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Background: Many literature reviews report vitamin E supplementation as a benefit chemopreventive and adjuvant therapy in breast and prostate cancers. We investigated in the present work, alpha-tocopherol (α-T) expression (the current active form of vitamin E) from tissues of Congolese patients neither smokers nor alcohol drinkers and without intake antioxidant vitamins supplement. Methods: α-T was analysed in one normal placenta of nine weeks of gestation and in nineteen cancerous tissues, including seven breast cancers, six prostate cancers, and six gestational choriocarcinomas. The study was performed by immunohistochemistry method after diagnosis confirmation by histological analysis. Results: α-T staining in membrane cells and collagen fibers presented a moderate expression in healthy sections of tissues (positive control), but the labelling was strong in breast, prostate adenocarcinomas, and in choriocarcinomas. Conclusion: Tumors immunohistochemistry of α-tocopherol in breast, prostate cancers and in choriocarcinoma show elevated immunostaining suggesting a probable oncogenic effect of the micronutrient.

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in a cross-sectional study that enrolled schizophrenia patients with (n = 40) and without (n = 40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial least squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), which lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA, and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Objective:To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms.Methods:Forty women aged 18–45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is,Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putidaandCitobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle.Results:Significant changes in Δ (actual − 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes inH. alvei,M. Morganii, P. putidaduring the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase.Discussion:Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.

This review updates the findings about the anatomical distribution (using immunohistochemical techniques) and possible functions of D-glutamate in the central nervous system of mammals, as well as compares the distribution of D-glutamate with the distribution of the most studied D-amino acids: D-serine and D-aspartate. The protocol used to obtain highly specific antisera directed against D-amino acids is also reported. Immunoreactivity for D-glutamate was found in dendrites and cell bodies, but not in nerve fibers. Perikarya containing D-glutamate were found in the mesencephalon and thalamus. The highest density of cell bodies was found in the dorsal raphe nucleus, the mesencephalic central grey matter, the superior colliculus, and in the subparafascicular thalamic nucleus. In comparison with the distribution of immunoreactive cell bodies containing D-serine or D-aspartate, the distribution of D-glutamate-immunoreactive perikarya is less widespread. Currently, the physiological actions mediated by D-glutamate in the brain are unknown but the restricted neuroanatomical distribution of this D-amino acid suggests that D-glutamate could be involved in very specific physiological mechanisms. In this sense, the possible functional roles of D-glutamate are discussed.

Objectives To examine oxidative & nitrosative stress (O&NS) biomarkers at the end of term in relation to perinatal affective symptoms, neuro-immune biomarkers and pregnancy-related outcome variables. Methods We measured plasma advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP), -sulfhydryl (-SH), peroxides (LOOH) and paraoxonase (PON)1 activity in pregnant women with and without prenatal depression and non-pregnant controls. Results Pregnancy is accompanied by significantly increased AOPP and NOx, and lowered TRAP, -SH and LOOH. Increased O&NS and lowered LOOH and -SH levels are associated with prenatal depressive and physio-somatic symptoms (fatigue, pain, dyspepsia, gastro-intestinal symptoms). Increased AOPP and NOx are significantly associated with lowered –SH, TRAP and zinc, and with increased haptoglobin and C-reactive protein levels. Increased O&NS and lowered TRAP and PON 1 activity, at the end of term predict mother (e.g. hyperpigmentation, labor duration, caesarian section, cord length, breast milk flow) and baby (e.g. sleep and feeding problems) outcome characteristics. Conclusions Pregnancy is accompanied by interrelated signs of O&NS, lowered antioxidant defenses and activated neuro-immune pathways. Increased O&NS at the end of term is associated with perinatal depressive and physio-somatic symptoms and may predict obstetric and behavioral complications in mother and baby.

Immunoglubulin (Ig)M responses directed to oxida- tive specific epitopes (OSEs) and nitric oxide (NO)-adducts are significantly associated with major depression and physio- somatic symptoms. End of term serum IgM responses to OSEs and NO-adducts were assayed in pregnant women with ( n =24) and without prenatal depression ( n = 25) as well as in 24 non- pregnant women. Associations of IgM/IgA responses to Gram- negative gut commensal bacteria (leaky gut index) and IgA/IgM responses to tryptophan catabo lites (TRYCATs) were analyzed. IgM responses to OSEs, but not NO-adducts, were significantly reduced at the end of term. There we re no significant associations between IgM responses to OSEs and perinatal depression, whilst IgM responses to NO-adducts, especially NO-cysteinyl, were significantly associated with a lifetime major depression. IgM responses to OSEs and NO-cysteinyl were significantly associat- ed with IgA/IgM responses to Gram-negative bacteria, especially Morganella morganii , Klebsiella pneumoniae and Citrobacter koseri . IgM responses to NO-adducts and OSEs, especially malondialdehyde and myristic acid, and C-reactive protein (CRP) were inversely associated with TRYCAT pathway activity, whilst a lifetime depression and Pseudomonas putida were pos- itively associated. The attenuation of natural IgM-mediated re- sponses to OSEs at the end of term may indicate lowered activity of this part of the compensatory ( anti-)inflammatory reflex sys- tem and may be partly explained by lowered bacterial transloca- tion. Increased IgM responses to N O-cysteinyl is a biomarker of lifetime depression and may be in duced by bacterial transloca- tion. Natural IgM-mediated autoimmune responses, increased nitrosylation and higher CRP levels may have negative regulato- ry effects on the TRYCAT pathway.

Deficit schizophrenia is accompanied by mucosa-associated activation of the tryptophan catabolite (TRYCAT) pathway, as indicated by increased IgA responses to noxious (NOX) TRYCATs, but not regulatory or protective (PRO) TRYCATs, suggesting increased neurotoxic, excitotoxic, inflammatory, and oxidative potential. No previous studies examined IgM-mediated autoimmune responses to the TRYCAT pathway in deficit versus nondeficit schizophrenia. We measured IgM responses to NOX TRYCATs, namely, quinolinic acid (QA), 3-OH-kynurenine (3HK), picolinic acid (PA), and xanthurenic (XA) acid, and PRO TRYCATs, including kynurenic acid (KA) and anthranilic acid (AA), in 40 healthy controls and 40 deficit and 40 nondeficit schizophrenic patients. We computed the IgM responses to NOX (QA + PA + 3HK + XA)/PRO (AA + KA) ratio and ∆ differences in IgA - IgM TRYCAT values and NOX/PRO ratio. Deficit schizophrenia is characterized by significantly attenuated IgM responses to all TRYCATs and NOX/PRO ratio and highly increased ∆IgA - IgM NOX/PRO ratio as compared to nondeficit schizophrenia and healthy controls. The negative symptoms of schizophrenia are significantly and positively associated with increased IgM responses directed against the KA/3HK ratio and ∆IgA - IgM NOX/PRO ratio. The findings support the view that deficit schizophrenia is a distinct subtype of schizophrenia that may be significantly discriminated from nondeficit schizophrenia. Deficit schizophrenia is accompanied by a highly specific defect in IgM isotype-mediated regulatory responses directed to the TRYCAT pathway. Lowered IgM regulatory responses together with mucosa-derived activation of the TRYCAT pathway may contribute to neuroprogression, negative symptoms, and deficit schizophrenia. All in all, a highly specific defect in the compensatory (anti-)inflammatory reflex system (CIRS), namely, natural IgM-mediated regulatory responses, may underpin deficit schizophrenia.

Evidence suggests that activation of the tryptophan catabolite (TRYCAT) pathway is involved in the pathophysiology of schizophrenia. However, no previous study examined whether TRYCAT pathway activation is associated with deficit schizophrenia. We measured IgA responses to TRYCATs, namely quinolinic acid, picolinic acid, kynurenic acid, xanthurenic acid, and anthranilic acid and 3-OH-kynurenine, in 40 healthy controls and in schizophrenic patients with (n = 40) and without (n = 40) deficit, defined according to the Schedule for the Deficit Syndrome (SDS). Primary deficit schizophrenia is accompanied by an activated TRYCAT pathway as compared to controls and nondeficit schizophrenia. Participants with deficit schizophrenia show increased IgA responses to xanthurenic acid, picolinic acid, and quinolinic acid and relatively lowered IgA responses to kynurenic and anthranilic acids, as compared to patients with nondeficit schizophrenia. Both schizophrenia subgroups show increased IgA responses to 3-OH-kynurenine as compared to controls. The IgA responses to noxious TRYCATs, namely xanthurenic acid, picolinic acid, quinolinic acid, and 3-OH-kynurenine, but not protective TRYCATS, namely anthranilic acid and kunyrenic acid, are significantly higher in deficit schizophrenia than in controls. The negative symptoms of schizophrenia are significantly and positively associated with increased IgA responses directed against picolinic acid and inversely with anthranilic acid, whereas no significant associations between positive symptoms and IgA responses to TRYCATs were found. In conclusion, primary deficit schizophrenia is characterized by TRYCAT pathway activation and differs from nondeficit schizophrenia by a highly specific TRYCAT pattern suggesting increased excitotoxicity, cytotoxicity, and neurotoxicity, as well as inflammation and oxidative stress. The specific alterations in IgA responses to TRYCATs provide further insight for the biological delineation of deficit versus nondeficit schizophrenia.

Introduction. The available immunohistochemical techniques have documented restricted distribution of vitamins in the mammalian brain. The aim of the study was to develop a highly specific antiserum directed against pantothenic acid to explore the presence of this vitamin in the mammalian brain. Material and methods. According to ELISA tests, the anti-pantothenic acid antiserum used showed a good affinity (10 –8 M) and specificity. The antiserum was raised in rabbits. Using an indirect immunoperoxidase technique, the mapping of pantothenic acid-immunoreactive structures was carried out in the rat brain. Results. Pantothenic acid-immunoreactive perikarya were exclusively found in the intermediate part of the lateral septal nucleus. These cells were generally small, round, fusiform or pyramidal and showed 2–3 long (50–100 μm) immunoreactive dendrites. Any immunoreactive axons containing pantothenic acid were detected. Conclusions. The very restricted anatomical distribution of the pantothenic acid suggests that this vitamin could be involved in some specific neurophysiological mechanisms.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity.The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors.We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia (“OSOS”); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated).Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

The aim of the present study is to delineate the associations between body image dissatisfaction in pregnant women and immune-inflammatory biomarkers, i.e., C-reactive protein (CRP), zinc and IgA/IgM responses to tryptophan and tryptophan catabolites (TRYCATs).We assessed 49 pregnant and 24 non-pregnant females and assessed Body Image Satisfaction (BIS) scores at the end of term (T1), and 2-4 days (T2) and 4-6 weeks (T3) after delivery. Subjects were divided in those with a lowered BIS score (≤ 3) versus those with a higher score.Logistic regression analysis showed that a lowered T1 BIS score was predicted by CRP levels and IgA responses to tryptophan (negative) and TRYCATs (positive), perinatal depression, body mass index (BMI) and age. The sum of quinolinic acid, kynurenine, 3-OH-kynurenine and 3-OH-anthranilic acid (reflecting brain quinolinic acid contents) was the single best predictor. In addition, a large part of the variance in the T1, T2 and T3 BIS scores was explained by IgA responses to tryptophan and TRYCATs, especially quinolinic acid.Body image dissatisfaction is strongly associated with inflammation and mucosa-derived IDO activation independently from depression, pregnancy, BMI and age. IgA responses to peripheral TRYCATs, which determine brain quinolinic acid concentrations, also predict body image dissatisfaction.

There is some evidence that lowered tryptophan and an activated tryptophan catabolite (TRYCAT) pathway play a role in depression, somatoform disorder, and postpartum blues. The aim of this study is to delineate the associations between the TRYCAT pathway and premenstrual syndrome (PMS) and perinatal depressive and physio-somatic symptoms. We examine the associations between end of term serum IgM and IgA responses to tryptophan and 9 TRYCATs in relation to zinc, C-reactive protein (CRP), and haptoglobin and prenatal physio-somatic (previously known as psychosomatic) symptoms (fatigue, back pain, muscle pain, dyspepsia, obstipation) and prenatal and postnatal depression and anxiety symptoms as measured using the Edinburgh Postnatal Depression Scale (EPDS), Hamilton Depression Rating Scale (HAMD), and Spielberger's State Anxiety Inventory (STAI). We included pregnant females with (n = 24) and without depression (n = 25) and 24 non-pregnant females. There were no significant associations between the IgA/IgM responses to tryptophan and TRYCATs and prenatal and postnatal depression/anxiety symptoms, except for lowered IgA responses to anthranilic acid in prenatal depression. A large part of the variance in IgA responses to most TRYCATs was explained by PMS and haptoglobin (positively) and CRP (inversely) levels. The IgA responses to TRYCATs were significantly increased in PMS, in particular picolinic, anthranilic, xanthurenic and kynurenic acid, and 3OH-kynurenine. Variance (62.5%) in physio-somatic symptoms at the end of term was explained by PMS, previous depressions, zinc (inversely), CRP and haptoglobin (both positively), and the IgM responses to quinolinic acid (positively), anthranilic acid, and tryptophan (both negatively). The results suggest that mucosa-derived TRYCAT pathway activation is significantly associated with PMS, but not with perinatal depression/anxiety symptoms. Physio-somatic symptoms in pregnancy have an immune-inflammatory pathophysiology. Induction of the TRYCAT pathway appears to be more related to physio-somatic than to depression symptoms.

Using an immunohistochemical technique, we have studied the distribution of kynuneric acid (KYNA) and 3-hydroxyanthranilic acid (3-HAA) in a rat brain injury model (trauma). The study was carried out inducing a cerebral ablation of the frontal motor cortex. Two mouse monoclonal specific antibodies previously developed by our group directed against KYNA and 3-HAA were used. In control animals (sham-operated), the expression of both KYNA and 3-HAA was not observed. In animals in which the ablation was performed, the highest number of immunoreactive cells containing KYNA or 3-HAA was observed in the region surrounding the lesion and the number of these cells decreased moving away from the lesion. KYNA and 3-HAA were also observed in the white matter (ipsilateral side) located close to the injured region and in some cells placed in the white matter of the contralateral side. The distribution of KYNA and 3-HAA perfectly matched with the peripheral injured regions. The results found were identical independently of the perfusion date of animals (17, 30 or 54 days after brain injury). For the first time, the presence of KYNA and 3-HAA has been described in a rat trauma model. Moreover, by using a double immunocytochemistry protocol, it has been demonstrated that both metabolites were located in astrocytes. The findings observed suggest that, in cerebral trauma, KYNA and 3-HAA are involved in tissue damage and that these compounds could act, respectively, as a neuroprotector and a neurotoxic. This means that, in trauma, a counterbalance occurs and that a regulation of the indoleamine 2,3 dioxygenase (IDO) pathway could be required after a brain injury in order to decrease the deleterious effects of ending metabolites (the neurotoxic picolinic acid). Moreover, the localization of KYNA and 3-HAA in the contralateral side of the lesion suggests that the IDO pathway is also involved in the sprouting and pathfinding that follows a traumatic brain injury.

Rationale Deficit schizophrenia, as defined by the Schedule for Deficit Syndrome, may represent a distinct diagnostic class defined by neurocognitive impairments coupled with changes in IgA/IgM responses to tryptophan catabolites (TRYCATs). Adequate classifications should be based on supervised and unsupervised learning rather than on consensus criteria. Methods This study used machine learning as means to provide a more accurate classification of patients with stable phase schizophrenia. Results We found that using negative symptoms as discriminatory variables, schizophrenia patients may be divided into two distinct classes modelled by (A) impairments in IgA/IgM responses to noxious and generally more protective tryptophan catabolites, (B) impairments in episodic and semantic memory, paired associative learning and false memory creation, and (C) psychotic, excitation, hostility, mannerism, negative, and affective symptoms. The first cluster shows increased negative, psychotic, excitation, hostility, mannerism, depression and anxiety symptoms, and more neuroimmune and cognitive disorders and is therefore called "major neurocognitive psychosis" (MNP). The second cluster, called "simple neurocognitive psychosis" (SNP) is discriminated from normal controls by the same features although the impairments are less well developed than in MNP. The latter is additionally externally validated by lowered quality of life, body mass (reflecting a leptosome body type), and education (reflecting lower cognitive reserve). Conclusions Previous distinctions including "type 1" (positive)/"type 2" (negative) and DSM-IV-TR (eg, paranoid) schizophrenia could not be validated using machine learning techniques. Previous names of the illness, including schizophrenia, are not very adequate because they do not describe the features of the illness, namely, interrelated neuroimmune, cognitive, and clinical features. Stable-phase schizophrenia consists of 2 relevant qualitatively distinct categories or nosological entities with SNP being a less well-developed phenotype, while MNP is the full blown phenotype or core illness. Major neurocognitive psychosis and SNP should be added to the DSM-5 and incorporated into the Research Domain Criteria project.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that currently has no cure. At present, the only approved treatment for ALS is Riluzole, a glutamate release blocker that improves life expectancy by 3–6 months. ALS-Endotherapia (GEMALS) is a novel therapeutic approach to treat ALS and the aim of the present study was to investigate the potential beneficial effects of this novel treatment. A total of 31 patients with ALS were assessed in the current study. Deceleration of the disease was observed in 83.87% (P

The depression, anxiety and physiosomatic symptoms (DAPS) of schizophrenia are associated with negative symptoms and changes in tryptophan catabolite (TRYCAT) patterning. The aim of this study is to delineate the associations between DAPS and psychosis, hostility, excitation, and mannerism (PHEM) symptoms, cognitive tests as measured using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and IgA/IgM responses to TRYCATs. We included 40 healthy controls and 80 participants with schizophrenia. Depression and anxiety symptoms were measured with The Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales, respectively. Physiosomatic symptoms were assessed with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF). Negative symptoms as well as CERAD tests, including Verbal Fluency Test (VFT), Mini-Mental State Examination (MMSE), Word List Memory (WLM), and WL Delayed Recall were measured, while ratios of IgA responses to noxious/protective TRYCATs (IgA NOX_PRO) were computed. Schizophrenia symptoms consisted of two dimensions, a first comprising PHEM and negative symptoms, and a second DAPS symptoms. A large part of the variance in DAPS was explained by psychotic symptoms and WLM. Of the variance in HAM-D, 58.9% was explained by the regression on excitement, IgA NOX_PRO ratio, WLM, and VFT; 29.9% of the variance in HAM-A by psychotic symptoms and IgA NOX/PRO; and 45.5% of the variance in FF score by psychotic symptoms, IgA NOX/PRO, and WLM. Neural network modeling shows that PHEM, IgA NOX_PRO, WLM, and MMSE are the dominant variables predicting DAPS. DAPS appear to be driven by PHEM and negative symptoms coupled with impairments in episodic memory, especially false memory creation, while all symptom dimension and cognitive impairments may be driven by an increased production of noxious TRYCATs, including picolinic, quinolinic, and xanthurenic acid.

Aim We aimed to delineate the effects of immunoglobulin (Ig)M-mediated autoimmune responses directed against malondialdehyde (MDA) and nitroso (SNO) adducts on nitro-oxidative stress and depressive and physiosomatic symptoms (DPSS) at the end of term. Methods IgM responses to MDA, NO (nitroso) adducts formed by nitrosylation, and NO2 tyrosine formed by nitration were measured as well as hydroperoxides (ferrous oxidation xylenol orange), advanced protein oxidation products (AOPP), and NO metabolite (NOx) levels in women at the end of term pregnancy and in normal controls. Results IgM responses to MDA were significantly and inversely associated with AOPP, ferrous oxidation xylenol orange, and NOx and DPSS. IgM responses to NO adducts were significantly and inversely associated with DPSS and positively with NOx levels. There were significant associations between IgM responses to MDA, NO adducts, and NO2 tyrosine. The DPSS score was predicted by AOPP and a lifetime history of premenstrual syndrome (both positively) and IgM responses to NO adducts (inversely). Furthermore, 71.8% of the variance in the index of nitro-oxidative stress was explained by lowered IgM responses to MDA, antioxidant levels (zinc, total radical trapping parameter), and inflammatory mediators. Conclusion Lowered levels of IgM responses to MDA during pregnancy are accompanied by a reduced regulation of nitro-oxidative processes thereby explaining increased oxidative and nitrosative stress biomarkers in association with DPSS. IgM responses to NO adducts, which reflect nitrosylation as a consequence of increased NO production, regulate DPSS symptoms at the end of term and are a trait marker of major depression. IgM responses to MDA are a key part of the compensatory anti-inflammatory responses system.

Deficit schizophrenia is characterized by neurocognitive impairments and changes in the patterning of IgA/IgM responses to plasma tryptophan catabolites (TRYCATs). In the current study, supervised pattern recognition methods, including logistic regression analysis (LRA), Support Vector Machine (SVM), and Soft Independent Modeling of Class Analogy (SIMCA), were used to examine whether deficit schizophrenia is a discrete diagnostic class with respect to Consortium To Establish a Registry for Alzheimer’s disease (CERAD) and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests and IgA/IgM responses to noxious (NOX) and generally more protective (PRO) TRYCATs. We recruited patients with (n = 40) and without (n = 40) deficit schizophrenia and healthy volunteers (n = 40). The combined use of TRYCAT and CERAD features strongly segregates deficit from nondeficit schizophrenia and healthy controls. Three out of the top five most important features in LRA, SVM and SIMCA agreed, namely two different NOX/PRO TRYCAT ratios and false memory recall. SIMCA shows that deficit schizophrenia is significantly separated from nondeficit schizophrenia and controls with as top 6 features IgA responses to picolinic acid, IgM responses to 3-OH-kynurenine and kynurenic acid, and impairments in Word List Memory and Verbal Fluency Tests and Mini-Mental State Examination. Nevertheless, nondeficit schizophrenia was not significantly separated from controls. The results show that schizophrenia is not a unitary disease with mere continuous differences in severity of illness between apparent subtypes. Deficit schizophrenia is a qualitatively distinct class defined by neuroimmune (autoimmune responses to TRYCATs) and neurocognitive (episodic and semantic memory) features coupled or not with clinical (negative) symptoms.

Background Evidence has implicated the translocation of commensal Gram-negative bacteria (Gram-B) due to leaky gut in the pathophysiology of depression and physio-somatic symptoms (e.g. fatigue, pain, irritable bowel syndrome, malaise, etc.). In addition, the leaky gut may contribute to immune- inflammatory activation and oxidative stress. This study investigated whether bacterial translocation is associated with perinatal depression and anxiety scores and with prenatal physio-somatic symptoms and immune-inflammatory biomarkers, including the tryptophan catabolite (TRYCAT) pathway. Method Data were collected in pregnant women at the end of term (T1) and 4-6 weeks after delivery (T2) as well as in non-pregnant controls. We examined the associations between serum IgM/IgA responses to Gram-B at the end of term and depression (Edinburgh Postnatal Depression Scale -EPDS) and anxiety (Spielberger's State Anxiety Inventory -STAI) symptoms. Results Levels of C-reactive protein, zinc, haptoglobin, hematocrit and IgA/IgM responses to 9 TRYCATs were also measured. No significant associations of the IgA/IgM responses to Gram-B with prenatal depression and anxiety were observed. Increased IgA/IgM responses to Gram-B predict higher levels of haptoglobin, hematocrit and TRYCATs, in particular quinolinic acid and the quinolinic acid / kynurenic acid ratio. IgA responses to Gram-B were significantly lowered in pregnant women compared to age-matched non-pregnant women, while IgM responses were significantly elevated in participants with alcohol consumption. Physio-somatic symptoms at the end of term were significantly associated with IgM responses to Klebsiella pneumonia. Postnatal anxiety was significantly predicted by IgA responses to Pseudomonas aeruginosa. Conclusions Our findings suggest that pregnancy may protect against bacterial translocation, while alcohol use may increase bacterial translocation. The results suggest that end of term mucosa-derived immune responses to Gram-B contribute to immune activation, physio-somatic symptoms at the end of term and postnatal anxiety. Highlights • Immune responses to Gram - Bacteria associate with physio-somatic symptoms in pregnancy. • IgA responses to Pseudomonas aeruginosa predict anxiety symptoms after delivery. • Pregnancy may have a protective effect against bacterial translocation. • Alcohol use increases leaky gut and bacterial translocation.

In a single transient middle cerebral artery occlusion model of stroke and using immunohistochemical techniques, the effects of a new therapeutic approach named Gemst (a member of the Poly-L-Lysine innovative therapies) have been studied in the rat brain. The expression of inflammatory (CD45, CD11b), oxidative (NO-tryptophan, NO2-tyrosine) and indoleamine 2, 3-dioxygenase pathway (kynurenic acid, 3-hydroxy anthranilic acid) markers has been evaluated in early and late phases of stroke. For this purpose, we have developed eight highly specific monoclonal antibodies directed against some of these markers. In the early phase (3 and 5 days of the stroke, we observed no effect of Gemst treatment (7.5 mg/day, subcutaneously for 3, 5 days). In the late phase (21 days) of stroke and exclusively in the ipsilateral side of non-treated animals an overexpression of kynurenic acid, 3-hydroxy anthranilic acid, CD45, CD11b, GFAP and ionized calcium-binding adapter molecule 1 (IBA-1) was found. In treated animals, the overexpression of the four former markers was completely abolished whereas the overexpression of the two latter ones was decreased down to normal levels. Gemst reversed the pathological conditions of stroke to normal situations. Gemst exerts a multifunctional action: down-regulates the indoleamine 2, 3-dioxygenase pathway and abolishes brain infiltration, microglial activation and gliosis. Moreover, Gemst has no effect on the expression of doublecortin, a protein involved in neuronal migration. Gemst could be a new drug for the treatment of stroke since it reverses the pathological findings of stroke and normalizes brain tissue conditions following the ischemic insult.

Evidence indicates that schizophrenia and in particular negative symptoms and deficit schizophrenia are accompanied by neurocognitive impairments and changes in the patterning of the tryptophan catabolite (TRYCAT) pathway. This cross-sectional study was carried out to examine the associations between cognitive functions (as measured with Consortium to Establish a Registry for Alzheimer’s disease (CERAD)) and TRYCAT pathway patterning in patients with (n = 40) and without (n = 40) deficit schizophrenia and normal controls (n = 40). Cognitive measures were assessed with the Verbal Fluency Test (VFT), Boston Naming Test (BNT), Mini-Mental State Examination (MMSE), Word List Memory (WLM), Constructional Praxis, Word List Recall (WLRecall), and Word List Recognition (WLRecognition), while TRYCAT measurements assessed the IgA/IgM responses to noxious TRYCATs, namely quinolinic acid (QA), 3-OH-kynurenine (3HK), picolinic acid (PA), and xanthurenic (XA) acid, and more protective (PRO) TRYCATs, including kynurenic acid (KA) and anthranilic acid (AA). IgA NOX/PRO, IgM KA/3HK, and IgA/IgM NOX/PRO ratios were computed. Schizophrenia was accompanied by lower VFT and WLM, while BNT (dysnomia) and MMSE are significantly lower in multiple- than first-episode schizophrenia. Deficit schizophrenia is strongly associated with worse outcomes on VFT, MMSE, WLM, WLRecall, WLRecognition, and delayed recall savings and increased false memories. Around 40–50% of the variance in negative symptoms’ scores was explained by VFT, WLM, WLRecall, and MMSE. Increases in IgA NOX/PRO, IgM KA/3HK, and/or IgA/IgM NOX/PRO ratios were associated with impairments in VFT, BNT, MMSE, WLM, WLRecall, WLRecognition, and false-memory creation. In conclusion, nondeficit schizophrenia is accompanied by mild memory impairments, while disease progression is accompanied by broader cognitive impairments. Deficit schizophrenia and negative symptoms are strongly associated with deficits in working memory, delayed recall and recognition, and increased false-memory creation. These cognitive impairments and memory deficits are in part explained by increased production and/or attenuated regulation of TRYCATs with neurotoxic, excitotoxic, immune-inflammatory, oxidative, and nitrosative potential, which may contribute to neuroprogression.

Objectives: Chronic experimental autoimmune encephalomyelitis (EAE) was induced in rats to evaluate the potential protective effect of GEMSP, a mixture made up of fatty acids (FA), vitamins, and amino acids or their derivatives, linked to Poly-L-Lysine, on the myelin sheath of the optic nerve. Methods: To evaluate the effects of GEMSP on the optic nerve, animals were divided into three experimental groups: (1) EAE rats treated with GEMSP; (2) EAE rats treated with 0.9% NaCl; and (3) control, non-EAE rats. Using electron microscopy, we investigated the possibility that this new drug candidate has a myelin-protective role. Results: A marginally significant reduction in the thickness of the myelin around optic nerve medium-size axons (diameter between 0.8–1.3 mm) was found in EAE rats. Treatment of EAE rats with GEMSP ameliorated myelin damage. Significantly increased myelin thickness was found when animals in groups 2 and 3 were compared. However, the number of myelinated axons studied was not altered in groups 1 or 2 when compared to controls. Discussion: Our results suggest that in a model of demyelination, GEMSP protects and enhances the formation of the myelin sheath of the optic nerve and therefore could be a potential drug candidate to reduce optic nerve pathogenesis in multiple sclerosis (MS).

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale).The incidence of positive autoimmune activity against 5-HT was significantly higher (p0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.

Objective There is evidence that major depression is characterized by oxidative and nitrosative stress (O&NS). The aim of this study is to examine IgM-mediated autoimmune responses against a variety of modified neo-epitopes formed by O&NS damage to self-epitopes in chronic depression. Methods Serum IgM antibodies directed against conjugated oleic and azelaic acid, malondialdehyde (MDA), phosphatidyl inositol (Pi), and conjugated nitric-oxide (NO) adducts, i.e., NO-tryptophan, NO-tyrosine, NO-arginine, and NO-cysteinyl, were determined in 33 healthy controls and 74 depressed patients subdivided into 28 patients with chronic (duration >2 year) and 46 without chronic depression. Results Serum IgM levels against all neoepitopes were significantly higher in depressed patients than in healthy controls. Moreover, the IgM levels were significantly higher, except Pi, in chronically depressed patients than in non-chronically depressed patients. Conclusions Depression is characterized by IgM-related autoimmune responses directed against neo-epitopes that are normally hidden from the immune system but that became immunogenic secondary to damage by O&NS. The results show that the generation of neoantigenic determinants that lead to (auto)immune responses is strongly associated with chronic depression. Discussion The damage caused by O&NS to auto-epitopes and the consequent formation of O&NS modified neoantigenic determinants may increase the risk to develop depression and in particular chronic depression through transition to autoimmune reactions. This has implications for understanding the immuno-inflammatory and oxidative-autoimmune pathways that lead to chronic depression and neuroprogression in that illness.

Using an immunohistochemical technique, we have studied the distribution of 3-OH-anthranilic acid (3-HAA) in the rat brain. Our study was carried out in control animals and in rats in which a stroke model (single transient middle cerebral artery occlusion) was performed. A monoclonal antibody directed against 3-HAA was also developed. 3-HAA was exclusively observed in the infarcted regions (ipsilateral striatum/cerebral cortex), 2, 5 and 21 days after the induction of stroke. In control rats and in the contralateral side of the stroke animals, no immunoreactivity for 3-HAA was visualized. Under pathological conditions (from early phases of stroke), we reported for the first time the presence of 3-HAA in the mammalian brain. By double immunohistochemistry, the coexistence of 3-HAA and GFAP was observed in astrocytes. The distribution of 3-HAA matched perfectly with the infarcted regions. Our findings suggest that, in stroke, 3-HAA could be involved in the tissue damage observed in the infarcted regions, since it is well known that 3-HAA exerts cytotoxic effects.

Endotherapia (GEMSP) is a novel therapeutic approach for multiple sclerosis (MS). The aim of the present study was to demonstrate the efficiency of Endotherapia in the follow-up of 193 patients with MS. The efficiency coefficient that was evaluated was the Expanded Disability Status Scale (EDSS) score, which is a functional scale of MS progression. The evaluated score of each patient during follow-up visits was compared with the theoretical score of the disease progression without GEMSP. The evolution of the EDSS score was evaluated according to the inclusion score. The quantitative global study of the EDSS score highlighted a statistically significant difference between the final average scores of the treatment with GEMSP (M) and worldwide reference (R) groups. The improvement of the M group compared with the R group was 24.5%. According to the final EDSS scores, the study highlighted a difference in favor of the M group with 62.0% for scores ≤3, 7.8% for scores between 3 and 6 and 19.6% for scores ≥6. According to the qualitative evolution of the EDSS scores, the improvements in favor of group M were 49.3% for scores ≤3, 79.1% for scores between 3 and 6 and 19.5% for scores ≥6. The qualitative study of the EDSS score showed a statistically significant success percentage; the success percentages were between 59.1 and 90.0%. In a larger population of MS patients, the data confirm the beneficial effects of GEMSP that were previously reported in pre-clinical and clinical studies. In addition, 78% of patients showed an improvement or deceleration of the disease.

A highly specific monoclonal antibody directed against nitric oxide-tryptophan (NO-W) with good affinity (10-9 M) and specificity was developed. In the rat brain, using an indirect immunoperoxidase technique, cell bodies containing NO-W were exclusively found in the intermediate and dorsal parts of the lateral septal nucleus. No immunoreactive fibres were found in the rat brain. This work reports the first visualization and the morphological characteristics of cell bodies containing NO-W in the mammalian brain. The restricted distribution of NO-W in the rat brain suggests that this molecule could be involved in specific physiological mechanisms.

It is known that kynurenic acid (KYNA) exerts a neuroprotective effect against the neuronal loss induced by ischemia; acting as a scavenger, and exerting antioxidant action. In order to study the distribution of KYNA, a highly specific monoclonal antibody directed against KYNA was developed. This distribution was studied in control rats and in animals in which a middle cerebral artery occlusion (stroke model) was induced. By double immunohistochemistry, astrocytes containing KYNA and GFAP were exclusively found in the ipsilateral cerebral cortex and/or striatum, at 2, 5 and 21days after the induction of stroke. In control animals and in the contralateral side of the stroke animals, no immunoreactivity for KYNA was found. Under pathological conditions, the presence of KYNA is reported for the first time in the mammalian brain from early phases of stroke. The distribution of KYNA matches perfectly with the infarcted regions suggesting that, in stroke, this overexpressed molecule could be involved in neuroprotective/scavenger/antioxidant mechanisms.

OBJECTIVE: Depression is accompanied by activation of immuno-inflammatory and oxidative and nitrosative stress (IO&NS) pathways, and increased IgM/IgA responses to lipopolysaccharide (LPS) of gram-negative commensal bacteria. The latter suggests that bacterial translocation has caused IgM/IgA responses directed against LPS. Bacterial translocation may drive IO&NS responses. METHOD: To examine the associations between IgM/IgA responses to LPS and IO&NS measurements, including plasma/serum interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin, lysozyme, oxidized LDL (oxLDL) antibodies, peroxides, and IgM (auto)immune responses against malondialdehyde (MDA), azelaic acid, phophatidyl inositol (Pi), NO-tryptophan and NO-tyrosine in depressed patients and controls. RESULTS: We found significant positive associations between IgM/IgA responses to LPS and oxLDL antibodies, IgM responses against MDA, azelaic acid, Pi, NO-tryptophan, and NO-tyrosine. The IgA responses to LPS were correlated with lysozyme. There were no significant positive correlations between the IgM/IgA responses to LPS and IL-1 and neopterin. CONCLUSION: The findings show that in depression there is an association between increased bacterial translocation and lysozyme production, an antibacterial compound, O&NS processes, and autoimmune responses directed against O&NS generated neoantigenic determinants. It is suggested that bacterial translocation may drive IO&NS pathways in depression and thus play a role in its pathophysiology.

PURPOSE OF REVIEW: Multiple sclerosis (MS) is an autoimmune and inflammatory disease of the central nervous system (CNS) that causes neurological disability in young adults and that to date has no cure. Until now, expensive and only partially efficacious therapies have become available. For this reason, researchers, clinicians and pharmaceutical companies are currently investigating new drugs for the treatment of MS. Here, we review the most recent data on drug candidates for MS. RECENT FINDINGS: In the preclinical phase, such drug candidates have shown a beneficial effect on the onset of experimental autoimmune encephalomyelitis (microtubule-stabilizing drugs, MS14, Lithium, GEMSP...), a decrease in CNS cell infiltrates (recombinant T cell receptor ligand, lovastatin-rolipram, ribavirin, GEMSP...), prevention of demyelination (lovastatin-rolipram, calpain inhibitor, lithium...); and a reduction of axonal loss (phenytoin, lovastatin-rolipram, calpain inhibitor). In clinical trials, drug candidates against MS have shown safety (rituximab, ustekinumab, intravenous immunoglobulin, laquinimod, BHT-3009, fumarate, chaperonin 10, GEMSP...), an improvement of gadolinium-enhanced lesions (protiramer, fingolimod, laquinimod, BHT-3009, fumarate, daclizumab...), and an improvement of the relapse rate (fingolimod, fumarate...). SUMMARY: Future research into MS should focus on a combination of therapies and on the development of drugs directed against the remitting and progressive phases of the disease. In this sense, MS is a very complex multifactorial disease that requires treatment able to cover all the aspects of MS and not only the anti-inflammatory aspect.

Using highly specific antisera directed against vitamins, the distribution of pyridoxal-, pyridoxine-, vitamin C- and nicotinamide-immunoreactive structures in the monkey (Macaca fascicularis) brain was studied. Neither immunoreactive structures containing pyridoxine or nicotinamide, nor immunoreactive fibers containing vitamin C were found in the monkey brain. However, this work reports the first visualization and the morphological characteristics of pyridoxal- and vitamin C-immunoreactive cell bodies in the mammalian central nervous system using an indirect immunoperoxidase technique. A high density of pyridoxal-immunoreactive cell bodies was found in the paraventricular hypothalamic nucleus and in the supraoptic nucleus and a low density of the same was observed in the periventricular hypothalamic region, whereas a moderate density of vitamin C-immunoreactive cell bodies was observed in the somatosensorial cortex (precentral gyrus). Immunoreactive fibers containing pyridoxal were only visualized in the anterior commissure. The restricted distribution of pyridoxal and vitamin C in the monkey brain suggests that both vitamins could be involved in very specific physiological mechanisms.

GEMSP is a mixture of functional polypeptides: fatty acids linked to poly-L-Lysine (PL), antioxidants linked to PL, free radical scavengers linked to PL, and amino acids linked to PL (patent numbers 6114388 (USA) and 792167 (EU)). In this review, we update the data on this new drug reported in the literature. There is evidence suggesting that GEMSP is a good candidate for the treatment of multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system characterized by focal leukocyte inflammation, demyelization and axonal degeneration, resulting in nerve cell dysfunction. Experimental autoimmune encephalomyelitis (EAE) is the main animal model used in the study of MS, a T cell-mediated autoimmune disease of the central nervous system. EAE has many clinical and histopathological similarities to MS. In this model, preclinical studies on GEMSP have demonstrated that the drug strongly inhibits brain leukocyte infiltration and completely abolishes EAE episodes and clinical scores, and it also appears that GEMSP preserves myelin integrity. In general, treatment with the free constituents of GEMSP (not linked to the inert carrier protein) is poorly active against brain leukocyte infiltration in EAE-immunized animals. This means that free molecules (not linked to PL) exert a very poor action on such infiltration and that these molecules are either rapidly incorporated into the metabolism or are degraded. Moreover, with immunocytochemical techniques, it has been demonstrated that one component of GEMSP, the methionine compound, is stored inside the motoneurons of the ventral horn of the spinal cord. However, this component of GEMSP has not been found in the brain. The new candidate for MS therapy has shown no toxicity either in experimental animals or in humans. An open clinical trial in humans has demonstrated that GEMSP is completely safe. In addition, the approved drugs for the treatment of MS exert marked side effects, but no side effects have been reported following the administration of GEMSP. The results obtained at six months of treatment with low doses of GEMSP (0.75 mg/day) in that open clinical trial in humans were as follows: 55% of the patients maintained a stable expanded disability status scale (EDSS) value and 18% of the patients had a decreased EDSS value instead of a normal progression of 0.25 point on the mean EDSS scale. We focus our review on the following topics: 1) EAE models and clinical evaluation; 2) the synthesis of GEMSP; 3) the effects of GEMSP dosage on EAE; 4) the effects of GEMSP on brain leukocyte infiltration; 5) GEMSP inside motoneurons; 6) the role of the components of GEMSP; and 7) GEMSP in MS patients, GEMSP toxicity, and side effects. In conclusion, all the data reported indicate that GEMSP is a new potential drug candidate for the treatment of MS.

Amyotrophic lateral sclerosis (ALS) is a fatal disease involving selective and progressive degeneration and death of motor neurons. ALS is a multifactorial disease in which oxidative stress, glutamate excitotoxicity, intracellular aggregates, neurofilamentous disorganization, zinc excitotoxicity, mitochondrial damage, neuroinflammation, abnormalities in growth factors and apoptosis play a role. Any therapeutic approach to delay or stop the evolution of ALS should therefore ideally target these multiple pathways leading to motor neuron death. We have developed a combination therapy (Gemals) composed of functional polypeptides (fatty acids, free radical scavengers and amino acids linked to poly-L-lysine), chosen according to their known potentiality for regeneration or protection of neuronal components such as myelin, axon transport and mitochondria. We found that Gemals significantly extended lifespan and improved electromyographic parameters in a SOD1(G93A) rat model. The use of two drug concentrations indicated a possible dose dependence. These initial findings open the way to further investigation necessary to validate this new drug as a candidate for ALS treatment.

NO and ONOO- are involved in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer disease, and multiple sclerosis. The direct quantification of these radical species in vivo is not relevant because not technically reliable. To overcome these difficulties, the identification of circulating antibodies directed against NO- and NO2-modified self antigens, indirectly visualized the NO and ONOO- overproduction. The present report firstly describes that immunoglobulins of G, M and A isotypes recognized a pattern of NO-modified self antigens and NO2-tyrosine for each pathology. In Alzheimer disease and secondary progressive multiple sclerosis, immunoglobulins of A isotype were found. Conversely, in remitting relapsing form of multiple sclerosis, immunoglobulins of M isotype were increased. In amyotrophic lateral sclerosis, G, M, A isotypes were found. These data opens news perspectives for the follow up of these neurodegenerative diseases.

International audience; The present study examined dopamine-immunoreactive neuronal structures using immunohistochemistry in conjunction with an anti-dopamine antiserum, following injection of l-3,4-dihydroxyphenylalanine (L-DOPA) with or without an inhibitor of monoamine oxidase (Pargyline) in the cat brain. L-DOPA injection made it possible to detect dopamine immunoreactivity in presumptive serotonergic and noradrenergic cell bodies and axons. Weak to moderate dopamine immunoreactivity was observed in non-aminergic cells (possibly so-called "D" cells containing aromatic L-amino acid decarboxylase (AADC)) in several hypothalamic, midbrain, pontine and medullary nuclei. Intense dopamine immunoreactivity became visible in a large number of cells and axons (possibly containing AADC) with wide distribution in the brain following administration of L-DOPA with Pargyline. AADC is most likely active in cells and axons that take up L-DOPA, where it decarboxylates the L-DOPA to dopamine. However, newly synthesized dopamine in such cells is rapidly oxidized by monoamine oxidase.

We have previously demonstrated that in endothelium-denuded arteries, S-nitrosation of cysteine residues is a mechanism of formation of releasable nitric oxide (NO) stores, accounting for the long-lasting relaxation induced by S-nitrosating agents like S-nitrosoglutathione (GSNO). Here, we have investigated whether such effects could also be obtained in arteries exhibiting oxidative stress-associated endothelial dysfunction. Rats were implanted or not with a minipump delivering saline or angiotensin II for 14 days. As expected, aorta from angiotensin II-infused rats exhibited increased level of superoxide anions (as evaluated with dihydroethidine as fluorescent probe) and a reduced relaxation to acetylcholine in comparison to saline group. Unlike aortic rings with endothelium from controls, those from angiotensin II-infused rats exhibited persistent hyporesponsiveness to phenylephrine after pre-exposure to GSNO, as well as relaxation upon addition of N-acetylcysteine (NAC, which can displace NO from cysteine–NO residues) or HgCl2 (which cleaves S–NO bonds). In aorta from angiotensin II-infused rats, GSNO also induced a persistent increase in cysteine–NO residues (as determined using anti-cysteine–NO antiserum), which was blunted by NAC and HgCl2. These data indicate that (i) the vasorelaxant influence of releasable NO stores is unmasked by endothelial dysfunction (ii) S-nitrosation of cysteine residues remains an effective mechanism of formation of releasable NO stores in arteries exhibited oxidative stress-associated endothelial dysfunction. Thus, formation of releasable NO stores by S-nitrosating agents allows targeted vasculoprotective effects of NO at sites of endothelial dysfunction.

Vitamin C (Vit C) is an important antioxidant, exerts powerful neuroprotective brain effects and plays a role in neuronal development and maturation. Vit C is present in brain tissue at higher concentrations than in other organs, but its detailed distribution in brain is unknown. Immunohistochemical detection of this vitamin has been performed by using a highly specific antibody against Vit C. The aim of the present work was to analyze the distribution of Vit C in children's brainstems during postnatal development, comparing two groups of ages: younger and older than one year of life. In general, the same areas showing neurons with Vit C in young cases are also immunostained at older ages. The distribution of neurons containing Vit C was broader in the brainstems of older children, suggesting that brainstem neurons maintain or even increase their ability to retain Vit C along the life span. Immunohistochemical labeling revealed only cell bodies containing this vitamin, and no immunoreactive fibers were observed. The distribution pattern of Vit C in children's brainstems suggests a possible role of Vit C in brain homeostatic regulation. In addition, the constant presence of Vit C in neurons of locus coeruleus supports the important role of Vit C in noradrenaline synthesis, which seemed to be maintained along postnatal development.

International audience; The distribution of thiamine-immunoreactive structures was studied in the brain of the monkey using an indirect immunoperoxidase technique. Fibers containing thiamine, but no thiamine-immunoreactive cell bodies, were found. The highest density of fibers containing thiamine was observed in the pulvinar nucleus and in the region extending from the pulvinar nucleus to the caudate nucleus. In the mesencephalon, immunoreactive fibers containing thiamine were only found at rostral level close to the medial lemniscus (at the mesencephalic–diencephalic junction). In the thalamus, the distribution of thiamine-immunoreactive structures was more widespread. Thus, immunoreactive fibers were found in nuclei close to the midline (centrum medianum/parafascicular complex), in the ventrolateral thalamus (medial geniculate nucleus, inferior pulvinar nucleus), and in the dorsolateral thalamus (lateral posterior nucleus, pulvinar nucleus). Finally, in the anterior commissure and in the cerebral cortex a low density immunoreactive fibers was visualized. Thus, in the brainstem, no immunoreactive structures were visualized in the medulla oblongata, pons, or in the medial–caudal mesencephalon, and no immunoreactive fibers were observed in the cerebellum, hypothalamus and in the basal ganglia. The present report describes the first visualization and the morphological characteristics (thick, smooth and short, medium or long in length) of the thiamine-immunoreactive fibers in the primate central nervous system using an antiserum directed against this vitamin. The distribution of thiamine-immunoreactive structures in the monkey brain suggests that this vitamin could be involved in several physiological mechanisms.

Immunoreactivity to p-tyramine, one of the natural trace amines, was studied in the rat brain by an anti-p-tyramine antibody. Immunoreactivity to this amine is very weak in the nigrostriatal dopaminergic neurons and terminals, and weak in the locus coeruleus noradrenergic ones. It was intensified in these structures after monoamine oxidase inhibition. On the other hand, this amine was highly concentrated in the median eminence of the mediobasal hypothalamus, in which its physiological function on prolactin release has been demonstrated.

Nitric oxide (NO) has been implicated as an important pathogenic mediator in several inflammatory and autoimmune diseases. We have developed experimental autoimmune encephalomyelitis (EAE) and adjuvant-induced arthritis in the Lewis rat as experimental models for multiple sclerosis, and rheumatoid arthritis, respectively, in order to investigate the role of NO in the inflammatory process. We have used the monoclonal antibody anti-NO-cysteine (Cys)-G-bovine serum albumin (BSA) developed in our laboratory as an inhibitor of the toxic effect of NO to determine the implication of NO in the creation of neoepitopes and therefore in the symptomatology of these two diseases. In addition, we have detected a significant level of circulating endogenous antibodies directed against nitrosylated and nitrated epitopes in the sera of preimmunized rats. Our data demonstrate the ability of the monoclonal anti-NO-Cys-G-BSA antibody to modulate these diseases through NO neutralization, and further provide evidence for the in vivo synthesis of nitrosylated and nitrated neoepitopes that are stable enough to be highly immunogenic, thereby inducing inflammatory injuries and a humoral immune response. Our findings provide further evidence for the implication of the NO pathway in the pathogenesis of EAE and adjuvant-induced arthritis. summary

Resume Des anticorps circulants diriges contre de nombreuses cibles ont deja ete decrits dans la sclerose en plaques (SEP). A l'aide de tests Elisa, nous avons trouve des anticorps diriges contre : (i) des antigenes bacteriens : Pseudomonas aeruginosa et putida, Hafnia alvei, Proteus mirabilis, Morganella morganii, Citrobacter koserii et Klebsiella pneumoniae ; (ii) des petites molecules conjuguees : acides gras, acide azelaique, farnesyl-cysteine, residu malondialdehyde, NO-cysteine, NO-tyrosine, NO 2 -tyrosine, NO-tryptophane, NO-methionine, NO-histidine, NO-asparagine, NO-arginine, NO-phenylalanine et NO-serum albumine bovine. Pour les formes remittentes de la maladie, les titres en anticorps circulants d'isotypie M augmentent lors des poussees et diminuent pendant les phases de remission. Dans les formes secondairement progressives, des titres eleves en anticorps sont egalement trouves, mais la majorite de ces immunoglobulines sont d'isotypie A. Dans ce cadre, les cibles reconnues par ces anticorps sont des antigenes bacteriens. Des prelevements successifs effectues sur plusieurs dizaines de patients et sur plusieurs annees nous ont permis d'etablir des profils immunologiques evoluant avec le stade et la forme de la maladie. Nous avons egalement montre que le passage dans les formes secondairement progressives est visualise par des profils dans lesquels les reponses sont a la fois d'isotypie M et A (seulement pour les antigenes bacteriens). Cette approche methodologique constitue un modele encourageant pour le suivi biologique de la SEP en fonction du stade evolutif de la maladie.

Resume Cette etude porte sur l’evaluation d’anticorps presents dans le serum d’une population de 42 patientes ayant un cancer du sein dont le diagnostic a ete etabli il y a moins de 6 mois. Les echantillons ont ete testes sur plus de 30 antigenes a l’aide de tests immuno-enzymatiques. Plus de 80 % des malades ont des titres eleves, voire tres eleves en antiphosphatidylinositol (PtdIns) d’isotypie G. Ce resultat confirme nos donnees deja publiees sur des patients porteurs de tumeurs malignes. Nous avons egalement trouve des titres tres eleves en anticorps d’isotypie A diriges contre des preparations membranaires d’enterobacteries. Les parametres cliniques et histologiques ont ete mis en relation avec les titres des differents anticorps. On ne trouve pas de relation significative entre la taille tumorale, la presence ou non de ganglions, le type histologique et les titres en anti-PtdIns d’isotypie G. Quel que soit la valeur de ces parametres, les anti-PtdIns sont toujours eleves. En revanche, les anticorps anti-residu malondialdehyde, anti-NO-cysteine, anti-NO-phenylalanine, anti-NO-creatine, anti-NO-histidine d’isotypie M sont statistiquement inferieurs aux titres des controles, pour les patientes ayant des tumeurs T2. Les titres en anticorps diriges contre les preparations membranaires de Klebsiella pneumoniae et Morganella morganii sont statistiquement plus eleves lorsque la tumeur est un carcinome infiltrant canalaire peu differencie par rapport au meme type histologique plus differencie. Cette etude ouvre des perspectives nouvelles pour le suivi biologique dans le cancer du sein.

The ability of various nitric oxide (NO) donors to induce long-lasting inhibition of contraction in isolated arteries was compared. All the studied compounds elicited a relaxant effect in rat aortic rings precontracted with norepinephrine (NE). Almost maximal relaxation was obtained with 1 μM of each compound. The S -nitrosating agents S- nitrosoglutathione (GSNO), S -nitroso- N -acetylpenicillamine, S -nitroso- N -acetylcysteine, and sodium nitroprusside (1 μM) produced a decrease of the maximal effect of NE that persisted after removal of the drug. This hyporesponsiveness to NE was associated with a relaxant effect of N- acetylcysteine, a low-molecular weight thiol that can displace NO from cysteine-NO bonds. Such modifications of contraction were not observed in aortic rings previously exposed to 1 μM S- nitrosocysteine, glyceryl trinitrate, 3-morpholinosydnonimine, or 2-( N , N -diethylamino)-diazenolate-2-oxide (DEA-NO). The same differential effects of GSNO and DEA-NO on contraction were also observed in porcine coronary arteries. Rat aortic rings previously exposed to 100 μM GSNO, but not to 100 μM DEA-NO, displayed a persistent increase in NO content (determined by NO spin trapping) and cysteine-NO residues (determined by immunostaining with an anti-cysteine-NO antiserum). The GSNO-induced increase in cysteine-NO residues in aortic tissue was prevented by the thiolmodifying agent p -hydroxymercuribenzoic acid. This study shows that in isolated arteries, the effects of S- nitrosating agents differed from those of other NO-donating agents. S- Nitrosating agents induced a persistent inhibition of contraction, which was attributed to the formation of releasable NO stores by S- nitrosation of tissue thiols. These differential effects of NO donors may be important for orientating their therapeutic indications.

S-Nitrosation of cysteine residues plays an important role in nitric oxide (NO) signaling and transport. The aim of the present study was to investigate the role of S-nitrosothiols as a storage form of NO, which may account for the long-lasting effects in the vasculature. Rat aorta exposed to S-nitrosoglutathione (GSNO) displayed, even after washout of the drug, a persistent increase in cysteine-NO residues (detected by immunostaining using an antiserum that selectively recognized S-nitrosoproteins) and in NO content (detected by NO spin-trapping), a persistent attenuation of the effect of vasoconstrictors, and a relaxant response upon addition of low molecular weight (LMW) thiols. Rat mesenteric and porcine coronary artery exposed in vitro to GSNO, as well as aorta and mesenteric arteries removed from rats treated in vivo with GSNO, displayed similar modifications of contraction. In isolated aorta exposed to GSNO, the decrease of the contractile response and the relaxant effect of LMW thiols were both blunted by NO scavengers (oxyhemoglobin or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) or by a cyclic GMP-dependent protein kinase inhibitor (Rp-8-bromoguanosine-3',5'-cyclic monophosphorothioate). In these arteries, mercuric chloride (which cleaves the cysteine-NO bond) exerted a transient relaxation, completely abolished the one of LMW thiols, and blunted the increase in cysteine-NO residues and NO content. Together, these data support the idea that S-nitrosation of cysteine residues is involved in long-lasting effects of NO on arterial tone. They suggest that S-nitrosation of tissue thiols is a mechanism of formation of local NO stores from which biologically active NO can subsequently be released.

Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness. © 2014 Macmillan Publishers Limited. All rights reserved.

The development of multiple antibiotic resistance is a global problem. It is necessary to find new tools whose mechanisms of action differ from those of currently used antibiotics. It is known that fatty acids and cationic polypeptides are able to fight bacteria. Here, we describe the synthesis of fatty acids linked to a polypeptide with antibacterial activity. The linkage of fatty acids to a polypeptide is reported to increase the antibacterial effect of the linked fatty acid in comparison with free fatty acids (FA) or free poly-L-lysine (PLL) or a mixture of both (FA free + PLL free). A number of C6–C18 fatty acids were linked to PLL to obtain new synthetic products. These compounds were assessed in vitro to evaluate their antibacterial activity. Some fatty acid-PLLs showed a good ability to fight bacteria. Their bactericidal activity was evaluated, and, lauryl linked to PLL was found to be the most active product against both Gram-positive and Gram-negative bacteria. This new active component showed a good degree of specificity and reproducibility and its minimum inhibitory concentration (MIC) was comparatively good. The antibacterial activity of the lauryl-PLL compound suggests that it is a new and promising antimicrobial agent.

Inhaled nitric oxide (INO) therapy is currently used clinically to selectively dilate the pulmonary vasculature and to help treat persistent pulmonary hypertension and bronchopulmonary dysplasia in the neonate. However, in the presence of oxygen or superoxide, nitric oxide forms potentially harmful reactive nitrogen species. Using an experimental mice model, we examined the effects of concurrent hyperoxia and INO on protein tyrosine nitration and cysteine S-nitrosylation in pulmonary tissue. Data showed enhanced 3-nitrotyrosine staining within the airway epithelium and alveolar interstitium of mice lungs treated with hyperoxia, which did not increase significantly with INO administration. Within the alveolar interstitium, 3-nitrotyrosine staining was localized to macrophages. S-Nitrosocysteine staining in airway epithelium was significantly enhanced with INO administration regardless of oxygen content. These data suggest that the formation of protein S-nitrosocysteine is the major protein modification during administration of INO.

We examined by immunohistochemistry the effects of monoamine oxidase (MAO) inhibition on the content of dopamine (DA) and noradrenaline (NA) in locus coeruleus (LC) neurons of the rat. In normal rats, clusters of DA- and NA-immunopositive neurons were identified in the LC. Rats treated with intraperitoneal injections of pargyline, an MAO inhibitor, showed significantly stronger DA- and NA-staining intensities in LC neurons compared to normal rats. In LC noradrenergic neurons, it is believed that DA is formed in the cytoplasm and then transported into the storage vesicles where it is converted to NA, and the secreted NA is recycled by a reuptake mechanism and transported back into storage vesicles via the cytoplasm. Furthermore, LC neurons of the rat have been shown to contain DA- and NA-degrading MAO activities on the outer membranes of the mitochondria. Therefore, our findings suggest that endogenous MAO degrades not only part of the DA formed in the cytoplasm of LC neurons, but also part of the secreted NA that has been transported back into the cytoplasm.