Oxidative stress in Rett syndrome

Sierra, Cristina; Vilaseca, M. A.; Brandi, Nuria; Artuch, Rafael; Mira, Áurea; Nieto, M; Pineda, Merçè

doi:10.1016/s0387-7604(01)00369-2

Cited by 64 publications

(51 citation statements)

References 24 publications

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“…In fact, oxidative stress has been implicated in the pathophysiology of common neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, epileptic seizures and demyelination (Halliwell and Gutteridge 1996; Pérez-Severiano et al 2000;Bogdanov et al 2001;Karelson et al 2001;Méndez-Alvarez et al 2001;Behl and Moosmann 2002a, b;Stoy et al 2005;Berg and Youdim 2006;Mancuso et al 2007). Furthermore, there is compelling evidence that oxidative stress occurs in a variety of inborn errors of metabolism, including organic acidemias (Moyano et al 1997;Colome et al 2000;Fontella et al 2000;Kölker et al 2001a, b;de Oliveira Marques et al 2003;Fighera et al 2003;Latini et al 2003a, b;Wajner et al 2004) and other inherited metabolic disorders, such as tyrosinemia type I, Rett syndrome, X-linked adrenoleukodystrophy, Lesh-Nyhan disease, urea cycle defects and homocystinuria (Bird et al 1995;Sierra et al 2001;Streck et al 2001Streck et al , 2003Vargas et al 2004). …”

Section: Discussionmentioning

confidence: 99%

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

et al. 2009

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High levels of phenylalanine (Phe) are the biochemical hallmark of phenylketonuria (PKU), a neurometabolic disorder clinically characterized by severe mental retardation and other brain abnormalities, including cortical atrophy and microcephaly. Considering that the pathomechanisms leading to brain damage and particularly the marked cognitive impairment in this disease are poorly understood, in the present study we investigated the in vitro effect of Phe, at similar concentrations as to those found in brain of PKU patients, on important parameters of oxidative stress in the hippocampus and cerebral cortex of developing rats. We found that Phe induced in vitro lipid peroxidation (increase of TBA-RS values) and protein oxidative damage (sulfhydryl oxidation) in both cerebral structures. Furthermore, these effects were probably mediated by reactive oxygen species, since the lipid oxidative damage was totally prevented by the free radical scavengers alpha-tocopherol and melatonin, but not by L-NAME, a potent inhibitor of nitric oxide synthase. Accordingly, Phe did not induce nitric oxide synthesis, but significantly decreased the levels of reduced glutathione (GSH), the major brain antioxidant defense, in hippocampus and cerebral cortex supernatants. Phe also reduced the thiol groups of a commercial GSH solution in a cell-free medium. We also found that the major metabolites of Phe catabolism, phenylpyruvate, phenyllactate and phenylacetate also increased TBA-RS levels in cerebral cortex, but to a lesser degree. The data indicate that Phe elicits oxidative stress in the hippocampus, a structure mainly involved with learning/memory, and also in the cerebral cortex, which is severely damaged in PKU patients. It is therefore presumed that this pathomechanism may be involved at least in part in the severe cognitive deficit and in the characteristic cortical atrophy associated with dysmyelination and leukodystrophy observed in this disorder.

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Section: Discussionmentioning

confidence: 99%

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

et al. 2009

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“…These blood analyses also revealed a reduced activity of the pivotal scavenging enzyme superoxide dismutase (Sierra et al, 2001) as well as decreased vitamin E levels (Formichi et al, 1998). Recently, we confirmed an increased oxidative burden and mitochondrial dysfunction also in hippocampal tissue of male MeCP2-deficient ( Mecp2 −/y ) mice (Großer et al, 2012), by taking advantage of genetically-encoded optical redox indicators which allow to quantify redox conditions and dynamics (Hanson et al, 2004; Funke et al, 2011).…”

Section: Introductionmentioning

confidence: 98%

“…Various oxidative stress markers—such as non-protein-bound iron, protein carbonyls, malondialdehyde (MDA) and F2-isoprostanes—are increased in blood samples of Rett patients (Sierra et al, 2001; De Felice et al, 2009, 2011, 2012b). These blood analyses also revealed a reduced activity of the pivotal scavenging enzyme superoxide dismutase (Sierra et al, 2001) as well as decreased vitamin E levels (Formichi et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Systemic Radical Scavenger Treatment of a Mouse Model of Rett Syndrome: Merits and Limitations of the Vitamin E Derivative Trolox

Janc

Hüser

Dietrich

et al. 2016

Front. Cell. Neurosci.

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Rett syndrome (RTT) is a severe neurodevelopmental disorder typically arising from spontaneous mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene. The almost exclusively female Rett patients show an apparently normal development during their first 6–18 months of life. Subsequently, cognitive- and motor-impairment, hand stereotypies, loss of learned skills, epilepsy and irregular breathing manifest. Early mitochondrial impairment and oxidative challenge are considered to facilitate disease progression. Along this line, we recently confirmed in vitro that acute treatment with the vitamin E-derivative Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, ameliorates cellular redox balance and improves hypoxia tolerance in male MeCP2-deficient (Mecp2−/y) mouse hippocampus. Pursuing these promising findings, we performed a preclinical study to define the merit of systemic Trolox administration. Blinded, placebo-controlled in vivo treatment of male mice started at postnatal day (PD) 10–11 and continued for ~40 days. Compounds (vehicle only, 10 mg/kg or 40 mg/kg Trolox) were injected intraperitoneally every 48 h. Detailed phenotyping revealed that in Mecp2−/y mice, blood glucose levels, lipid peroxidation, synaptic short-term plasticity, hypoxia tolerance and certain forms of environmental exploration were improved by Trolox. Yet, body weight and size, motor function and the rate and regularity of breathing did not improve. In conclusion, in vivo Trolox treatment partially ameliorated a subset of symptoms of the complex Rett phenotype, thereby confirming a partial merit of the vitamin E-derivative based pharmacotherapy. Yet, it also became evident that frequent animal handling and the route of drug administration are critical issues to be optimized in future trials.

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“…Under pathological conditions, e.g., ischemia, the enhanced production of reactive oxygen species compromises the intrinsic antioxidant capacity of astrocytes and neurons and leads to oxidative stress and cell death. Several neurodegenerative disorders are also characterized by major perturbations in the glutathione system (23)(24)(25)(26). Reactive astrocytes represent a good source of glutathione and the mitochondrial glutathione pool appears to be of major importance (27,28).…”

mentioning

confidence: 99%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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A well-controlled T cell response to CNS injury may result in increased neuronal survival. However, the precise mechanism of T cell-induced neuroprotection is unknown. In this study, we report the unexpected finding that during culture of T cells, high levels of glutamate accumulate, which are efficiently cleared if T cells are cocultured with astrocytes. The T cell-derived glutamate elicits in turn, the release of neuroprotective thiols (cysteine, glutathione, and cysteinyl-glycine) and lactate from astrocytes. Media obtained from astrocytes conditioned in the presence of T cells reduce neuronal apoptosis induced by oxidative stress in primary neuronal cultures from 48 ± 14 to 9 ± 4% (p < 0.001). Inhibition of glutamate-dependent signaling during astrocyte-T cell cocultivation by a glutamate uptake inhibitor, l-aspartic acid β-hydroxamate, abolishes this neuroprotective effect. The ability of astrocytes to clear extracellular glutamate is impaired under conditions of oxidative stress. We demonstrate that T cells, via secreted cytokines, restore glutamate clearance capacity of astrocytes under oxidative conditions. Furthermore, under normoxic conditions, glutamate-buffering capacity of astrocytes is increased upon cocultivation with T cells. It is known that, following CNS injury, astrocytes can respond with beneficial or destructive effects on neurons. However, the context and signaling mechanisms for this dual astrocytic response are unknown. Our results implicate T cells as potential determinants of the context that elicits a protective role for astrocytes in the damaged CNS.

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Oxidative stress in Rett syndrome

Cited by 64 publications

References 24 publications

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

Systemic Radical Scavenger Treatment of a Mouse Model of Rett Syndrome: Merits and Limitations of the Vitamin E Derivative Trolox

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

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