ARTICLE | doi:10.20944/preprints201902.0182.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: schizophrenia; inflammation; neuro-immune; oxidative stress; TRYCATs; leaky gut
Online: 19 February 2019 (12:14:29 CET)
Deficit schizophrenia is characterized by leaky tight and adherens junctions and bacterial translocation. Here we examine whether (deficit) schizophrenia is accompanied by leaky paracellular, transcellular and vascular barriers in the gut and blood brain barriers. We measured IgA responses to occludin, claudin-5, E-cadherin and β-catenin (paracellular pathway, PARA), talin, actin, vinculin and epithelial intermediate filament (transcellular pathway, TRANS) and plasmalemma vesicle-associated protein (PLVAP, vascular pathway) in 78 schizophrenia patients and 40 controls. IgA responses to claudin-5, E-cadherin and β-catenin, the sum of the four PARA proteins and the ratio PARA/TRANS were significantly higher in deficit schizophrenia than in non-deficit schizophrenia and controls. A large part of the variance in PHEMN (psychosis, hostility, excitation, mannerism and negative) symptoms, psychomotor retardation, formal thought disorders, verbal fluency, word list memory, word list recall and executive functions was explained by the PARA/TRANS ratio coupled with plasma IgA responses to Gram-negative bacteria, IgM to malondialdehyde, CCL-11 (eotaxin), IgA levels of the ratio of noxious to more protective tryptophan catabolites (NOX/PRO TRYCATs) and a plasma immune activation index. Moreover, IgA levels to Gram-negative bacteria were significantly associated with IgA to E-cadherin, β-catenin and PLVAP, while IgA levels to claudin-5 were significantly predicted by IgA to E-cadherin, NOX/PRO TRYCAT ratio, Gram-negative bacteria and CCL11. The phenomenology of the deficit syndrome is to a large extent explained by the cumulative effects of lowered natural IgM, breakdown of the paracellular and vascular pathways, increased bacterial translocation, peripheral immune-inflammatory responses and indices of BBB breakdown.
ARTICLE | doi:10.20944/preprints201901.0141.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: schizophrenia; leaky gut; neuro-immune; inflammation; oxidative stress; TRYCATs; cytokines
Online: 15 January 2019 (07:17:55 CET)
In 2001, the first author of this paper reported that schizophrenia is associated with an increased frequency of the haptoglobin (Hp)-2 gene. The precursor of Hp-2 is zonulin, a molecule that affects intercellular tight junction integrity. Recently, we reported increased plasma IgA/IgM responses to Gram-negative bacteria in deficit schizophrenia indicating leaky gut and gut dysbiosis. The current study was performed to examine the integrity of the paracellular (tight and adherens junctions) and transcellular (cytoskeletal proteins) pathways in deficit versus non-deficit schizophrenia. We measured IgM responses to zonulin, occludin, E-cadherin, talin, actin and vinculin in association with IgA responses to Gram-negative bacteria, CCL-11, IgA responses to tryptophan catabolites (TRYCATs), immune activation and IgM to malondialdehyde (MDA) and NO-cysteinyl in 78 schizophrenia patients and 40 controls. We found that the ratio of IgM to zonulin + occudin / talin + actin + viculin (PARA/TRANS) was significantly greater in deficit than in non-deficit schizophrenia and higher in schizophrenia than controls and was significantly associated with increased IgA responses to Gram-negative bacteria. IgM responses to zonulin were positively associated with schizophrenia (versus controls), while IgM to occludin was significantly associated with deficit schizophrenia (versus non-deficit schizophrenia and controls). A large part of the variance (90.8%) in negative and PHEM (psychosis, hostility, excitation and mannerism) symptoms was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, IgM to E-cadherin and malondialdehyde (MDA) and memory dysfunctions, while 53.3% of the variance in the latter was explained by PARA/TRANS ratio, IgA to Gram-negative bacteria, CCL-11, TRYCATs and immune activation. The results show an upregulated paracellular pathway with breakdown of the tight and ahherens junctions and increased bacterial translocation in deficit schizophrenia. These dysfunctions in the intestinal paracellular route together with lowered natural IgM, immune activation and production of CCL-11 and TRYCATs contribute to the phenomenology of deficit schizophrenia.
ARTICLE | doi:10.20944/preprints201909.0329.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: premenstrual syndrome; chemokines; inflammation; neuro-immune; depression
Online: 29 September 2019 (06:29:54 CEST)
Objective: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. Results: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms may differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. Discussion: The novel case definition “MCAS” is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis.
ARTICLE | doi:10.20944/preprints201901.0108.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: schizophrenia, inflammation, nitrosative stress, tryptophan catabolites, cytokines, oxidative stress
Online: 11 January 2019 (10:37:50 CET)
BACKGROUND: Stable-phase schizophrenia may comprise two distinct nosological entities namely Major Neuro-Cognitive Psychosis (MNP, largely overlapping with the deficit syndrome) and simple NP (SNP), which are defined by neuroimmune and neurocognitive abnormalities. Furthermore, cognitive impairments and PHEM (psychotic, hostility, excitation, mannerism) and negative symptoms load on the same dimension.METHODS: The current study aimed to investigate associations of psychomotor retardation (PMR) and clinical as well as biomarker characteristics of schizophrenia. We recruited 40 healthy controls and 79 schizophrenia patients and measured IgA responses to tryptophan catabolites (TRYCATs), IgM to malondialdehyde and nitroso (NO)-cysteinyl, macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL-10, CCL-11 as well as PMR items of different rating scales and motor screening task (MOT). RESULTS: PMR differentiated schizophrenia from controls and MNP from SNP. In addition, PMR was strongly associated with executive functions, deficits in episodic and semantic memory, PHEM and negative (PHEMN) symptoms. Around 50% of the variance in PMR was predicted by the cumulative effects of immune activation, CCL-11, TRYCATs and NO-Cysteinyl levels, and lowered natural IgM. PRM may be reliably combined with PHEMN symptoms and memory and executive impairments into one latent vector reflecting overall psychopathology.CONCLUSIONS: Current findings indicate that PMR may be a key psychopathological feature of schizophrenia and mainly MNP. In addition, PMR and associated impairments in memory and executive functions, and PHEMN symptoms may be driven by deficits in the compensatory immune regulatory system (natural IgM) combined with increased production of neurotoxic immune products, namely TRYCATs and IgM to NO-cysteinyl, and an endogenous cognition deteriorating chemokine, namely CCL-11.
ARTICLE | doi:10.20944/preprints201810.0414.v1
Subject: Medicine & Pharmacology, Behavioral Neuroscience Keywords: immune, inflammation, natural IgM, B1 cells, oxidative stress, TRYCATs, schizophrenia, psychosis, psychiatry
Online: 18 October 2018 (10:55:52 CEST)
Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative specific epitopes (OSEs), which are a first line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls.Deficit schizophrenia was characterized by significantly increased IgA responses to Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii and Klebsiella pneumoniae as compared with non-deficit schizophrenia. The presence of deficit schizophrenia was highly predicted by increased IgA responses to Pseudomonas putida and IgM responses to all 5 Gram-negative bacteria and lowered natural IgM to MDA and azelaic acid with a bootstrap area under the ROC curve of 0.960 (2000 random curves). A large proportion of the variance (41.5%) in the PANSS negative score was explained by the regression on IgA responses to K. pneumoniae and IgM responses to the 5 enterobacteria coupled with lowered IgM antibodies to azelaic acid. There were significant associations between IgA levels to Gram-negative bacteria and Mini Mental State Examination, Boston naming test, Verbal Fluency and Word List Memory test scores.These findings provide further evidence that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by an increased impact of Gram-negative commensal bacteria coupled with a deficit in natural IgM, pointing to aberrations in B1 cells. It is concluded that increased bacterial translocation and deficits in the compensatory immune-regulatory system (CIRS) may drive negative symptoms and neurocognitive impairments, which are hallmarks of deficit schizophrenia.
ARTICLE | doi:10.20944/preprints201810.0083.v2
Subject: Medicine & Pharmacology, Behavioral Neuroscience Keywords: immune, inflammation, natural IgM autoimmune, oxidative stress, kynurenine, schizophrenia, psychosis
Online: 8 October 2018 (13:51:40 CEST)
Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in natural regulatory autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative specific epitopes (OSEs), nitroso (NO) and nitro (NO2) adducts in schizophrenia remain unknown.This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl and NO2-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls.Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO2-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2 – 42.2 %) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO2-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall.These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in lowered IgM responses to MDA and azelaic acid (part of the CIRS) attenuate the negative immune-regulatory feedback on the primary immune response and that this process may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.
ARTICLE | doi:10.20944/preprints202012.0457.v1
Subject: Medicine & Pharmacology, Allergology Keywords: deficit schizophrenia; neuro-immune; inflammation; oxidative and nitrosative stress; antioxidants; biomarkers; IgM; autoimmune
Online: 18 December 2020 (11:50:42 CET)
Recently, a breakdown of paracellular and vascular pathways and activated neuroimmune and oxidative pathways were established in (deficit) schizophrenia. The aim of the current study was to delineate a) the differences in these pathways between stable phase, first (FES) and multiple (MES) episode schizophrenia, and b) the pathways that determine the behavioral-cognitive-physical-psychosocial (BCPS)-worsening in FES/MES. This study included 21 FES and 58 FES patients and 40 healthy controls and measured indicants of serum IgA to C1q, and leaky gut, immune activation, and oxidative stress toxicity (OSTOX) biomarkers. We constructed a BCPS-worsening index by extracting a latent vector from symptomatic, neurocognitive, and quality of life data. FES patients showed significantly higher IgA to C1q, cadherin, catenin, plasmalemma vesicle-associated protein, and IgA/IgM to Gram-negative bacteria than FES patients and controls. In FES patients, the BCPS-worsening score was predicted (48.7%) by IgA to Klebsiella pneumoniae and lowered paraoxonase 1 activity. In MES patients, the BCPS-worsening score was explained (42.7%) by increased tumor necrosis factor-α, OSTOX, and number of episodes. In schizophrenia, 34.0% of the variance in the BCPS-worsening score was explained by IgA to K. pneumoniae, OSTOX, and number of episodes. Increased IgA to K. pneumoniae was the single best predictor of residual psychotic symptoms in FES and MES. This study delineated different mechanistic processes in FES, including breakdown of adherens junctions, bacterial translocation, and C1q circulating immune complexes; and FES, including immune and oxidative stress neurotoxic pathways. FES and MES comprise different staging subtypes, i.e., FES and MES with and without worsening.
ARTICLE | doi:10.20944/preprints202105.0182.v1
Subject: Medicine & Pharmacology, Allergology Keywords: chronic fatigue syndrome; Myalgic encephalomyelitis; oxidative stress; neuro-immune; inflammation; bacterial translocation
Online: 10 May 2021 (12:27:45 CEST)
Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs). Aims: To examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome. Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods. Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome. Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.
ARTICLE | doi:10.20944/preprints201908.0132.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: schizophrenia; inflammation; oxidative stress; neuro-immune; gut bacteria; antioxidants
Online: 11 August 2019 (14:58:43 CEST)
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 the 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.
ARTICLE | doi:10.20944/preprints202003.0416.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: menstrual cycle-related syndrome; neuroimmunomodulation; biomarkers; inflammation; oxidative stress; antioxidants
Online: 29 March 2020 (03:22:06 CEST)
Objective: To examine the associations between menstruation features and symptoms and hormone-immune-metabolic biomarkers. Methods: Forty-one women completed questionnaires assessing characteristic menstruation symptoms, duration of menstrual cycle and number of pads used/day and completed the Daily Record of Severity of Problems (DRSP) during the consecutive days of their menstrual cycle. Menses-related symptoms (MsRS) were computed from the sum of 10 pre- and post-menses symptoms and the menstruation blood and duration index (MBDI) was computed based on the daily number of pads and duration of menses. We assayed serum levels of various biomarkers at days 7, 14, 21, and 28 of the subjects’ menstrual cycle. Results: MBDI was significantly associated with a) MsRS including low abdominal cramps, and gastro-intestinal (GI) and pain symptoms (positively); b) plasma levels of haptoglobin (Hp), CCL5, insulin growth factor (IGF)-1, and plasminogen activator inhibitor (PAI)1 (all positively); and c) estradiol and paraoxonase (PON)1 arylesterase activity (both inversely). MsRS were significantly predicted by CCL5 and IGF-1 (both positively) and progesterone (inversely). Low-abdominal cramps, and gastro-intestinal and pain symptoms were associated with lower progesterone levels. The MBDI+MsRS score was significantly predicted by the cumulative effects of (in descending order of importance): Hp, IGF-1, PON1 arylesterase, estradiol and PAI. Conclusion: Menstruation-related features including estimated blood loss, duration of menses, cramps, pain and GI symptoms are associated with hormone-immune-metabolic biomarkers, which mechanistically may explain those features. Women with an increased MBDI+MsRS index ≥ 0.666 percentile may be considered to have menstruation-related distress, including dysmenorrhea symptoms.
ARTICLE | doi:10.20944/preprints202001.0077.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: premenstrual syndrome; depression; anxiety; antioxidants; neuro-immune; inflammation; oxidative stress
Online: 9 January 2020 (08:17:43 CET)
Objective: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is > 0.666 percentile. We assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. Results: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in women with MCAS. The total DRSP score was predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. Conclusion: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC-associated symptoms while sex hormones may have a protective effect against oxidative stress toxicity.
ARTICLE | doi:10.20944/preprints202005.0145.v1
Subject: Keywords: oxidative stress; antioxidants; biomarkers; deficit schizophrenia; inflammation; cytokines; neuro-immune
Online: 9 May 2020 (03:29:18 CEST)
Background: There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: To compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. Methods: We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n=40) and non-deficit (n=40) schizophrenia and healthy controls (n=40). Results: Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (Odds ratio=3.15, p<0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. Discussion: Our findings indicate that with increasing overall severity of schizophrenia, neuro-immune and neuro-oxidative (especially protein oxidation indicating chlorinative stress) toxicities become more prominent and together with lowered antioxidant defenses and impairments in innate immunity-associated resilience against neurotoxic processes shape a distinct nosological entity, namely deficit schizophrenia.
ARTICLE | doi:10.20944/preprints202001.0285.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: oxidative stress; neuroimmunomodulation; major depression; inflammation; neurotoxicity; schizophrenia
Online: 24 January 2020 (14:46:17 CET)
Oxidative stress toxicity (OSTOX), as well as lowered antioxidant defenses (ANTIOX), play a role in temporal lobe epilepsy (TLE). Nevertheless, the associations between OSTOX/ANTIOX and psychiatric comorbidities in TLE are largely unknown.Thus, this study examines plasma malondialdehyde (MDA), lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP) and sulfhydryl (-SH) groups in Depression due to TLE (n=25); Anxiety Disorders due to TLE (n=27); Psychotic Disorder due to TLE (n=25); “pure TLE” (n=27); and healthy controls (n=40).TLE and mesial temporal sclerosis (MTS) were characterized by significant increases in OSTOX (MDA, AOPP, LOOH) and lowered ANTIOX (-SH groups, TRAP). The discrimination of pure TLE from controls yielded a significant area under the ROC curve for MDA (0.999), AOPP (0.851), -SH groups (0.899) and the OSTOX/ANTIOX ratio (0.996). Seizure frequency is significantly associated with increased MDA and lowered LOOH and NOx levels. Increased MDA was associated with the severity of depressive and physiosomatic symptoms, whilst increased AOPP levels predicted suicidal ideation. Depression and anxiety disorders co-occurring with TLE showed significantly lower MDA levels than TLE without any comorbidities. The psychotic and negative symptoms of TLE are associated with increased MDA levels and excitation with increased LOOH and lowered TRAP levels.These results indicate that oxidative stress toxicity especially protein oxidation and aldehyde formation coupled with lowered -SH groups play a key role in the pathophysiology of TLE/MTS. Increased aldehyde formation also impacts psychopathology, psychosis, as well as negative and depressive symptoms.
ARTICLE | doi:10.20944/preprints201911.0135.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: cytokines, neuro-immune, inflammation, antioxidants, oxidative stress, paraoxonase 1
Online: 12 November 2019 (17:02:22 CET)
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 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), 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.