MRI scans detect 'brain rust' in schizophrenia: Oxidative stress

"Using a new kind of MRI measurement, neuroscientists reported higher levels of oxidative stress in patients with schizophrenia, when compared both to healthy individuals and those with bipolar disorder."



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The 6,000-Calorie Diet | Overeating leads to insulin resistance in days.The Scientist Magazine®

Between October 2013 and July 2014, six healthy, middle-aged men reported to Temple University Hospital in north Philadelphia. For seven days, researchers confined each subject to his hospital bed and told him to select breakfast, lunch, and dinner, along with three daily snacks, from the hospital menu containing typical American cuisine: eggs, fried chicken, hamburgers, French fries, etc. The intake totaled a whopping 6,000 calories—about 2.5 times the men’s normal diet.

The high-calorie diet worked as planned, with participants already showing signs of insulin resistance by day two. By the end of the week, the men showed a 50-percent decrease in their insulin-stimulated glucose uptake. (They also gained an average of 3.5 kg, all of it fat.) Then it became a question of what was causing the problem. Fatty acid levels didn’t go up; in fact, they went down slightly. A survey of five proinflammatory cytokines also ruled out inflammation as a cause. And there were no signs of increased ER stress in biopsied adipose tissue. “So I’m pretty sure that none of these three had anything to do with this massive insulin resistance,” Boden says. “What we did find was that oxidative stress went up. And not only did it go up, but it went up exactly at the same rate as insulin resistance went up.”

Here's the paper:-

Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men.

Juvenile Antioxidant Treatment Prevents Adult Deficits in a Developmental Model of Schizophrenia: Neuron

Highlights

• •Presymptomatic antioxidant treatment prevents loss of parvalbumin in NVHL rats
• •Antioxidant treatment prevents altered prefrontal electrophysiology in NVHL rats
• •Prepulse inhibition deficits are prevented by antioxidants

Summary

Abnormal development can lead to deficits in adult brain function, a trajectory
likely underlying adolescent-onset psychiatric conditions such as
schizophrenia. Developmental manipulations yielding adult deficits in
rodents provide an opportunity to explore mechanisms involved in a
delayed emergence of anomalies driven by developmental alterations. Here
we assessed whether oxidative stress during presymptomatic stages
causes adult anomalies in rats with a neonatal ventral hippocampal
lesion, a developmental rodent model useful for schizophrenia research.
Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine
prevented the reduction of prefrontal parvalbumin interneuron activity
observed in this model, as well as electrophysiological and behavioral
deficits relevant to schizophrenia. Adolescent treatment with the
glutathione peroxidase mimic ebselen also reversed behavioral deficits
in this animal model. These findings suggest that presymptomatic
oxidative stress yields abnormal adult brain function in a
developmentally compromised brain, and highlight redox modulation as a
potential target for early intervention.

Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines.

There is an increasing recognition that mitochondrial dysfunction is
associated with autism spectrum disorders. However, little attention has
been given to the etiology of mitochondrial dysfunction and how
mitochondrial abnormalities might interact with other physiological
disturbances such as oxidative stress. Reserve capacity is a measure of
the ability of the mitochondria to respond to physiological stress. In
this study, we demonstrate, for the first time, that lymphoblastoid cell
lines (LCLs) derived from children with autistic disorder (AD) have an
abnormal mitochondrial reserve capacity before and after exposure to
reactive oxygen species (ROS). Ten (44%) of 22 AD LCLs exhibited
abnormally high reserve capacity at baseline and a sharp depletion of
reserve capacity when challenged with ROS. This depletion of reserve
capacity was found to be directly related to an atypical simultaneous
increase in both proton-leak respiration and adenosine
triphosphate-linked respiration in response to increased ROS in this AD
LCL subgroup. In this AD LCL subgroup, 48-hour pretreatment with
N-acetylcysteine, a glutathione precursor, prevented these abnormalities
and improved glutathione metabolism, suggesting a role for altered
glutathione metabolism associated with this type of mitochondrial
dysfunction. The results of this study suggest that a significant
subgroup of AD children may have alterations in mitochondrial function,
which could render them more vulnerable to a pro-oxidant
microenvironment as well as intrinsic and extrinsic sources of ROS such
as immune activation and pro-oxidant environmental toxins. These
findings are consistent with the notion that AD is caused by a
combination of genetic and environmental factors.

Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients.

Because increasing evidence point to the convergence of environmental
and genetic risk factors to drive redox dysregulation in schizophrenia,
we aim to clarify whether the metabolic anomalies associated with early
psychosis reflect an adaptation to oxidative stress. Metabolomic
profiling was performed to characterize the response to oxidative stress
in fibroblasts from control individuals (n = 20) and early psychosis
patients (n = 30), and in all, 282 metabolites were identified. In
addition to the expected redox/antioxidant response, oxidative stress
induced a decrease of lysolipid levels in fibroblasts from healthy
controls that were largely muted in fibroblasts from patients. Most
notably, fibroblasts from patients showed disrupted extracellular
matrix- and arginine-related metabolism after oxidative stress,
indicating impairments beyond the redox system. Plasma membrane and
extracellular matrix, 2 regulators of neuronal activity and plasticity,
appeared as particularly susceptible to oxidative stress and thus
provide novel mechanistic insights for pathophysiological understanding
of early stages of psychosis. Statistically, antipsychotic medication at
the time of biopsy was not accounting for these anomalies in the
metabolism of patients' fibroblasts, indicating that they might be
intrinsic to the disease. Although these results are preliminary and
should be confirmed in a larger group of patients, they nevertheless
indicate that the metabolic signature of reactivity to oxidative stress
may provide reliable early markers of psychosis. Developing protective
measures aimed at normalizing the disrupted pathways should prevent the
pathological consequences of environmental stressors.

Natural plant compound prevents Alzheimer's disease in mice -- ScienceDaily

A chemical that's found in fruits and vegetables from strawberries to
cucumbers appears to stop memory loss that accompanies Alzheimer's
disease in mice, scientists at the Salk Institute for Biological Studies
have discovered. In experiments on mice that normally develop
Alzheimer's symptoms less than a year after birth, a daily dose of the
compound -- -a flavonol called fisetin -- -prevented the progressive
memory and learning impairments. The drug, however, did not alter the
formation of amyloid plaques in the brain, accumulations of proteins
which are commonly blamed for Alzheimer's disease. The new finding
suggests a way to treat Alzheimer's symptoms independently of targeting
amyloid plaques.

PLOS ONE: Oxidative Stress Induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort

There is increasing recognition that mitochondrial dysfunction is associated with the autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction or how mitochondrial abnormalities might interact with other physiological disturbances associated with autism, such as oxidative stress. In the current study we used respirometry to examine reserve capacity, a measure of the mitochondrial ability to respond to physiological stress, in lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) as well as age and gender-matched control LCLs. We demonstrate, for the first time, that LCLs derived from children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases intracellular reactive oxygen species (ROS). Specifically, the AD LCLs exhibit a higher reserve capacity at baseline and a sharper depletion of reserve capacity when ROS exposure is increased, as compared to control LCLs. Detailed investigation indicated that reserve capacity abnormalities seen in AD LCLs were the result of higher ATP-linked respiration and maximal respiratory capacity at baseline combined with a marked increase in proton leak respiration as ROS was increased. We further demonstrate that these reserve capacity abnormalities are driven by a subgroup of eight (32%) of 25 AD LCLs. Additional investigation of this subgroup of AD LCLs with reserve capacity abnormalities revealed that it demonstrated a greater reliance on glycolysis and on uncoupling protein 2 to regulate oxidative stress at the inner mitochondria membrane. This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxicants. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors.

Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder.

Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3-nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation [lipid hydroperoxides (LPH), 8-isoprostane (8-Iso), 4-hydroxy-2-nonenal (4-HNE)] were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3-nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8-Iso was found increased in the BD group while 4-HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins. Oxidative stress has been shown to be higher in the brain of patients with bipolar disorder (BD). Here, we demonstrated increased levels of protein oxidation in synaptosomes from postmortem prefrontal cortex from patients from BD group, while 3-nitrotyrosine was increased in mitochondria from BD and schizophrenia (SCZ) groups. Moreover, lipid peroxidation was found increased in the BD when compared with controls; suggesting that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.

Low vitamin D causes brain damage

"In addition to being essential for maintaining bone health, newer evidence shows that vitamin D serves important roles in other organs and tissue, including the brain. Published in Free Radical Biology and Medicine, the UK study showed that middle-aged rats that were fed a diet low in vitamin D for several months developed free radical damage to the brain, and many different brain proteins were damaged as identified by redox proteomics. These rats also showed a significant decrease in cognitive performance on tests of learning and memory."

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Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases.

 Nuclear respiratory factor 1 (NRF1) serves as a transcription factor that activates the expression of a wide range of nuclear genes essential for mitochondrial biogenesis and function, including mitochondrial respiratory complex subunits, heme biosynthetic enzymes, and regulatory factors involved in the replication and transcription of mitochondrial DNA. Increasing evidence indicates that mitochondrial function is severely compromised in the brains of aging-related neurodegenerative diseases. To identify the comprehensive set of human NRF1 target genes potentially relevant to the pathogenesis of neurodegenerative diseases, we analyzed the NRF1 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset retrieved from the Encyclopedia of DNA Elements (ENCODE) project. Overall, we identified 2,470 highly stringent ChIP-Seq peaks on protein-coding genes in SK-N-SH human neuroblastoma cells. They were accumulated in the proximal promoter regions with an existence of the NRF1-binding consensus sequence. The set of ChIP-Seq-based NRF1 target genes included known NRF1 targets such as EIF2S1, EIF2S2, CYCS, FMR1, FXR2, E2F6, CD47, and TOMM34. By pathway analysis, the molecules located in the core pathways related to mitochondrial respiratory function were determined to be highly enriched in NRF1 target genes. Furthermore, we found that NRF1 target genes play a pivotal role in regulation of extra-mitochondrial biological processes, including RNA metabolism, splicing, cell cycle, DNA damage repair, protein translation initiation, and ubiquitin-mediated protein degradation. We identified a panel of neurodegenerative disease-related genes, such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) for Parkinson's disease, as well as PSENEN (Pen2) and MAPT (tau) for Alzheimer's disease, as previously unrecognized NRF1 targets. These results suggest a logical hypothesis that aberrant regulation of NRF1 and its targets might contribute to the pathogenesis of human neurodegenerative diseases via perturbation of diverse mitochondrial and extra-mitochondrial functions.

PLOS ONE: Oxidative Stress Enhances Neurodegeneration Markers Induced by Herpes Simplex Virus Type 1 Infection in Human Neuroblastoma Cells

Mounting evidence suggests that Herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer’s disease (AD). Previous work from our laboratory has shown HSV-1 infection to induce the most important pathological hallmarks of AD brains. Oxidative damage is one of the earliest events of AD and is thought to play a crucial role in the onset and development of the disease. Indeed, many studies show the biomarkers of oxidative stress to be elevated in AD brains. In the present work the combined effects of HSV-1 infection and oxidative stress on Aβ levels and autophagy (neurodegeneration markers characteristic of AD) were investigated. Oxidative stress significantly potentiated the accumulation of intracellular Aβ mediated by HSV-1 infection, and further inhibited its secretion to the extracellular medium. It also triggered the accumulation of autophagic compartments without increasing the degradation of long-lived proteins, and enhanced the inhibition of the autophagic flux induced by HSV-1. These effects of oxidative stress were not due to enhanced virus replication. Together, these results suggest that HSV-1 infection and oxidative damage interact to promote the neurodegeneration events seen in AD.

Antioxidants—too much of a good thing?

 In older men, a natural antioxidant compound found in red grapes and other plants—called resveratrol—blocks many of the cardiovascular benefits of exercise, according to research published in The Journal of Physiology.

ACTH protects mature oligodendroglia from excitotoxic and inflammation-related damage in vitro.

Corticosteroids (CS) are widely employed to treat relapses in multiple sclerosis (MS). Endogenous ACTH is a 39-amino acid peptide that, among other functions, stimulates CS production. Exogenous ACTH 1-39 is used to treat MS relapses, presumably by stimulating endogenous CS production. However, unlike CS, ACTH binds to melanocortin receptors, found in the central nervous system (CNS) as well as on inflammatory cells. Since glia are implicated in MS and other neurodegenerative diseases, and oligodendroglia (OL) are more sensitive to injury than other glia, we characterized the protective effects of ACTH on OL in vitro without the confounding effects of CS. Rat brain cultures containing OL, astrocytes (AS), and microglia (MG) were incubated for 1 day with potentially cytotoxic agents with or without preincubation with ACTH 1-39. The cytotoxic agents killed 55-70% of mature OL, but caused little or no death of AS or MG at the concentrations used. ACTH protected OL from death induced by staurosporine, AMPA, NMDA, kainate, quinolinic acid, or reactive oxygen species, but did not protect against kynurenic acid or nitric oxide. The protective effects of ACTH were dose dependent, and decreased OL death induced by the different agents by 30-60% at 200 nM ACTH. We show for the first time that melanocortin 4 receptor is expressed on OL in addition to MG and AS. In summary, ACTH 1-39 protects OL in vitro from several excitotoxic and inflammation-related insults. ACTH may be activating melanocortin receptors on OL or alternately on AS or MG to prevent OL death.

An Antioxidant May Prevent Neuron Loss In Schizophrenia And Depression

MNT "Gamma-aminobutyric acid (GABA) deficits have been implicated in schizophrenia and depression. In schizophrenia, deficits have been particularly well-described for a subtype of GABA neuron, the parvalbumin fast-spiking interneurons. The activity of these neurons is critical for proper cognitive and emotional functioning. Parvalbumin neurons are particularly vulnerable to oxidative stress, a factor that may emerge commonly in development, particularly in the context of psychiatric disorders like schizophrenia or bipolar disorder, where compromised mitochondrial function plays a role. parvalbumin neurons may be protected from this effect by N-acetylcysteine, also known as Mucomyst, a medication commonly prescribed to protect the liver against the toxic effects of acetaminophen (Tylenol) overdose, reports a new study in the current issue of Biological Psychiatry. "

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Green tea and red wine extracts interrupt Alzheimer's disease pathway in cells

In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of the amyloid protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.

Lipid and protein oxidation in female patients with chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a widely recognized problem, characterized by prolonged, debilitating fatigue and a characteristic group of accompanying symptoms, that occurs four times more frequently in women than in men. The aim of the study was to determine the existence of oxidative stress and its possible consequences in female patients with CFS.

MATERIAL AND METHODS:

Twenty-four women aged 15-45 who fulfilled the diagnostic criteria for CFS with no comorbidities were recruited and were age matched to a control group of 19 healthy women. After conducting the routine laboratory tests, levels of the lipid oxidation product malondialdehyde (MDA) and protein oxidation protein carbonyl (CO) were determined.

RESULTS:

The CFS group had higher levels of triglycerides (p = 0.03), MDA (p = 0.03) and CO (p = 0.002) and lower levels of HDL cholesterol (p = 0.001) than the control group. There were no significant differences in the levels of total protein, total cholesterol or LDL cholesterol.

CONCLUSIONS:

The CFS group had an unfavorable lipid profile and signs of oxidative stress induced damage to lipids and proteins. These results might be indicative of early proatherogenic processes in this group of patients who are otherwise at low risk for atherosclerosis. Antioxidant treatment and life style changes are indicated for women with CFS, as well as closer observation in order to assess the degree of atherosclerosis.

Modulation of experimental herpes encephalitis-associated neurotoxicity through sulforaphane treatment. Schachtele SJ, Hu S, L

Reactive oxygen species (ROS) produced by brain-infiltrating macrophages and neutrophils, as well as resident microglia, are pivotal to pathogen clearance during viral brain infection. However, unchecked free radical generation is also responsible for damage to and cytotoxicity of critical host tissue bystander to primary infection. These unwanted effects of excessive ROS are combated by local cellular production of antioxidant enzymes, including heme oxygenase-1 (HO-1) and glutathione peroxidase 1 (Gpx1). In this study, we showed that experimental murine herpes encephalitis triggered robust ROS production, as well as an opposing upregulation of the antioxidants HO-1 and Gpx1. This antioxidant response was insufficient to prevent tissue damage, neurotoxicity, and mortality associated with viral brain infection. Previous studies corroborate our data supporting astrocytes as the major antioxidant producer in brain cell cultures exposed to HSV-1 stimulated microglia. We hypothesized that stimulating opposing antioxidative responses in astrocytes, as well as neurons, would mitigate the effects of ROS-mediated neurotoxicity both in vitro and during viral brain infection in vivo. Here, we demonstrate that the addition of sulforaphane, a potent stimulator of antioxidant responses, enhanced HO-1 and Gpx1 expression in astrocytes through the activation of nuclear factor-E2-related factor 2 (Nrf2). Additionally, sulforaphane treatment was found to be effective in reducing neurotoxicity associated with HSV-stimulated microglial ROS production. Finally, intraperitoneal injections of sulforaphane into mice during active HSV infection reduced neuroinflammation via a decrease in brain-infiltrating leukocytes, macrophage- and neutrophil-produced ROS, and MHCII-positive, activated microglia. These data support a key role for astrocyte-produced antioxidants in modulating oxidative stress and neuronal damage in response to viral infection.

Viral Catalase Protects Herpes Simplex Virus from Inactivation by Hydrogen Peroxide.

Herpes simplex virus (HSV-1) was shown to contain catalase, an enzyme able to detoxify hydrogen peroxide by converting it to water and oxygen. Studies with a catalase inhibitor indicated that virus-associated catalase can have a role in protecting the virus from oxidative inactivation. HSV-1 was found to be more sensitive to killing by hydrogen peroxide in the presence of a catalase inhibitor than in its absence. The results suggest a protective role for catalase during the time HSV-1 spends in the oxidizing environment outside a host cell.

Powerful class of antioxidants may be potent Parkinson's treatment

A class of antioxidants called synthetic triterpenoids blocked development of Parkinson's in an animal model that develops the disease in a handful of days, said Dr. Bobby Thomas, neuroscientist at the Medical College of Georgia at Georgia Health Sciences University and corresponding author of the study in the journal Antioxidants & Redox Signaling. Thomas and his colleagues were able to block the death of dopamine-producing brain cells that occurs in Parkinson's by using the drugs to bolster Nrf2, a natural antioxidant and inflammation fighter.

Read more at: http://medicalxpress.com/news/2012-07-powerful-class-antioxidants-potent-parkinson.html#jCp

Certain Features Of Autism May Be Improved By Antioxidant (N-acetyl cysteine)

The antioxidant, N-Acetylcysteine, or NAC, lowered irritability in children with autism as well as reducing the children's repetitive behaviors. The researchers emphasized that the findings must be confirmed in a larger trial before NAC can be recommended for children with autism.