Periodontal diseases and depression: A pre-clinical in vivo study.

AIM: To analyse, through a pre-clinical in vivo model, the possible mechanisms linking depression and periodontitis at behavioural, microbiological and molecular levels. MATERIALS AND METHODS: Periodontitis (P) was induced in Wistar:Han rats (oral gavages with Porphyromonas gingivalis and Fusobacterium nucleatum) during 12 weeks, followed by a 3-week period of Chronic Mild Stress (CMS) induction. Four groups (n = 12 rats/group) were obtained: periodontitis and CMS (P+CMS+); periodontitis without CMS; CMS without periodontitis; and control. Periodontal clinical variables, alveolar bone levels (ABL), depressive-like behaviour, microbial counts and expression of inflammatory mediators in plasma and brain frontal cortex (FC), were measured. ANOVA tests were applied. RESULTS: The highest values for ABL occurred in the P+CMS+ group, which also presented the highest expression of pro-inflammatory mediators (TNF-α, IL-1ß and NF-kB) in frontal cortex, related to the lipoprotein APOA1-mediated transport of bacterial lipopolysaccharide to the brain and the detection of F. nucleatum in the brain parenchyma. A dysregulation of the hypothalamic-pituitary-adrenal stress axis, reflected by the increase in plasma corticosterone and glucocorticoid receptor levels in FC, was also found in this group. CONCLUSIONS: Neuroinflammation induced by F. nucleatum (through a leaky mouth) might act as the linking mechanism between periodontal diseases and depression.

Expression and Functionality Study of 9 Toll-Like Receptors in 33 Drug-Naïve Non-Affective First Episode Psychosis Individuals: A 3-Month Study.

Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1-9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1-9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-α) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.

The effect of excess weight on circulating inflammatory cytokines in drug-naïve first-episode psychosis individuals.

BACKGROUND: Low-grade inflammation has been repeatedly associated with both excess weight and psychosis. However, no previous studies have addressed the direct effect of body mass index (BMI) on basal serum cytokines in individuals with first-episode psychosis (FEP). OBJECTIVES: The aim of this study is to analyze the effect of BMI on basal serum cytokine levels in FEP patients and control subjects, separating the total sample into two groups: normal-weight and overweight individuals. METHODS: This is a prospective and open-label study. We selected 75 FEP patients and 75 healthy controls with similar characteristics to patients according to the following variables: sex, age, and cannabis and tobacco consumption. Both controls and patients were separated into two groups according to their BMI: subjects with a BMI under 25 were considered as normal weight and those with a BMI equal to or more than 25 were considered as overweight. Serum levels of 21 cytokines/chemokines were measured at baseline using the Human High Sensitivity T Cell Magnetic Bead Panel protocol from the Milliplex® Map Kit. We compared the basal serum levels of the 21 cytokines between control and patient groups according to their BMI. RESULTS: In the normal-weight group, IL-8 was the only cytokine that was higher in patients than in the control group (p = 0.001), whereas in the overweight group, serum levels of two pro-inflammatory cytokines (IL-6, p = 0.000; IL-1ß, p = 0.003), two chemokines (IL-8, p = 0.001; MIP-1ß, p = 0.001), four Th-1 and Th-2 cytokines (IL-13, p = 0.009; IL-2, p = 0.001; IL-7, p = 0.001; IL-12p70, p = 0.010), and one Type-3 cytokine (IL-23, p = 0.010) were higher in patients than in controls. CONCLUSIONS: Most differences in the basal serum cytokine levels between patients and healthy volunteers were found in the overweight group. These findings suggest that excess weight can alter the homeostasis of the immune system and therefore may have an additive pro-inflammatory effect on the one produced by psychosis in the central nervous system.

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.

Oleoylethanolamide prevents neuroimmune HMGB1/TLR4/NF-kB danger signaling in rat frontal cortex and depressive-like behavior induced by ethanol binge administration.

Alcohol abuse is frequently characterized by a specific pattern of intake in binge drinking episodes, inducing neuroinflammation and brain damage. Here, we characterized the temporal profile of neuroinflammation in rats exposed to intragastric binge ethanol administrations (3 times/day × 4 days) and tested the anti-inflammatory/neuroprotective properties of the satiety factor oleoylethanolamide (OEA). Pre-treatment with OEA (5 mg/kg, i.p.) previous each alcohol gavage blocked the expression of high mobility group box 1 (HMGB1) danger signal and the innate immunity Toll-like receptors 4 (TLR4) in frontal cortex, and inhibited the nuclear factor-kappa B (NF-kB) proinflammatory cascade induced by alcohol binge administration. OEA reduced the levels of interleukin-1beta (IL-1ß), the monocyte chemoattractant protein-1 (MCP-1), and the enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in ethanol binged animals. Elevations in plasma tumor necrosis factor alpha (TNF-α) and IL-1ß after ethanol were also inhibited by OEA. OEA also prevented ethanol-induced lipid peroxidation, caspase-8 and pro-apoptotic caspase-3 activation in frontal cortex. Additionally, OEA blocked the rise in blood corticosterone levels after ethanol with no alteration in blood ethanol levels and may affect ethanol-induced gut permeability for endotoxin. Finally, OEA, administered as a pre-treatment during the ethanol binge, exerted antidepressant-like effects during acute withdrawal. Altogether, results highlight a beneficial profile of OEA as a potent anti-inflammatory, antioxidant, neuroprotective and antidepressant-like compound to treat alcohol abuse.

Stress Increases the Negative Effects of Chronic Pain on Hippocampal Neurogenesis.

BACKGROUND: Patients with chronic pain often suffer from affective disorders and cognitive decline, which significantly impairs their quality of life. In addition, many of these patients also experience stress unrelated to their illness, which can aggravate their symptoms. These nociceptive inputs are received by the hippocampus, in which maladaptive neuroplastic changes may occur in the conditions of chronic pain. The hippocampus is a structure involved in emotionality, learning, and memory, and the proliferating cells in the granular layer of the hippocampal dentate gyrus respond to chronic pain by slowing their turnover. However, whether the maturation, survival, and integration of newborn cells in the hippocampus are affected by chronic pain remains unclear. In addition, it is unknown whether an added stress may increase this effect. METHODS: We have evaluated the proliferation, differentiation, and survival of newborn hippocampal cells in a rat model of neuropathic pain (chronic constriction injury), with or without stress (chronic immobilization), by assessing the incorporation of bromodeoxyuridine into proliferating cells and immunostaining. RESULTS: The data obtained indicated that there was a decrease in the number of proliferating cells 8 days after nerve injury in animals subjected to neuropathic pain, an effect that was exacerbated by stress. Moreover, 4 weeks after nerve injury, neuropathic pain was associated with a loss of neuroblasts and the reduced survival of new mature neurons in the hippocampal granular layer, phenomena that also were increased by stress. By contrast, the rate of differentiation was not affected in this paradigm. CONCLUSIONS: Neuropathic pain negatively influences hippocampal neurogenesis (proliferation and survival), and this effect is exacerbated by stress. These neuroplastic changes may account for the affective and cognitive impairment seen in patients with chronic pain.

Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress.

BACKGROUND: The innate immune response is the first line of defence against invading microorganisms and it is also activated in different neurologic/neurodegenerative pathological scenarios. As a result, the family of the innate immune toll-like receptors (TLRs) and, in particular, the genetic/pharmacological manipulation of the TLR-4 signalling pathway emerges as a potential therapeutic strategy. Growing evidence relates stress exposure with altered immune responses, but the precise role of TLR-4 remains partly unknown. METHODS: The present study aimed to elucidate whether the elements of the TLR-4 signalling pathway are activated after acute stress exposure in rat brain frontal cortex and its role in the regulation of the stress-induced neuroinflammatory response, by means of its pharmacological modulation with the intravenous administration of the TLR-4 specific inhibitor TAK-242. Considering that TLR-4 responds predominantly to lipopolysaccharide from gram-negative bacteria, we checked whether increased intestinal permeability and a resultant bacterial translocation is a potential regulatory mechanism of stress-induced TLR-4 activation. RESULTS: Acute restraint stress exposure upregulates TLR-4 expression both at the mRNA and protein level. Stress-induced TLR-4 upregulation is prevented by the protocol of antibiotic intestinal decontamination made to reduce indigenous gastrointestinal microflora, suggesting a role for bacterial translocation on TLR-4 signalling pathway activation. TAK-242 pre-stress administration prevents the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats. CONCLUSIONS: The use of TAK-242 or other TLR-4 signalling pathway inhibitory compounds could be considered as a potential therapeutic adjuvant strategy to constrain the inflammatory process taking place after stress exposure and in stress-related neuropsychiatric diseases.

Systemic administration of oleoylethanolamide protects from neuroinflammation and anhedonia induced by LPS in rats.

BACKGROUND: The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile. METHODS: We tested whether oleoylethanolamide/palmitoylethanolamide (10 mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5 mg/kg, i.p.) in rats. RESULTS: Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1ß, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2(-)) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both acylethanolamides reduced the expression of hypothalamic markers of thermoregulation interleukin-1ß, cyclooxygenase-2, and prostaglandin E2, and potentiated the hypothermic response after lipopolysaccharide. Interestingly, only oleoylethanolamide disrupted lipopolysaccharide-induced anhedonia in a saccharine preference test. CONCLUSIONS: Results indicate that oleoylethanolamide and palmitoylethanolamide have antiinflammatory/neuroprotective properties and suggest a role for these acylethanolamides as modulators of CNS pathologies with a neuroinflammatory component.

Association between neutrophil to lymphocyte ratio and inflammatory biomarkers in patients with a first episode of psychosis.

Neutrophil to lymphocyte ratio (NLR) has been proposed as an emerging marker of the immune system alterations in psychotic disorders. However, it is not entirely clear whether NLR elevation is a characteristic of the psychotic disorder itself, which inflammatory pathways activation is detecting, or which possible confounding variables could alter its interpretation. We aimed to analyze the relationship of NLR values with a panel of inflammatory and oxidative/nitrosative stress biomarkers and main potential confounding factors in a well-characterized cohort of 97 patients with a first episode of psychosis (FEP) and 77 matched healthy controls (HC). In the FEP group, NLR values presented a moderate, positive correlation with the pro-inflammatory mediator Prostaglandin E2 levels (r = 0.36, p < 0.001) and a small but significant, positive correlation with cannabis use (r = 0.25, p = 0.017). After controlling for cannabis use, the association between NLR and PGE2 remained significant (beta = 0.31, p = 0.012). In the HC group, NLR values negatively correlated with body mass index (BMI, r = -0.24, p = 0.035) and positively correlated with tobacco use (r = 0.25, p = 0.031). These findings support a relationship between the elevation of NLR values and an elevated expression of proinflammatory pathways related to stress response in patients with a FEP. In addition, our study highlights the importance of considering variables such as cannabis or tobacco consumption, and BMI when interpreting the results of studies aimed to establish a clinical use of NLR. These considerations may help future research to use NLR as a reliable biomarker to determine immune system status in this population.

Inflammatory activation and cholinergic anti-inflammatory system in eating disorders.

Dysfunctional serotoninergic regulation and hypothalamic-pituitary-adrenal (HPA) axis overreactivity have been consistently reported in research studies with eating disorders (ED). In addition, the links between stress response, serotonin function, HPA axis and inflammatory mechanisms in ED have also been suggested in a number of studies. In our study, inflammatory parameters in white blood cells were investigated in 26 female patients with ED and 25 healthy control subjects matched for sex, age and ethnicity. Patients were free of medication for at least two weeks at the time of the study. Results showed a significant increase in plasma levels of the proinflammatory cytokine IL1ß and the protein expression of cyclooxygenase 2 (COX2) in peripheral mononuclear blood cells (PMBCs) in ED patients compared with controls. As well as a significant increase of the oxidative-nitrosative marker TBARS (Thiobarbituric Acid Reactive Substances) in plasma. These findings were associated with increased expression of the alpha7 subunit of the nicotinic receptor (α7nAChR) in PMBC in ED patients independent of plasma cotinine levels. These results suggest that a pro-inflammatory and oxidant phenotype might be present in ED patients. Further research on cellular inflammatory and anti-inflammatory pathways might be oriented to investigate differences between ED subtypes and to search for new potential targets for pharmacological treatment.

Depressive-like states heighten the aversion to painful stimuli in a rat model of comorbid chronic pain and depression.

BACKGROUND: Chronic pain and depression are two complex states with sensory/somatic and emotional components, and they may mutually exacerbate one another in conditions of comorbidity, leading to a poorer prognosis. METHODS: The authors have evaluated the sensory and emotional components in a rat model combining chronic constriction injury (CCI, a model of chronic neuropathic pain) with unpredictable chronic mild stress (CMS, an experimental model of depression). In addition, the phosphorylation/activation of the extracellular signal-regulated kinases 1 and 2 and neuronal density was also evaluated in the anterior cingulate cortex. Four groups were tested: sham-control, sham-CMS, CCI-control, and CCI-CMS. RESULTS: CMS selectively heightens aversion to painful experiences in animals subjected to CCI, as measured in the place escape/avoidance test at 20, 25, and 30 min (CCI-CMS (mean±SEM): 75.68±3.32, 66.75±4.70, 77.54±3.60 vs. CCI-control: 44.66±6.07, 43.17±6.92, 52.83±5.92, respectively), in conjunction with an increase in the accumulation of phosphorylation/activation of the extracellular signal-regulated kinases (CCI-CMS: 4.17±0.52 vs. sham-control: 0.96±0.05) and a decrease in neuronal density in the anterior cingulate cortex. In contrast, chronic pain did not exacerbate the characteristic profile of depression (anhedonia and behavioral despair) in rats subjected to CMS. Furthermore, depression enhances the perception of some specific modalities of sensorial pain such as cold allodynia but has no influence on mechanical threshold. CONCLUSIONS: These findings support the theory that depression leads to emotional dysfunction in the interpretation of pain in patients suffering chronic pain. In addition, combined animal models of pain-depression may provide a valuable tool to study the comorbidity of pain and depression.

Antioxidant defense system and family environment in adolescents with family history of psychosis.

BACKGROUND: Our objective was to determine antioxidant defence activity in healthy controls (HC) and healthy unaffected second-degree relatives of patients with early onset psychosis (HC-FHP), and to assess its relationship with familiar environment measured using the Family Environment Scale (FES). METHODS: We included 82 HC and 14 HC-FHP aged between 9 and 17 years. Total antioxidant status, lipid peroxidation, antioxidant enzyme activities and glutathione levels were determined in blood samples. RESULTS: There was a significant decrease in the total antioxidant level in the HC-FHP group compared with the HC group (OR = 2.94; p = 0.009), but no between-group differences in the Global Assessment of Functioning (GAF) scale scores. For the FES, the HC-FHP group had significantly higher scores in the cohesion (p = 0.007) and intellectual-cultural dimensions (p=0.025). After adjusting for these two FES dimensions, total antioxidant status remained significantly different between groups (OR = 10.86, p = 0.009). CONCLUSIONS: Although causal relationships cannot be assumed, we can state that family environment is not playing a role in inducing oxidative stress in these healthy subjects. It could be hypothesized that families with affected relatives protect themselves from psychosis with positive environmental factors such as cohesion and intellectual-cultural activities.

Inflammation biomarkers in suicide attempts and their relation to abuse, global functioning and cognition.

OBJECTIVES: To explore the link between cytokines and suicide attempts and their relationship with the psychological aspects of this complex multifactorial phenomenon. METHODS: 96 participants, including 20 patients with a recent suicide attempt and diagnosis of Major Depression Disorder (MDD), 33 MDD patients with a lifetime history of suicide attempt, 23 non-attempter MDD patients, and 20 healthy controls underwent an assessment on depressive symptoms, global functioning, aggressive behaviour, presence of abuse and attention performance. Additionally, all participants had a blood extraction for IL-2, IL2-R, IL-4, IL-6, and TNF-α plasma levels analysis. RESULTS: IL-6 levels were significantly different across groups (F(3,89)=3.690; p = 0.015), with higher concentrations in both recent (p = 0.04) and distant (p = 0.015) attempt in comparison to MDD non-attempters. IL-6 was associated with adult physical abuse (B = 2.591; p = 0.021), lower global functioning score (B = -0.512; p = 0.011), and poorer performance on attention (B = -0.897; p = 0.011). CONCLUSIONS: Recent and distant suicidal behaviour is associated with elevated IL-6 levels, which may be influenced by stressful and traumatic experiences. Elevated concentrations of IL-6 could have a negative impact on attention, increasing suicide risk. More research is needed to clarify the role of cytokines in suicide-related features to explore novel treatments and more effective preventive interventions.

The effects of mango leaf extract during adolescence and adulthood in a rat model of schizophrenia.

There is evidence that in schizophrenia, imbalances in inflammatory and oxidative processes occur during pregnancy and in the early postnatal period, generating interest in the potential therapeutic efficacy of anti-inflammatory and antioxidant compounds. Mangiferin is a polyphenolic compound abundant in the leaves of Mangifera indica L. that has robust antioxidant and anti-inflammatory properties, making it a potential candidate for preventive or co-adjuvant therapy in schizophrenia. Hence, this study set-out to evaluate the effect of mango leaf extract (MLE) in a model of schizophrenia based on maternal immune activation, in which Poly I:C (4 mg/kg) is administered intravenously to pregnant rats. Young adult (postnatal day 60-70) or adolescent (postnatal day 35-49) male offspring received MLE (50 mg/kg of mangiferin) daily, and the effects of MLE in adolescence were compared to those of risperidone, assessing behavior, brain magnetic resonance imaging (MRI), and oxidative/inflammatory and antioxidant mediators in the adult offspring. MLE treatment in adulthood reversed the deficit in prepulse inhibition (PPI) but it failed to attenuate the sensitivity to amphetamine and the deficit in novel object recognition (NOR) induced. By contrast, adolescent MLE treatment prevented the sensorimotor gating deficit in the PPI test, producing an effect similar to that of risperidone. This MLE treatment also produced a reduction in grooming behavior, but it had no effect on anxiety or novel object recognition memory. MRI studies revealed that adolescent MLE administration partially counteracted the cortical shrinkage, and cerebellum and ventricle enlargement. In addition, MLE administration in adolescence reduced iNOS mediated inflammatory activation and it promoted the expression of biomarkers of compensatory antioxidant activity in the prefrontal cortex and hippocampus, as witnessed through the reduction of Keap1 and the accumulation of NRF2 and HO1. Together, these findings suggest that MLE might be an alternative therapeutic or preventive add-on strategy to improve the clinical expression of schizophrenia in adulthood, while also modifying the time course of this disease at earlier stages in populations at high-risk.

Sphk2 deletion is involved in structural abnormalities and Th17 response but does not aggravate colon inflammation induced by sub-chronic stress.

The chronic inflammatory process that characterizes inflammatory bowel diseases (IBD) is mainly driven by T-cell response to microbial and environmental antigens. Psychological stress is a potential trigger of clinical flares of IBD, and sphingosine-1-phosphate (S1P) is involved in T-cell recruitment. Hence, stress impact and the absence of sphingosine kinase 2 (Sphk2), an enzyme of S1P metabolism, were evaluated in the colon of mice after sub-chronic stress exposure. Here, we show that sub-chronic stress increased S1P in the mouse colon, possibly due to a decrease in its degradation enzymes and Sphk2. S1P accumulation could lead to inflammation and immune dysregulation reflected by upregulation of toll-like receptor 4 (TLR4) pathway, inhibition of anti-inflammatory mechanisms, cytokine-expression profile towards a T-helper lymphocyte 17 (Th17) polarization, plasmacytosis, decrease in IgA+ lymphoid lineage cells (CD45+)/B cells/plasmablasts, and increase in IgM+ B cells. Stress also enhanced intestinal permeability. Sphk2 knockout mice presented a cytokine-expression profile towards a boosted Th17 response, lower expression of claudin 3,4,7,8, and structural abnormalities in the colon. Intestinal pathophysiology should consider stress and S1P as modulators of the immune response. S1P-based drugs, including Sphk2 potentiation, represent a promising approach to treat IBD.

The role of BDNF and NGF plasma levels in first-episode schizophrenia: A longitudinal study.

Neurotrophins have been proposed to be involved in biological mechanisms which might underlie different clinical outcomes in schizophrenia. The aims of the present study were to examine the BDNF/NGF plasma levels in a cohort of first-episode schizophrenia (FES) patients in remission as potential biological predictors of relapse; to study the associations between these neurotrophins and the symptomatology severity through different stages after a FES in two independent cohorts. 2EPs-Cohort: 69 first-episode in clinical remission were included. BDNF/NGF plasma levels and symptom severity were measured at enrollment and at 3-year or at the time of the second episode/relapse. FLAMM-PEPs-Cohort: 65 first-episodes were also included. BDNF/NGF and symptom severity were obtained at enrollment and 2-year follow-up. Symptomatology was assessed with the Marder-PANSS-Factor scores. Plasma neurotrophins did not differ significantly over time and neither BDNF/NGF were predictors of relapse. Besides, in remission stages, baseline BDNF levels showed significant correlations with both positive and negative symptoms (p<0.05); NGF, with negative symptomatology (p<0.01). Similarly, in the FLAMM-PEPs-Cohort, baseline BDNF/NGF levels showed significant correlations with negative symptoms (and not positive symptomatology) at follow-up (p<0.05). In both cohorts, lower levels correlated with higher symptom severity. Findings did not support a role for BDNF/NGF plasma levels as biomarkers of relapse in FES patients. Nevertheless, baseline BDNF/NGF may lead to be considered potentially useful biomarkers of long-term severity in schizophrenia and of the underlying illness traits, specially of negative symptomatology severity. More longitudinal studies in FES samples and adding a control group are warranted to replicate these findings.

Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia­reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS.

BACKGROUND: Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212-2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial-type nitric oxide synthase (eNOS) expression. METHODS: Male 20-week-old Zucker diabetic fatty rats were treated with vehicle, WIN, the selective CB1 or CB2 receptor antagonists AM251 and AM630, respectively, AM251 + WIN or AM630 + WIN. Hearts were isolated from these rats, and the cardiac functional response to ischaemia/reperfusion injury was evaluated. In addition, cardiac iNOS and eNOS expression were determined by western blot. RESULTS: WIN significantly improved cardiac recovery after ischaemia/ reperfusion in the hearts from Zucker diabetic fatty rats by restoring coronary perfusion pressure and heart rate to preischaemic levels. Additionally, WIN decreased cardiac iNOS expression and increased eNOS expression after ischaemia/reperfusion in diabetic hearts. WIN-induced cardiac functional recovery was completely blocked by the CB2 antagonist AM630. However, changes in NOS isoenzyme expression were not affected by the CB antagonists. CONCLUSIONS: This study shows a cardioprotective effect of a cannabinoid agonist on ischaemia/reperfusion injury in an experimental model of a metabolic disorder. The activation mainly of CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect. These initial studies have provided the basis for future research in this field.

Association Between Medication Adherence and Oxidative Stress in Patients With First-Episode Mania.

Poor adherence is a major problem in patients with manic episodes that impairs functionality and has unknown effects on oxidative stress. The objective of this study was to analyze the relationship between adherence to medication, severity of symptoms and oxidative stress in a sample of patients with a first episode of mania. A longitudinal, 6-month study was performed in 60 patients, who were classified as adherent and non-adherent to medication (mainly antipsychotics). Blood levels of oxidative stress parameters and expression of the antioxidant nuclear transcription factor NRF2 in mononuclear cells of peripheral blood were assessed at baseline and at the end of follow-up. In addition, clinical symptoms and functioning were evaluated. Linear multivariate regression was used to determine the relationship between adherence, oxidative stress, and clinical symptoms. Finally, 44 patients completed follow-up. The results of this study showed that at 6-month follow-up, adherence was significantly associated with better functioning and reduced clinical symptoms. Additionally, more severe symptoms were associated with increased levels of oxidative stress and antioxidant parameters. At study completion, non-adherents exhibited greater levels of antioxidants than adherent patients. In conclusion, poor adherence to medication is associated with a poorer prognosis in the medium term and causes increased antioxidant response.

Stress mediators regulate brain prostaglandin synthesis and peroxisome proliferator-activated receptor-gamma activation after stress in rats.

Stress exposure leads to oxidative/nitrosative and neuroinflammatory changes that have been shown to be regulated by antiinflammatory pathways in the brain. In particular, acute restraint stress is followed by cyclooxygenase (COX)-2 up-regulation and subsequent proinflammatory prostaglandin (PG) E2 release in rat brain cortex. Concomitantly, the synthesis of the antiinflammatory prostaglandin 15d-PGJ(2) and the activation of its nuclear target the peroxisome proliferator-activated receptor (PPAR)-gamma are also produced. This study aimed to determine the possible role of the main stress mediators: catecholamines, glucocorticoids, and excitatory amino acids (glutamate) in the above-mentioned stress-related effects. By using specific pharmacological tools, our results show that the main mediators of the stress response are implicated in the regulation of prostaglandin synthesis and PPARgamma activation in rat brain cortex described after acute restraint stress exposure. Pharmacological inhibition (predominantly through beta-adrenergic receptor) of the stress-released catecholamines in the central nervous system regulates 15d-PGJ(2) and PGE(2) synthesis, by reducing COX-2 overexpression, and reduces PPARgamma activation. Stress-produced glucocorticoids carry out their effects on prostaglandin synthesis through their interaction with mineralocorticoid and glucocorticoid receptors to a very similar degree. However, in the case of PPARgamma regulation, only the actions through the glucocorticoid receptor seem to be relevant. Finally, the selective blockade of the N-methyl-d-aspartate type of glutamate receptor after stress also negatively regulates 15d-PGJ(2) and PGE(2) production by COX-2 down-regulation and decrease in PPARgamma transcriptional activity and expression. In conclusion, we show here that the main stress mediators, catecholamines, GCs, and glutamate, concomitantly regulate the activation of proinflammatory and antiinflammatory pathways in a possible coregulatory mechanism of the inflammatory process induced in rat brain cortex by acute restraint stress exposure.

Expression of nitrotyrosine and oxidative consequences in the trabecular meshwork of patients with primary open-angle glaucoma.

PURPOSE: To evaluate the possible correlation between the visual field defects in patients with primary open-angle glaucoma (POAG) and the expression and enzymatic activity of nitric oxide synthase (NOS) isoenzymes and nitrotyrosine in trabecular meshwork (TM) samples. METHODS: TM specimens were collected from 146 patients with POAG by using standard filtration surgery. Visual field defects were evaluated by perimetry. Expression of endothelial (e)NOS and inducible (i)NOS were evaluated by quantitative RT-PCR. Constitutive (Ca2+-dependent) and iNOS (Ca2+-independent) activities were measured by the conversion of L-[14C]-arginine to L-[14C]-citrulline. In four TM specimens from POAG-affected eyes and in three human donor control eyes, 3-nitrotyrosine was localized by immunohistochemistry. The marker of lipid peroxidation malondialdehyde (MDA) was measured by the thiobarbituric acid test in samples of aqueous humor (AH) from 48 patients with either POAG or cataracts. RESULTS: The results showed an upregulation of iNOS and a downregulation of calcium-dependent NOS correlated with visual field defects. Expression and activity of iNOS increased in parallel with visual field defects. However, constitutive activity decreased as the visual field defect increased. Nitrotyrosine was observed only in the cells of the TM specimens from eyes with severe POAG. CONCLUSIONS: The increased expression and activity of iNOS in the TM of patients with POAG are proportional to the visual field defect and could lead to the increased of nitrotyrosine levels which may serve as marker of oxidative stress in the progression of cell death of the TM in POAG.