Regionally Impaired Redox Homeostasis in the Brain of Rats Subjected to Global Perinatal Asphyxia: Sustained Effect up to 14 Postnatal Days

Labor and delivery entail a complex and sequential metabolic and physiologic cascade, culminating in most circumstances in successful childbirth, although delivery can be a risky episode if oxygen supply is interrupted, resulting in perinatal asphyxia (PA). PA causes an energy failure, leading to cell dysfunction and death if re-oxygenation is not promptly restored. PA is associated with long-term effects, challenging the ability of the brain to cope with stressors occurring along with life. We review here relevant targets responsible for metabolic cascades linked to neurodevelopmental impairments, that we have identified with a model of global PA in rats. Severe PA induces a sustained effect on redox homeostasis, increasing oxidative stress, decreasing metabolic and tissue antioxidant capacity in vulnerable brain regions, which remains weeks after the insult. Catalase activity is decreased in mesencephalon and hippocampus from PA-exposed (AS), compared to control neonates (CS), in parallel with increased cleaved caspase-3 levels, associated with decreased glutathione reductase and glutathione peroxidase activity, a shift towards the TIGAR-dependent pentose phosphate pathway, and delayed calpain-dependent cell death. The brain damage continues long after the re-oxygenation period, extending for weeks after PA, affecting neurons and glial cells, including myelination in grey and white matter. The resulting vulnerability was investigated with organotypic cultures built from AS and CS rat newborns, showing that substantia nigra TH-dopamine-positive cells from AS were more vulnerable to 1 mM of H2O2 than those from CS animals. Several therapeutic strategies are discussed, including hypothermia; N-acetylcysteine; memantine; nicotinamide, and intranasally administered mesenchymal stem cell secretomes, promising clinical translation.

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(Ascorb)ing Pb Neurotoxicity in the Developing Brain

Antioxidants ◽

10.3390/antiox9121311 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1311

Author(s):

Faraz Ahmad ◽

Ping Liu

Keyword(s):

Ascorbic Acid ◽

Animal Studies ◽

Redox Homeostasis ◽

Special Role ◽

Developmental Exposure ◽

Brain Functions ◽

Brain States ◽

Pb Exposure ◽

The Brain ◽

Potent Therapeutic Agent

Lead (Pb) neurotoxicity is a major concern, particularly in children. Developmental exposure to Pb can alter neurodevelopmental trajectory and has permanent neuropathological consequences, including an increased vulnerability to further stressors. Ascorbic acid is among most researched antioxidant nutrients and has a special role in maintaining redox homeostasis in physiological and physio-pathological brain states. Furthermore, because of its capacity to chelate metal ions, ascorbic acid may particularly serve as a potent therapeutic agent in Pb poisoning. The present review first discusses the major consequences of Pb exposure in children and then proceeds to present evidence from human and animal studies for ascorbic acid as an efficient ameliorative supplemental nutrient in Pb poisoning, with a particular focus on developmental Pb neurotoxicity. In doing so, it is hoped that there is a revitalization for further research on understanding the brain functions of this essential, safe, and readily available vitamin in physiological states, as well to justify and establish it as an effective neuroprotective and modulatory factor in the pathologies of the nervous system, including developmental neuropathologies.

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Failure of the Brain Glucagon-Like Peptide-1-Mediated Control of Intestinal Redox Homeostasis in a Rat Model of Sporadic Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox10071118 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1118

Author(s):

Jan Homolak ◽

Ana Babic Perhoc ◽

Ana Knezovic ◽

Jelena Osmanovic Barilar ◽

Melita Salkovic-Petrisic

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rat Model ◽

Redox Homeostasis ◽

Brain State ◽

Gastrointestinal Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The Brain

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer’s disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore (i) gastrointestinal homeostasis in the STZ-icv model (ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and (iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and low molecular weight thiols (LMWT), protein sulfhydryls (SH), and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that (i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, (ii) brain GLP-1R signaling is involved in systemic redox regulation, (iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.

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Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽

10.3390/antiox10030357 ◽

2021 ◽

Vol 10 (3) ◽

pp. 357

Author(s):

Mojca Trstenjak Prebanda ◽

Petra Matjan-Štefin ◽

Boris Turk ◽

Nataša Kopitar-Jerala

Keyword(s):

Mouse Model ◽

Redox Homeostasis ◽

Underlying Mechanism ◽

Loss Of Function ◽

Altered Expression ◽

Lps Challenge ◽

Progressive Myoclonus Epilepsy ◽

Myoclonus Epilepsy ◽

The Brain ◽

Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

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PECULIARITIES OF THE RADIATION PATTERN OF THE BRAIN AND INTERNAL ORGANS OF NEWBORNS WHO UNDERWENT SEVERE PERINATAL ASPHYXIA AND UNDERWENT GENERAL THERAPEUTIC HYPOTHERMIA, ACCORDING TO THE PILOT STUDY RESULTS

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2021-100-1-30-35 ◽

2021 ◽

Vol 100 (1) ◽

pp. 30-35

Author(s):

N.S. Vorotyntseva ◽

◽

V.V. Orlova ◽

A.N. Motina ◽

A.D. Novikova ◽

...

Keyword(s):

Therapeutic Hypothermia ◽

Perinatal Asphyxia ◽

Control Group ◽

Internal Organs ◽

X Ray ◽

Abdominal Organs ◽

Study Results ◽

Negative Effect ◽

Chest X Ray ◽

The Brain

Objective of the research: to study the features of the radiological picture of the brain and internal organs of newborns with severe perinatal asphyxia, who underwent general therapeutic hypothermia (GTH). Materials and methods: the study included 116 newborns with severe perinatal asphyxia. GTH was performed in 72 patients (group 1), 44 children did not receive hypothermia in the 2 (control) group. In the first 6 hours of life, children of groups 1 and 2 underwent ultrasound of the brain and abdominal organs and chest x-ray. The complex ultrasound scan was repeated at 3–5, 7–10, 14–16 and 21–28 days. Repeated chest x-ray was carried out strictly according to the indications. Results: GTH reduced the incidence of organic brain lesions by 18% in children with severe perinatal asphyxia (p0,05). The study revealed a number of undesirable consequences associated with GTH. Transient effusion into the abdominal and thoracic cavities was diagnosed by ultrasound in 8 (11%) patients after hypothermia, while there were no such changes in children in the control group (p<0,05). X-ray of the chest in newborns who received GTH during the first 14 days revealed edematous-hemorrhagic changes in the lungs more often than in patients of the control group – 55 (76%) and 24 (55%), respectively (p<0,05). Conclusions: GTH effectively prevented the development of severe post-hypoxic changes in the brain. The negative effect of hypothermia on microcirculation was manifested by the development of effusion into the serous cavities and edematous-hemorrhagic syndrome.

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S-Adenosylmethionine Deficiency and Brain Accumulation of S-Adenosylhomocysteine in Thioacetamide-Induced Acute Liver Failure

Nutrients ◽

10.3390/nu12072135 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2135

Author(s):

Anna Maria Czarnecka ◽

Wojciech Hilgier ◽

Magdalena Zielińska

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Redox Homeostasis ◽

Cerebral Function ◽

Total Glutathione ◽

Cellular Redox ◽

Therapeutic Value ◽

Transsulfuration Pathway ◽

Subsequent Hydrolysis ◽

The Brain

Background: Acute liver failure (ALF) impairs cerebral function and induces hepatic encephalopathy (HE) due to the accumulation of neurotoxic and neuroactive substances in the brain. Cerebral oxidative stress (OS), under control of the glutathione-based defense system, contributes to the HE pathogenesis. Glutathione synthesis is regulated by cysteine synthesized from homocysteine via the transsulfuration pathway present in the brain. The transsulfuration-transmethylation interdependence is controlled by a methyl group donor, S-adenosylmethionine (AdoMet) conversion to S-adenosylhomocysteine (AdoHcy), whose removal by subsequent hydrolysis to homocysteine counteract AdoHcy accumulation-induced OS and excitotoxicity. Methods: Rats received three consecutive intraperitoneal injections of thioacetamide (TAA) at 24 h intervals. We measured AdoMet and AdoHcy concentrations by HPLC-FD, glutathione (GSH/GSSG) ratio (Quantification kit). Results: AdoMet/AdoHcy ratio was reduced in the brain but not in the liver. The total glutathione level and GSH/GSSG ratio, decreased in TAA rats, were restored by AdoMet treatment. Conclusion: Data indicate that disturbance of redox homeostasis caused by AdoHcy in the TAA rat brain may represent a deleterious mechanism of brain damage in HE. The correction of the GSH/GSSG ratio following AdoMet administration indicates its therapeutic value in maintaining cellular redox potential in the cerebral cortex of ALF rats.

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Reversal of age-associated oxidative stress in mice by PFT, a novel kefir product

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738420950149 ◽

2020 ◽

Vol 34 ◽

pp. 205873842095014

Author(s):

Mamdooh Ghoneum ◽

Shaymaa Abdulmalek ◽

Deyu Pan

Keyword(s):

Oxidative Stress ◽

Low Density Lipoprotein ◽

Redox Homeostasis ◽

Density Lipoprotein ◽

Antioxidant Enzyme Activities ◽

Protective Effects ◽

Oxidative Stress Biomarkers ◽

Age Related ◽

Total Antioxidant ◽

The Brain

Introduction: Oxidative stress is a key contributor to aging and age-related diseases. In the present study, we examine the protective effects of PFT, a novel kefir product, against age-associated oxidative stress using aged (10-month-old) mice. Methods: Mice were treated with PFT orally at a daily dose of 2 mg/kg body weight over 6 weeks, and antioxidant status, protein oxidation, and lipid peroxidation were studied in the brain, liver, and blood. Results: PFT supplementation significantly reduced the oxidative stress biomarkers malondialdehyde (MDA) and nitric oxide; reversed the reductions in glutathione (GSH) levels, total antioxidant capacity (TAC), and anti-hydroxyl radical (AHR) content; enhanced the antioxidant enzyme activities of glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD); inhibited the liver enzyme levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT); significantly reduced triglyceride (TG), total cholesterol (TC), and low density lipoprotein (LDL) levels; and significantly elevated high density lipoprotein (HDL) levels. Interestingly, PFT supplementation reversed the oxidative changes associated with aging, thus bringing levels to within the limits of the young control mice in the brain, liver, and blood. We also note that PFT affects the redox homeostasis of young mice and that it is corrected post-treatment with PFT. Conclusion: Our findings show the effectiveness of dietary PFT supplementation in modulating age-associated oxidative stress in mice and motivate further studies of PFT’s effects in reducing age-associated disorders where free radicals and oxidative stress are the major cause.

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Gestational caloric restriction improves redox homeostasis parameters in the brain of Wistar rats: a screening from birth to adulthood

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2019.02.002 ◽

2019 ◽

Vol 67 ◽

pp. 138-148 ◽

Cited By ~ 2

Author(s):

Vinícius Stone ◽

Mariana Scortegagna Crestani ◽

André Brum Saccomori ◽

Bárbara Mariño dal Magro ◽

Rafael Moura Maurmann ◽

...

Keyword(s):

Caloric Restriction ◽

Wistar Rats ◽

Redox Homeostasis ◽

The Brain

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Glutathione in the Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22095010 ◽

2021 ◽

Vol 22 (9) ◽

pp. 5010

Author(s):

Koji Aoyama

Keyword(s):

Neurodegenerative Diseases ◽

Regulatory Mechanism ◽

Excitatory Amino Acid ◽

Redox Homeostasis ◽

Disease Onset ◽

Glutamate Transporter ◽

Antioxidant Defense System ◽

Common Finding ◽

Potential Therapeutic Application ◽

The Brain

Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.

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