Cannabinoids and Sleep: Exploring Biological Mechanisms and Therapeutic Potentials.

The endogenous cannabinoid system (ECS) plays a critical role in the regulation of various physiological functions, including sleep, mood, and neuroinflammation. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinomimimetics, and some N-acylethanolamides, particularly palmitoyethanolamide, have emerged as potential therapeutic agents for the management of sleep disorders. THC, the psychoactive component of cannabis, may initially promote sleep, but, in the long term, alters sleep architecture, while CBD shows promise in improving sleep quality without psychoactive effects. Clinical studies suggest that CBD modulates endocannabinoid signaling through several receptor sites, offering a multifaceted approach to sleep regulation. Similarly, palmitoylethanolamide (PEA), in addition to interacting with the endocannabinoid system, acts as an agonist on peroxisome proliferator-activated receptors (PPARs). The favorable safety profile of CBD and PEA and the potential for long-term use make them an attractive alternative to conventional pharmacotherapy. The integration of the latter two compounds into comprehensive treatment strategies, together with cognitive-behavioral therapy for insomnia (CBT-I), represents a holistic approach to address the multifactorial nature of sleep disorders. Further research is needed to establish the optimal dosage, safety, and efficacy in different patient populations, but the therapeutic potential of CBD and PEA offers hope for improved sleep quality and general well-being.

Exploring the Interplay between Complex Post-Traumatic Stress Disorder and Obsessive-Compulsive Disorder Severity: Implications for Clinical Practice.

Background and Objectives: Traumatic events adversely affect the clinical course of obsessive-compulsive disorder (OCD). Our study explores the correlation between prolonged interpersonal trauma and the severity of symptoms related to OCD and anxiety disorders. Materials and Methods: The study follows a cross-sectional and observational design, employing the International Trauma Questionnaire (ITQ) to examine areas linked to interpersonal trauma, the Hamilton Anxiety Rating Scale (HAM-A), and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to assess anxious and obsessive-compulsive symptoms, respectively. Descriptive analysis, analysis of variance (ANOVA), and logistic regression analyses were conducted. Results: We recruited 107 OCD-diagnosed patients, categorizing them into subgroups based on the presence or absence of complex post-traumatic stress disorder (cPTSD). The ANOVA revealed statistically significant differences between the two groups in the onset age of OCD (p = 0.083), psychiatric familial history (p = 0.023), HAM-A, and Y-BOCS (p < 0.0001). Logistic regression indicated a statistically significant association between the presence of cPTSD and Y-BOCS scores (p < 0.0001). Conclusions: The coexistence of cPTSD in OCD exacerbates obsessive-compulsive symptoms and increases the burden of anxiety. Further advancements in this field are crucial for mitigating the impact of early trauma on the trajectory of OCD and associated anxious symptoms.

Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic.

COVID-19, initially regarded as specific lung disease, exhibits an extremely broad spectrum of symptoms. Extrapulmonary manifestations of the disease also include important neuropsychiatric symptoms with atypical characteristics. Are these disturbances linked to stress accompanying every systemic infection, or are due to specific neurobiological changes associated with COVID-19? Evidence accumulated so far indicates that the pathophysiology of COVID-19 is characterized by systemic inflammation, hypoxia resulting from respiratory failure, and neuroinflammation (either due to viral neurotropism or in response to cytokine storm), all affecting the brain. It is reasonable to hypothesize that all these events may initiate or worsen psychiatric and cognitive disorders. Damage to the brain triggers a specific type of reactive response mounted by neuroglia cells, in particular by astrocytes which are the homeostatic cell par excellence. Astrocytes undergo complex morphological, biochemical, and functional remodeling aimed at mobilizing the regenerative potential of the central nervous system. If the brain is not directly damaged, resolution of systemic pathology usually results in restoration of the physiological homeostatic status of neuroglial cells. The completeness and dynamics of this process in pathological conditions remain largely unknown. In a subset of patients, glial cells could fail to recover after infection thus promoting the onset and progression of COVID-19-related neuropsychiatric diseases. There is evidence from post-mortem examinations of the brains of COVID-19 patients of alterations in both astrocytes and microglia. In conclusion, COVID-19 activates a huge reactive response of glial cells, that physiologically act as the main controller of the inflammatory, protective and regenerative events. However, in some patients the restoration of glial physiological state does not occur, thus compromising glial function and ultimately resulting in homeostatic failure underlying a set of specific neuropsychiatric symptoms related to COVID-19.

Chronotype is associated with affective temperaments, clinical severity and worse treatment outcomes in bipolar disorders: results from a two-center, cross-sectional study.

OBJECTIVE: The present study was aimed at investigating the clinical correlates of evening chronotype in a population of subjects suffering from bipolar disorders (BD). METHODS: We assessed chronotype using the Morningness-Eveningness Questionnaire. We administered the brief Temperament Evaluation of Memphis, Pisa, and San Diego, the Barratt Impulsiveness Scale, and the Alda Scale to evaluate affective temperaments, impulsiveness, and response to mood stabilisers. We performed bivariate analyses and ran a logistic regression model to analyse clinical variables associated with evening chronotype. RESULTS: In our sample (n = 178), subjects with an evening chronotype (n = 56, 31.5%) more often suffered from BD type I and reported higher prevalence of seasonality, antidepressant-induced mood switches, psychotic, aggressive, mixed, and anxiety features, and substance use disorders. The number of lifetime suicide attempts and mood episodes was higher in this subgroup. Depressive, cyclothymic, irritable, and anxious temperament scores were higher among evening-chronotype subjects, who also displayed greater levels of impulsiveness and worse treatment response. At the logistic regression, evening chronotype was associated with depressive and irritable temperaments. CONCLUSIONS: Subjects with evening chronotype display higher clinical severity and worse BD course. Clinicians should evaluate the presence of evening chronotype in BD subjects, especially in those with irritable or depressive temperament.Key pointsEvening chronotype is a frequent clinical feature in subjects suffering from bipolar disorders (BD);Affective temperaments, particularly depressive and irritable, are associated with evening chronotype in BD;Evening chronotype underpins higher severity of the clinical picture in BD, as well as a worse response to mood stabiliser treatment;Circadian preferences should be systematically assessed in subjects suffering from BD, with particular attention to evening preference.

Factors associated with lifetime suicide attempts in bipolar disorder: results from an Italian nationwide study.

The purpose of the present study was to detect demographic and clinical factors associated with lifetime suicide attempts in Bipolar Disorder (BD). A total of 1673 bipolar patients from different psychiatric departments were compared according to the lifetime presence of suicide attempts on demographic/clinical variables. Owing to the large number of variables statistically related to the dependent variable (presence of suicide attempts) at the univariate analyses, preliminary multiple logistic regression analyses were realized. A final multivariable logistic regression was then performed, considering the presence of lifetime suicide attempts as the dependent variable and statistically significant demographic/clinical characteristics as independent variables. The final multivariable logistic regression analysis showed that an earlier age at first contact with psychiatric services (odds ratio [OR] = 0.97, p < 0.01), the presence of psychotic symptoms (OR = 1.56, p < 0.01) or hospitalizations (OR = 1.73, p < 0.01) in the last year, the attribution of symptoms to a psychiatric disorder (no versus yes: OR = 0.71, partly versus yes OR = 0.60, p < 0.01), and the administration of psychoeducation in the last year (OR = 1.49, p < 0.01) were all factors associated with lifetime suicide attempts in patients affected by BD. In addition, female patients resulted to have an increased association with life-long suicidal behavior compared to males (OR: 1.02, p < 0.01). Several clinical factors showed complex associations with lifetime suicide attempts in bipolar patients. These patients, therefore, require strict clinical monitoring for their predisposition to a less symptom stabilization. Future research will have to investigate the best management strategies to improve the prognosis of bipolar subjects presenting suicidal behavior.

Antisocial Personality Disorder in Bipolar Disorder: A Systematic Review.

Background and Objectives: Bipolar Disorder (BD) is a severe psychiatric disorder that worsens quality of life and functional impairment. Personality disorders (PDs), in particular Cluster B personality, have a high incidence among BD patients and is considered a poor prognostic factor. The study of this co-morbidity represents an important clinical and diagnostic challenge in psychiatry. Particularly, clinical overlap has been shown between antisocial personality disorder (ASPD) and BD that could worsen the course of both disorders. We aimed to detect the frequency of ASPD in bipolar patients with greater accuracy and the impact of ASPD on the clinical course of BD. Materials and Methods: A systematic literature search was conducted in PubMed, Embase, MEDLINE and the Cochrane Library through December 2020 without language or time restriction, according to PRISMA statement guidelines. Results: Initially, 3203 items were identified. After duplicates or irrelevant paper deletion, 17 studies met the inclusion criteria and were included in this review. ASPD was more frequent among BD patients, especially in BD type I. BD patients with ASPD as a comorbidity seemed to have early onset, higher number and more severe affective episodes, higher levels of aggressive and impulsive behaviors, suicidality and poor clinical outcome. ASPD symptoms in BD seem to be associated with a frequent comorbidity with addictive disorders (cocaine and alcohol) and criminal behaviors, probably due to a shared impulsivity core feature. Conclusions: Considering the shared symptoms such as impulsive and dangerous behaviors, in patients with only one disease, misdiagnosis is a common phenomenon due to the overlapping symptoms of ASPD and BD. It may be useful to recognize the co-occurrence of the disorders and better characterize the patient with ASPD and BD evaluating all dysfunctional aspects and their influence on core symptoms.

Affective Temperaments and Illness Severity in Patients with Bipolar Disorder.

Background and objectives: Bipolar disorder (BD) is one of the most burdensome psychiatric illnesses, being associated with a negative long-term outcome and the highest suicide rate. Although affective temperaments can impact on BD long-term outcome, their role remains poorly investigated. The aims of the present study are to describe the clinical characteristics of patients with BD more frequently associated with the different affective temperaments and to assess the relation between affective temperaments and severity of clinical picture in a sample of patients with BD. Materials and Methods: A total of 199 patients have been recruited in the outpatients units of two university sites. Patients' psychiatric symptoms, affective temperaments, and quality of life were investigated through validated assessment instruments. Results: Predominant cyclothymic and irritable temperaments are associated to higher number of relapses, poorer quality of life, higher rates of aggressive behaviors, and suicide attempts. Conversely, the predominant hyperthymic disposition was a protective factor for several outcome measures, including relapse rate, severity of anxiety, depressive and manic symptoms, suicidality, and earlier age at onset. One limitation of the present study is that the recruitment took place in two university sites; therefore, our findings cannot be fully generalized to the whole community of BD patients. Other limitations are the lack of a control group and the cross-sectional design of the study. Conclusions: The early identification of affective temperaments can help clinicians to identify those BD patients who are more likely to show a poor long-term outcome. An early screening of affective temperaments can be useful to develop targeted integrated pharmacological and psychosocial interventions.

Correction to: Efficacy of the interpersonal and social rhythm therapy (IPSRT) in patients with bipolar disorder: results from a real-world, controlled trial.

[This corrects the article DOI: 10.1186/s12991-020-00266-7.].

Efficacy of the interpersonal and social rhythm therapy (IPSRT) in patients with bipolar disorder: results from a real-world, controlled trial.

BACKGROUND: Bipolar disorder (BD) is one of the most burdensome mental disorders, with a lifetime prevalence of 2.4%, with a prevalence of 0.6% for bipolar type I and 0.4% for bipolar type II. Several interventions have been developed to implement the treatment strategy of bipolar disorder, including the Interpersonal and Social Rhythm Therapy (IPSRT). This intervention has been specifically developed to manage patients' stressful life events, improve the disruptions of social and circadian rhythms and increase adherence to medications. The aim of the present study is to assess the efficacy of IPSRT on affective and anxiety psychopathology, social functioning, response to pharmacological treatment and affective morbidity index (AMI) in BD patients. METHODS: BD patients were consecutively recruited at the Mood Disorder Unit of the University of Campania "Luigi Vanvitelli" and randomly assigned to the experimental group receiving the IPSRT or to the Treatment as Usual (TAU) group. Patients were assessed at baseline, after 3 and 6 months with several validated assessment tools and with the affective morbidity index. RESULTS: At the end of the intervention, compared to controls, patients from the experimental group reported a significant improvement in anxious depressive and manic symptomatology, global functioning; and response to mood stabilizers. Patients in the IPSRT group reported a reduction at the AMI score. CONCLUSIONS: IPSRT has been confirmed to be effective in improving the clinical symptomology of BD patients and in improving the affective morbidity index. Further studies with longer follow-up are needed in order to assess the stability of the results.Trial registration The study was approved by the local ethical review board (N001567/28.01.2018).

Looking for a Treatment for the Early Stage of Alzheimer's Disease: Preclinical Evidence with Co-Ultramicronized Palmitoylethanolamide and Luteolin.

BACKGROUND: At the earliest stage of Alzheimer's disease (AD), although patients are still asymptomatic, cerebral alterations have already been triggered. In addition to beta amyloid (Aß) accumulation, both glial alterations and neuroinflammation have been documented at this stage. Starting treatment at this prodromal AD stage could be a valuable therapeutic strategy. AD requires long-term care; therefore, only compounds with a high safety profile can be used, such as the new formulation containing palmitoylethanolamide and luteolin (co-ultra PEALut) already approved for human use. Therefore, we investigated it in an in vivo pharmacological study that focused on the prodromal stage of AD. METHODS: We tested the anti-inflammatory and neuroprotective effects of co-ultra PEALut (5 mg/Kg) administered for 14 days in rats that received once, 5 µg Aß(1-42) into the hippocampus. RESULTS: Glial activation and elevated levels of proinflammatory mediators were observed in Aß-infused rats. Early administration of co-ultra PEALut prevented the Aß-induced astrogliosis and microgliosis, the upregulation in gene expression of pro-inflammatory cytokines and enzymes, as well as the reduction of mRNA levels BDNF and GDNF. Our findings also highlight an important neuroprotective effect of co-ultra PEALut treatment, which promoted neuronal survival. CONCLUSIONS: Our results reveal the presence of cellular and molecular modifications in the prodromal stage of AD. Moreover, the data presented here demonstrate the ability of co-ultra PEALut to normalize such Aß-induced alterations, suggesting it as a valuable therapeutic strategy.

Parental bonding, childhood maltreatment and eating disorder psychopathology: an investigation of their interactions.

PURPOSE: Childhood trauma and parental bonding have been widely recognized as risk factors for eating disorders (EDs). However, their interplay in determining ED psychopathology has been poorly investigated. Consequently, we have assessed their interaction with core ED psychopathological symptoms. METHODS: Fifty-seven patients with anorexia nervosa, 43 with bulimia nervosa and 77 healthy women completed the Childhood Trauma Questionnaire, the Parental Bonding Instrument and the Eating Disorder Inventory-2. Chi square test and regression analyses with a moderation model were performed to investigate the interplay between childhood trauma, parental bonding and ED symptoms such as ineffectiveness, social insecurity, drive to thinness, interoceptive awareness, impulsivity and perfectionism. RESULTS: Compared to controls, patients with EDs showed higher levels of trauma and parental control perception and lower levels of parental care. Childhood maltreatment was more prevalent in patients with the affectionless control parental style. Moderation analyses revealed that higher maternal control significantly predicted the ED symptom of social insecurity only when participants experienced lower levels of emotional abuse. CONCLUSIONS: These findings demonstrate an interplay between deranged problematic parental bonding and childhood trauma in promoting a possible vulnerability to social insecurity, one of the most central dimensions of ED psychopathology. This interaction might have psychotherapeutic implications. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.

Affective Temperaments and Clinical Course of Bipolar Disorder: An Exploratory Study of Differences among Patients with and without a History of Violent Suicide Attempts.

Background and Objectives: Suicide is the leading cause of death in patients with Bipolar Disorder (BD). In particular, the high mortality rate is due to violent suicide attempts. Several risk factors associated with suicide attempts in patients with BD have been identified. Affective temperaments are associated with suicidal risk, but their predictive role is still understudied. The aim of this study is to assess the relationship between affective temperaments and personal history of violent suicide attempts. Materials and Methods: 74 patients with Bipolar Disorder type I (BD-I) or II (BD-II) were included. All patients filled in the short version of Munster Temperament Evaluation of the Memphis, Pisa, Paris and San Diego (short TEMPS-M) and the Temperament and Character Inventory, revised version (TCI-R). The sample was divided into two groups on the basis of a positive history for suicidal attempts and the suicidal group was further divided into two subgroups according to violent suicide attempts. Results: Violent suicide attempts were positively associated with the cyclothymic temperament and inversely to the hyperthymic one. BD-I patients and patients with a clinical history of rapid cycling were significantly more represented in the group of patients with a history of violent suicide attempts. Conclusions: Our study highlights that several clinical and temperamental characteristics are associated with violent suicide attempts, suggesting the importance of affective temperaments in the clinical management of patients with BPI.

HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia.

BACKGROUND: Diarrhea is a severe complication in HIV-1-infected patients with Trans-activator of transcription (HIV-1 Tat) protein being recognized as a major underlying cause. Beside its direct enterotoxic effects, Tat protein has been recently shown to affect enteric glial cell (EGC) activity. EGCs regulate intestinal inflammatory responses by secreting pro-inflammatory molecules; nonetheless, they might also release immune-regulatory factors, as palmytoilethanolamide (PEA), which exerts anti-inflammatory effects by activating PPARα receptors. We aimed at clarifying whether EGCs are involved in HIV-1 Tat-induced diarrhea and if PEA exerts antidiarrheal activity. METHODS: Diarrhea was induced by intracolonic administration of HIV-1 Tat protein in rats at day 1. PEA alone or in the presence of peroxisome proliferator-activated receptor (PPAR) antagonists was given intraperitoneally from day 2 to day 7. S100B, iNOS, NF-kappaB, TLR4 and GFAP expression were evaluated in submucosal plexi, while S100B and NO levels were measured in EGC submucosal plexi lysates, respectively. To verify whether PEA effects were PPARα-mediated, PPARα-/- mice were also used. After 7 days from diarrhea induction, endogenous PEA levels were measured in submucosal plexi homogenates deriving from rats and PPARα-/- mice. RESULTS: HIV-1 Tat protein induced rapid onset diarrhea alongside with a significant activation of EGCs. Tat administration significantly increased all hallmarks of neuroinflammation by triggering TLR4 and NF-kappaB activation and S100B and iNOS expression. Endogenous PEA levels were increased following HIV-1 Tat exposure in both wildtype and knockout animals. In PPARα-/- mice, PEA displayed no effects. In wildtype rats, PEA, via PPARα-dependent mechanism, resulted in a significant antidiarrheal activity in parallel with marked reduction of EGC-sustained neuroinflammation. CONCLUSIONS: EGCs mediate HIV-1 Tat-induced diarrhea by sustaining the intestinal neuroinflammatory response. These effects are regulated by PEA through a selective PPARα-dependent mechanism. PEA might be considered as an adjuvant therapy in HIV-1-induced diarrhea.

Insecure Attachment and Hypothalamus-Pituitary-Adrenal Axis Functioning in People With Eating Disorders.

OBJECTIVE: Childhood attachment experiences affect adult emotion regulation and ability to cope with stressors. Therefore, insecure attachment may influence the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and a dysregulation of HPA axis has been found in insecure attached healthy individuals. The effects of attachment on HPA axis activity have never been investigated in eating disorders (EDs). Therefore, we assessed the relationships between insecure attachment and the cortisol awakening response (CAR) in adults with EDs. METHODS: Seventy-eight patients with EDs (43 with anorexia nervosa, 35 with bulimia nervosa) were recruited. They completed the Experience in Close Relationships questionnaire, which provides a rating of two insecure attachment dimensions (anxiety and avoidance) and collected saliva samples to measure the CAR. Differences in the CAR between groups with high and low attachment anxiety and between groups with high and low attachment avoidance were evaluated by repeated measures two-way analysis of variance. RESULTS: Patients with high attachment anxiety showed a reduced CAR compared with those with low attachment anxiety (F1,76 = 7.31, p = .008). The CAR did not differ between the groups with high and low attachment avoidance (F1,76 = 0.01, p = .93). Patients with high levels of insecure attachment showed a more severe eating-related psychopathology. CONCLUSIONS: Our data show, for the first time, a specific association of the anxious attachment with the HPA axis activity in EDs and suggest a possible role of attachment in the biological vulnerability to stress of adult patients with EDs.

Palmitoylethanolamide Exerts Antiproliferative Effect and Downregulates VEGF Signaling in Caco-2 Human Colon Carcinoma Cell Line Through a Selective PPAR-α-Dependent Inhibition of Akt/mTOR Pathway.

Palmitoylethanolamide (PEA) is a nutraceutical compound that has been demonstrated to improve intestinal inflammation. We aimed at evaluating its antiproliferative and antiangiogenic effects in human colon adenocarcinoma Caco-2 cell line. Caco-2 cells were treated with increasing concentrations of PEA (0.001, 0.01 and 0.1 µM) in the presence of peroxisome proliferator-activated receptor-a (PPAR-α) or PPAR-γ antagonists. Cell proliferation was evaluated by performing a MTT assay. Vascular endothelial growth factor (VEGF) release was estimated by ELISA, while the expression of VEGF receptor and the activation of the Akt/mammalian target of rapamycin (mTOR) pathway were evaluated by western blot analysis. PEA caused a significant and concentration-dependent decrease of Caco-2 cell proliferation at 48 h. PEA administration significantly reduced in a concentration-dependent manner VEGF secretion and VEGF receptor expression. Inhibition of Akt phosphorylation and a downstream decrease of phospho-mTOR and of p-p70S6K were observed as compared with untreated cells. PPAR-α, but not PPAR-γ antagonist, reverted all effects of PEA. PEA is able to decrease cell proliferation and angiogenesis. The antiangiogenic effect of PEA depends on the specific inhibition of the AkT/mTOR axis, through the activation of PPAR-α pathway. If supported by in vivo models, our data pave the way to PEA co-administration to the current chemotherapeutic regimens for colon carcinoma. Copyright © 2016 John Wiley & Sons, Ltd.

Olanzapine Is Faster than Haloperidol in Inducing Metabolic Abnormalities in Schizophrenic and Bipolar Patients.

The effects of olanzapine and haloperidol on metabolic parameters in bipolar patients have been evaluated much less comprehensively than in schizophrenic patients. Therefore, in this study, medical records of 343 schizophrenic and bipolar patients treated with haloperidol or olanzapine for 1 year were retrospectively reviewed and metabolic outcomes were evaluated. After 12 months of follow-up, 25.9% of patients showed ≥3 metabolic abnormalities with a point prevalence of 27.2% in the bipolar and 24.9% in the schizophrenic group: 22.0% of the schizophrenic patients treated with haloperidol and 29.8% of those treated with olanzapine achieved ≥3 metabolic alterations; in bipolar patients, these percentages were 15.8% of those treated with haloperidol and 37.8% of those treated with olanzapine (p < 0.0001). Significant changes were reported over time in fasting glucose, triglycerides and cholesterol blood levels, systolic and diastolic blood pressure, body weight, and BMI. Overall, a significant number of schizophrenic and bipolar patients treated with olanzapine showed ≥3 metabolic alterations in the first month of treatment when compared to those treated with haloperidol. Moreover, the number of olanzapine-treated patients developing metabolic changes in the first month was significantly higher in both diagnostic groups when compared to those who reached metabolic abnormal values in the subsequent 11 months. These data suggest that both antipsychotics could increase the metabolic risk in schizophrenic and bipolar patients with a higher prevalence in olanzapine-treated patients. On the other hand, olanzapine-treated patients seem to achieve metabolic abnormalities faster than haloperidol-treated subjects in both diagnostic groups.

Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation.

OBJECTIVE: Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice. DESIGN: Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPARγ antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs. RESULTS: PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPARγ, abolished PEA effects, in mice and in humans. CONCLUSIONS: Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.

Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats.

Although several findings indicate an association between adolescent cannabis abuse and the risk to develop schizophrenia later in life, the evidence for a causal relationship is still inconclusive. In the present study, we investigated the emergence of psychotic-like behavior in adult female rats chronically exposed to delta-9-tetrahydrocannabinol (THC) during adolescence. To this aim, female Sprague-Dawley rats were treated with THC during adolescence (PND 35-45) and, in adulthood (PND 75), a series of behavioral tests and biochemical assays were performed in order to investigate the long-term effects of adolescent THC exposure. Adolescent THC pretreatment leads to long-term behavioral alterations, characterized by recognition memory deficits, social withdrawal, altered emotional reactivity and sensitization to the locomotor activating effects of acute PCP. Moreover, since cortical disinhibition seems to be a key feature of many different animal models of schizophrenia and GABAergic hypofunction in the prefrontal cortex (PFC) has been observed in postmortem brains from schizophrenic patients, we then investigated the long-lasting consequences of adolescent THC exposure on GABAergic transmission in the adult rat PFC. Biochemical analyses revealed that adolescent THC exposure results in reduced GAD67 and basal GABA levels within the adult PFC. GAD67 expression is reduced both in parvalbumin (PV)- and cholecystokinin (CCK)-containing interneurons; this alteration may be related to the altered emotional reactivity triggered by adolescent THC, as silencing PFC GAD67 expression through a siRNA-mediated approach is sufficient to impact rats' behavior in the forced swim test. Finally, the cellular underpinnings of the observed sensitized response to acute PCP in adult THC-treated rats could be ascribed to the increased cFos immunoreactivity and glutamate levels in the PFC and dorsal striatum. The present findings support the hypothesis that adolescent THC exposure may represent a risk factor for the development of a complex psychotic-like behavior in adulthood.

OLIG2 over-expression impairs proliferation of human Down syndrome neural progenitors.

Mental retardation and early Alzheimer's disease (AD) have generally been attributed to progressive neuronal loss in the developing and mature Down syndrome (DS) brain. However, reduced neuronal production during development could also contribute to the smaller brain size and simplified gyral patterning seen in this disorder. Here, we show impairments in proliferation within the ventricular zone (VZ) of early DS fetal cortex and in cultured early passage DS human neural progenitors (HNPs). We find that the reduced proliferative rates correspond temporally with increased expression of the chromosome 21 (HSA21) associated, oligodendrocyte transcription factor OLIG2 at 14-18 weeks gestational age (GA) (period of neurogenesis). Moreover, the DS HNPs adopt more oligodendrocyte-specific features including increased oligodendrocyte marker expression, as well as a reduction in KCNA3 potassium channel expression and function. We further show that OLIG2 inhibition or over-expression regulates potassium channel expression levels and that activation or inhibition of these channels influences the rate of progenitor proliferation. Finally, neural progenitors from Olig2 over-expressing transgenic mice exhibit these same impairments in proliferation and potassium channel expression. These findings suggest that OLIG2 over-expression inhibits neural progenitor proliferation through changes in potassium channel activity, thereby contributing to the reduced neuronal numbers and brain size in DS.