Interactions Among Brain-Derived Neurotrophic Factor and Neuroimmune Pathways Are Key Components of the Major Psychiatric Disorders

Altufaili

Almulla

et al. 2022

Cells

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Background: a significant percentage of methamphetamine (MA) dependent patients develop psychosis. The associations between oxidative pathways and MA-induced psychosis (MIP) are not well delineated. Objective: the aim of this study is to delineate whether acute MA intoxication in MA dependent patients is accompanied by increased nitro-oxidative stress and whether the latter is associated with MIP. Method: we recruited 30 healthy younger males and 60 acutely intoxicated males with MA dependence and assessed severity of MA use and dependence and psychotic symptoms during intoxication, and serum oxidative toxicity (OSTOX) biomarkers including oxidized high (oxHDL) and low (oxLDL)-density lipoprotein, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO), and antioxidant defenses (ANTIOX) including HDL-cholesterol, zinc, glutathione peroxidase (GPx), total antioxidant capacity (TAC), and catalase-1. Results: a large part (50%, n = 30) of patients with MA dependence could be allocated to a cluster characterized by high psychosis ratings including delusions, suspiciousness, conceptual disorganization and difficulties abstract thinking and an increased OSTOX/ANTIOX ratio. Partial Least Squares analysis showed that 29.9% of the variance in MIP severity (a first factor extracted from psychosis, hostility, excitation, mannerism, and formal thought disorder scores) was explained by HDL, TAC and zinc (all inversely) and oxLDL (positively). MA dependence and dosing explained together 44.7% of the variance in the OSTOX/ANTIOX ratio. Conclusions: MA dependence and intoxication are associated with increased oxidative stress and lowered antioxidant defenses, both of which increase risk of MIP during acute intoxication. MA dependence is accompanied by increased atherogenicity due to lowered HDL and increased oxLDL and oxHDL.

Section: Discussionmentioning

confidence: 99%

Increased Lipid Peroxidation and Lowered Antioxidant Defenses Predict Methamphetamine Induced Psychosis

Altufaili

Almulla

et al. 2022

Cells

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“…Additionally, neuroprotective compounds including brain-derived neurotrophic factor (BDNF) are decreased in deficit schizophrenia [ 66 ]. Interactions between activated immune-inflammatory pathways and lowered BDNF may play a key role in schizophrenia [ 67 ]. Finally, the immune-inflammatory biomarkers and markers of the breakdown of paracellular pathways and tight and adherens junctions and lowered BDNF are not solitary events in schizophrenia but are part of a tight network of protein-protein interactions indicating multiple disorders in the Toll-Like Receptor-4, the Janus kinases/signal transducer and activator of the transcription proteins pathway, nuclear factor-κB signaling, microglial activation, gliogenesis, and lowered neuroprotection due to deficits in Wnt/catenin and neurotrophin signaling, adherens junction organization and miRNA maturation [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

In Schizophrenia, the Effects of the IL-6/IL-23/Th17 Axis on Health-Related Quality of Life and Disabilities Are Partly Mediated by Generalized Cognitive Decline and the Symptomatome

Al-Musawi

Al-Khfaji

et al. 2022

IJERPH

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Schizophrenia patients show increased disabilities and lower quality of life (DisQoL). Nevertheless, there are no data on whether the activation of the interleukin (IL)-6, IL-23, T helper (Th)-17 axis, and lower magnesium and calcium levels impact DisQoL scores. This study recruited 90 patients with schizophrenia (including 40 with deficit schizophrenia) and 40 healthy controls and assessed the World Health Association QoL instrument-Abbreviated version and Sheehan Disability scale, Brief Assessment of Cognition in Schizophrenia (BACS), IL-6, IL-23, IL-17, IL-21, IL-22, tumor necrosis factor (TNF)-α, magnesium and calcium. Regression analyses showed that a large part of the first factor extracted from the physical, psychological, social and environmental HR-QoL and interference with school/work, social life, and home responsibilities was predicted by a generalized cognitive deterioration (G-CoDe) index (a latent vector extracted from BACs scores), and the first vector extracted from various symptom domains (“symptomatome”), whereas the biomarkers had no effects. Partial Least Squares analysis showed that the IL6IL23Th17 axis and magnesium/calcium had highly significant total (indirect + direct) effects on HR-QoL/disabilities, which were mediated by G-CoDe and the symptomatome (a first factor extracted from negative and positive symptoms). The IL6IL23Th17 axis explained 63.1% of the variance in the behavioral-cognitive-psycho-social (BCPS) worsening index a single latent trait extracted from G-CoDe, symptomatome, HR-QoL and disability data. In summary, the BCPS worsening index is partly caused by the neuroimmunotoxic effects of the IL6IL23Th17 axis in subjects with lowered antioxidant defenses (magnesium and calcium), thereby probably damaging the neuronal circuits that may underpin deficit schizophrenia.

“…Moreover, in MDD, the neuroimmunotoxic effects of these cytokines/chemokines and CRP may exacerbate the neurotoxic consequences of increased lipid and protein oxidation, aldehyde formation, and hypernitrosylation (Maes et al, 2022a). Diminished antioxidant and neurotrophic defenses, including decreased levels of brain-derived neurotrophic factor (BDNF), and a relative deficiency in the compensatory immunoregulaty system (CIRS) further contribute to enhanced neurotoxic effects of the IRS (Maes and Carvalho, 2018;Maes et al, 2022a;Maes et al, 2009;Mehterov et al, 2022). New precision nomothetic models of MDD demonstrate that IRS activation and subsequent affective neurotoxicity dictate not only the phenome of MDD, but also the recurrence of illness (ROI) and suicidal behaviors (Maes, 2022;Maes et al, 2021;Vasupanrajit et al, 2021).…”

mentioning

confidence: 99%

The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium

Al-Naqeeb

Almulla

et al. 2022

Preprint

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Background. Major depressive disorder (MDD) is characterized by elevated activity of peripheral neuro-immune and neuro-oxidative pathways, which may cause neuro-affective toxicity by disrupting neuronal circuits in the brain. No study has explored peripheral indicators of neuroaxis damage in MDD in relation to serum inflammatory and insulin resistance (IR) biomarkers, calcium, and the physio-affective phenome consisting of depressive, anxious, chronic fatigue, and physiosomatic symptoms. Methods. Serum levels of phosphorylated tau protein 217 (P-tau217), platelet-derived growth factor receptor beta (PDGFR), neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), C-reactive protein (CRP), calcium and the HOMA2-insulin resistance (IR) index were measured in 94 MDD patients and 47 controls. Results. 61.1% of the variance in the physio-affective phenome (conceptualized as a factor extracted from depression, anxiety, fatigue and physiosomatic symptoms) is explained by the regression on GFAP, NF-L, P-tau2017, PDGFRβ and HOMA2-IR (all positively associated), and decreased calcium. In addition, CRP and HOMA2-IR predicted 28.9% of the variance in the neuroaxis index. We observed significant indirect effects of CRP and calcium on the physio-affective phenome which were partly mediated by the four neuroaxis biomarkers. Annotation and enrichment analysis revealed that the enlarged GFAP, P-tau217, PDGFR, and NF-L network was enriched in glial cell and neuronal projections, the cytoskeleton and axonal transport, including a mitochondrion. Conclusions: Peripheral inflammation and IR may damage the astroglial and neuronal projections thereby interfering with mitochondrial transport. This toxicity, combined with inflammation, IR and lowered calcium, may, at least in part, induce the phenome of MDD.