N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice

Otte, David-Marian; Sommersberg, Britta; Kudin, Alexei P.; Guerrero, Catalina Vacas; Albayram, Önder; Filiou, Michaela D.; Frisch, P; Yılmaz, Öznur; Drews, Eva; Turck, Christoph W.; Bilkei-Gorzó, András; Kunz, Wolfram S.; Beck, Hanno; Zimmer, Andreas

doi:10.1038/npp.2011.109

Cited by 87 publications

(85 citation statements)

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“…The genetic vulnerability factors involve either redox regulation genes directly affecting GSH metabolism, [19][20][21][22] or genes that indirectly lead to oxidative stress, including DISC1, PROD, G72, NRG and DTNBP1. [23][24][25][26][27] Environmental factors known to favor major psychiatric disorders also generate reactive oxygen species (ROS), which, if the redox regulation is impaired, will perturb the developing nervous system. As a consequence, two key systems essential for cognitive and affective functioning will be particularly affected: local microcircuits and long-range connections.…”

Section: Introductionmentioning

confidence: 99%

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

et al. 2014

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Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

et al. 2014

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“…S1). Power spectrum analysis of the extracellular recordings revealed prominent β oscillations (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) accompanied by smaller γ oscillations (30-60 Hz), reflecting rhythmic neuronal synchronization at these frequencies (Fig. S1).…”

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confidence: 99%

“…Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20). Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23)(24)(25)(26)(27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29).…”

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confidence: 99%

Perineuronal nets protect fast-spiking interneurons against oxidative stress

Cabungcal

Steullet

Morishita

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

419

391

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A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) constitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1, 2). To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons. Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3). For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4, 5). Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8). Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9-11). ...

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“…A N-acetilcisteína (NAC) tem se mostrado um composto interessante nesse sentido. Há evidência de que a NAC aumenta os níveis cerebrais de glutationa, com um resgate do prejuízo cognitivo causado por disfunção mitocondrial induzida em um modelo animal 82,83 . No transtorno bipolar, esse precursor da glutationa tem se mostrado eficaz em melhorar o funcionamento associado a sintomas depressivos em estudos preliminares 80,[84][85][86] .…”

Section: Estresse Oxidativounclassified

Marcadores periféricos e a fisiopatologia do transtorno bipolar

Magalhães¹,

Fries²,

Kapczinski³

2012

Rev. psiquiatr. clín.

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Introdução: O entendimento da fisiopatologia do transtorno bipolar vem tendo avanços consistentes nos últimos anos. Um enfoque na relação entre carga alostática e alterações sistêmicas vem tomando corpo, com o objetivo de se entender a frequente progressão da doença. Proeminentes entre os mediadores periféricos têm sido as moléculas que poderiam ser amplamente agrupadas em neurotrofinas, marcadores de estresse oxidativo e marcadores inflamatórios. Objetivo: Descrever achados recentes em relação à fisiopatologia sistêmica do transtorno bipolar, com enfoque especial em estudos brasileiros, tentando articular uma visão coerente do conhecimento atual do campo. Método: Revisão narrativa da literatura relacionada a neurotrofinas, estresse oxidativo e marcadores inflamatórios no transtorno bipolar. Resultados: Diversas fontes de evidência, provenientes tanto de estudos pré-clínicos quanto clínicos, revelam consistentemente alterações sistêmicas no transtorno bipolar. Os achados são especialmente robustos em pacientes com múltiplos episódios. Nesses, alterações relacionadas a episódios de mania e depressão são notáveis em neurotrofinas e dano oxidativo a lipídeos. Um número menor de estudos mostra alterações no sistema imune, em particular estados pró-inflamatórios. Conclusão: Alterações sistêmicas que correlacionam o transtorno bipolar a comorbidade clínica, disfunção cognitiva, incapacidade e mortalidade precoce começam a ser traçadas. Estudos envolvendo desenhos longitudinais, amostras populacionais e ensaios clínicos envolvendo marcadores periféricos devem ser incorporados no futuro próximo e reforçar a validade de uma noção de envolvimento multissistêmico no transtorno bipolar.Magalhães PVS, et al. / Rev Psiq Clín. 2012;39(2):60-7 Palavras-chave: Transtorno bipolar, inflamação, estresse oxidativo, neurotrofinas, fator neurotrófico derivado do cérebro, fisiopatologia, biomarcadores. ABSTRACT Introduction:The understanding of the pathophysiology of bipolar disorder has steadily advanced in the past few years. Thereby, a focus on allostatic load and systemic changes has appeared, with the aim to understand illness progression. Amongst the peripheral markers, molecules that can be widely classified into neurotrophins, oxidadive stress markers, and inflammation markers have been elevated. Objective: To describe recent findings regarding the systemic pathophysiology of bipolar disorder, with a special focus on Brazilian studies and to create a coherent view of the current knowledge in the field. Method: Narrative review of the literature regarding neurotrophins, oxidative stress, and inflammatory markers in bipolar disorder. Results: A diverse body of evidence, based on both pre-clinical and clinical studies, reveals consistent systemic changes in bipolar disorder. The findings are particularly robust in patients after multiple episodes. Thereby, remarkable changes related to manic and depressive episodes were found in neurotrophins and oxidative damage to lipids. Regarding to immune system alterations, in particular pro...

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N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice

Cited by 87 publications

References 83 publications

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

Perineuronal nets protect fast-spiking interneurons against oxidative stress

Marcadores periféricos e a fisiopatologia do transtorno bipolar

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