y participación en clase. Además, se pretendía obtener datos que demuestren la utilidad de la gamificación como herramienta docente en nuestro ámbito y animar a otros profesores a realizar innovaciones similares

CCL2 Inhibition of Pro-Resolving Mediators Potentiates Neuroinflammation in Astrocytes

The chemokine CCL2 participates in multiple neuroinflammatory processes, mainly through the recruitment of glial cells. However, CCL2 has also been proven to exert different types of actions on these cells, including the modification of their response to inflammatory stimuli. In the present study we analyzed the effect of CCL2 on the resolution of inflammation in astrocytes. We observed that genetic removal of CCL2 increases the expression of the enzymes responsible for the synthesis of specialized pro-resolving mediators arachidonate 15-lipoxygenase and arachidonate 5-lipoxygenase in the brain cortex of 5xFAD mice. The expression of FPR2 receptor, known to mediate the activity of pro-resolving mediators was also increased in mice lacking CCL2.The downregulation of these proteins by CCL2 was also observed in cultured astrocytes. This suggests that CCL2 inhibition of the resolution of inflammation could facilitate the progression of neuroinflammatory processes. The production of the pro-inflammatory cytokine IL-1beta by astrocytes was analyzed, and allowed us to confirm that CCL2 potentiates the activation of astrocytes trough the inhibition of pro-resolving pathways mediated by Resolvin D1. In addition, the analysis of the expression of TNFalpha, MIP1alpha and NOS2 further confirmed CCL2 inhibition of inflammation resolution in astrocytes