Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

Cuénod, Michel; Steullet, Pascal; Cabungcal, Jan-Harry; Dwir, Daniella; Khadimallah, Inès; Klauser, Paul; Conus, Philippe; Q., Kim

doi:10.1038/s41380-021-01374-w

Cited by 67 publications

(52 citation statements)

References 232 publications

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“…Enhanced oxidative stress and consequent mitochondrial dysfunction have been described in many different brain disorders ( 37 , 38 ). These include neurodevelopmental disorders, like ASD ( 1 ), ADHD ( 2 ), and ID ( 3 ); genetic disorders, like Rett ( 39 , 40 ), Fragile X ( 41 ), and Down syndromes ( 42 , 43 ); neurological disorders, like Alzheimer's and Parkinson's disease ( 44 ); and psychiatric disorders, like schizophrenia, depression and bipolar disorder ( 37 , 45 ). A variety of etiological genetic variants and environmental agents can seemingly trigger pathogenetic mechanisms which, in addition to producing disease-specific damage, ultimately converge upon this final common pathway.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Q10 Ubiquinol With Vitamins B and E in Neurodevelopmental Disorders: A Retrospective Chart Review

et al. 2022

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Increased oxidative stress and defective mitochondrial functioning are shared features among many brain disorders. The aim of this study was to verify retrospectively the clinical efficacy and safety of a metabolic support therapy with Q10 ubiquinol, vitamin E and complex-B vitamins in various neurodevelopmental disorders. This retrospective chart review study included 59 patients (mean age 10.1 ± 1.2 y.o., range 2.5–39 years; M:F = 2.47:1), diagnosed with Autism Spectrum Disorder (n = 17), Autism Spectrum Disorder with co-morbid Intellectual Disability (n = 19), Intellectual Disability or Global Developmental Delay (n = 15), Attention-Deficit/Hyperactivity Disorder (n = 3) and Intellectual Disability in Phelan-McDermid syndrome due to chr. 22q13.33 deletion (n = 5). After a minimum of 3 months of therapy, a positive outcome was recorded in 45/59 (76.27%) patients, with Clinical Global Impression—Improvement scores ranging between 1 (“very much improved”) and 3 (“minimally improved”). The most widespread improvements were recorded in cognition (n = 26, 44.1%), adaptative functioning (n = 26, 44.1%) and social motivation (n = 19, 32.2%). Improvement rates differed by diagnosis, being observed most consistently in Phelan-McDermid Syndrome (5/5, 100%), followed by Intellectual Disability/Global Developmental Delay (13/15, 86.7%), Autism Spectrum Disorder with co-morbid Intellectual Disability (15/19, 78.9%), Autism Spectrum Disorder (11/17, 64.7%) and ADHD (1/3, 33.3%). No significant adverse event or side effect leading to treatment discontinuation were recorded. Mild side effects were reported in 18 (30.5%) patients, with the most frequent being increased hyperactivity (9/59, 15.3%). This retrospective chart review suggests that metabolic support therapy with Q10 ubiquinol, vitamin E and complex-B vitamins is well tolerated and produces some improvement in the majority of patients with neurodevelopmental disorders, especially in the presence of intellectual disability. Randomized controlled trials for each single neurodevelopmental disorder are now warranted to conclusively demonstrate the efficacy of these mitochondrial bioenergetic and antioxidant agents and to estimate their therapeutic effect size.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Q10 Ubiquinol With Vitamins B and E in Neurodevelopmental Disorders: A Retrospective Chart Review

et al. 2022

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“…Importantly, the cellular and molecular mechanisms underlying sleep disturbances and altered brain oscillations during NREM sleep in SZ remain unclear. Accumulating evidence indicates that redox dysregulation and susceptibility to oxidative stress (OxS)-i.e., altered antioxidant systems, reduced antioxidant capacities and increased levels of OxS markers -are among the pathological mechanisms that contribute to the emergence of psychosis [65][66][67][68]. Thus, OxS alters the function of redoxsensitive proteins including NMDA receptors and T-type calcium channels, impairs PV interneuron activity and promotes inflammation processes, all of which represent hallmarks of the molecular and cellular pathological mechanisms associated with development of SZ.…”

Section: Introductionmentioning

confidence: 99%

Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm−/− mice

et al. 2022

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Schizophrenia is associated with alterations of sensory integration, cognitive processing and both sleep architecture and sleep oscillations in mouse models and human subjects, possibly through changes in thalamocortical dynamics. Oxidative stress (OxS) damage, including inflammation and the impairment of fast-spiking gamma-aminobutyric acid neurons have been hypothesized as a potential mechanism responsible for the onset and development of schizophrenia. Yet, the link between OxS and perturbation of thalamocortical dynamics and sleep remains unclear. Here, we sought to investigate the effects of OxS on sleep regulation by characterizing the dynamics of thalamocortical networks across sleep-wake states in a mouse model with a genetic deletion of the modifier subunit of glutamate-cysteine ligase (Gclm knockout, KO) using high-density electrophysiology in freely-moving mice. We found that Gcml KO mice exhibited a fragmented sleep architecture and impaired sleep homeostasis responses as revealed by the increased NREM sleep latencies, decreased slow-wave activities and spindle rate after sleep deprivation. These changes were associated with altered bursting activity and firing dynamics of neurons from the thalamic reticularis nucleus, anterior cingulate and anterodorsal thalamus. Administration of N-acetylcysteine (NAC), a clinically relevant antioxidant, rescued the sleep fragmentation and spindle rate through a renormalization of local neuronal dynamics in Gclm KO mice. Collectively, these findings provide novel evidence for a link between OxS and the deficits of frontal TC network dynamics as a possible mechanism underlying sleep abnormalities and impaired homeostatic responses observed in schizophrenia.

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“…Our first aim was to assess in mice the persistent impact of chronic SD applied during either peripuberty (P30–40, also described as pubescence [ 26 ] or adolescence [ 27 ]) or late adolescence (P50–60) on several behavioral phenotypes (locomotor activity in novel environments, exploration in anxiogenic environments, social interaction, pre-pulse inhibition and startle reactivity, and MK-801-induced hyperlocomotion). We also investigated how a genetic vulnerability to redox dysregulation relevant to schizophrenia and possibly other psychiatric disorders [ 28 ] modulates the long-lasting impact of SD when applied respectively during peripuberty and late adolescence. We postulated that a susceptibility to redox dysregulation exacerbates some effects of SD, since SD causes oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Time of exposure to social defeat stress during childhood and adolescence and redox dysregulation on long-lasting behavioral changes, a translational study

Schnider¹,

Jenni²,

Ramain

et al. 2022

Transl Psychiatry

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Traumatic events during childhood/early adolescence can cause long-lasting physiological and behavioral changes with increasing risk for psychiatric conditions including psychosis. Genetic factors and trauma (and their type, degree of repetition, time of occurrence) are believed to influence how traumatic experiences affect an individual. Here, we compared long-lasting behavioral effects of repeated social defeat stress (SD) applied during either peripuberty or late adolescence in adult male WT and Gclm-KO mice, a model of redox dysregulation relevant to schizophrenia. As SD disrupts redox homeostasis and causes oxidative stress, we hypothesized that KO mice would be particularly vulnerable to such stress. We first found that peripubertal and late adolescent SD led to different behavioral outcomes. Peripubertal SD induced anxiety-like behavior in anxiogenic environments, potentiated startle reflex, and increased sensitivity to the NMDA-receptor antagonist, MK-801. In contrast, late adolescent SD led to increased exploration in novel environments. Second, the long-lasting impact of peripubertal but not late adolescent SD differed in KO and WT mice. Peripubertal SD increased anxiety-like behavior in anxiogenic environments and MK-801-sensitivity mostly in KO mice, while it increased startle reflex in WT mice. These suggest that a redox dysregulation during peripuberty interacts with SD to remodel the trajectory of brain maturation, but does not play a significant role during later SD. As peripubertal SD induced persisting anxiety- and fear-related behaviors in male mice, we then investigated anxiety in a cohort of 89 early psychosis male patients for whom we had information about past abuse and clinical assessment during the first year of psychosis. We found that a first exposure to physical/sexual abuse (analogous to SD) before age 12, but not after, was associated with higher anxiety at 6–12 months after psychosis onset. This supports that childhood/peripuberty is a vulnerable period during which physical/sexual abuse in males has wide and long-lasting consequences.

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Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

Cited by 67 publications

References 232 publications

Efficacy and Safety of Q10 Ubiquinol With Vitamins B and E in Neurodevelopmental Disorders: A Retrospective Chart Review

Efficacy and Safety of Q10 Ubiquinol With Vitamins B and E in Neurodevelopmental Disorders: A Retrospective Chart Review

Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm−/− mice

Time of exposure to social defeat stress during childhood and adolescence and redox dysregulation on long-lasting behavioral changes, a translational study

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