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Updates on Mechanisms and Markers of Oxidative Stress in Neurological Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 16560

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Dr. Cinzia Signorini

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Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
Interests: isoprostanes; neuroprostanes; markers of oxidative stress; oxidative stress in human diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Claudio De Felice

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Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy
Interests: Rett syndrome; clinical trial; oxidative stress; intensive care neonatology

Special Issue Information

Dear Colleagues,

Oxidative stress, typically defined as an imbalance between the production of radical species and antioxidant defenses, is commonly evoked in a series of distinct neurological diseases originating from different causes, either genetic or idiopathic.

In neurological diseases, both lipids and proteins are suggested to be molecular targets of oxidative damage whereas oxidative signaling appears to be involved in epigenetic mechanisms. In this regard, several oxidative stress molecular players have so far been investigated regarding their involvement in the pathological mechanisms leading to neurological impairment. Likewise, antioxidant approaches have been suggested for managing oxidative stress in such conditions.

This Special Issue is to provide an update regarding new insights into mechanisms and markers of oxidative stress as a predominant and shared mechanism in neurological disorders.

Dr. Cinzia Signorini
Dr. Claudio De Felice
Guest Editors

Manuscript Submission Information

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Keywords

Neurological diseases
Experimental neurological diseases
Oxidative stress
Protein misfolding
Deuterated PUFAs
Antioxidant treatment
Lipid peroxidation
Epigenetics
Fatty acids
Neuroprostanes

Published Papers (5 papers)

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Research

14 pages, 16066 KiB

Open AccessArticle

Circulating 4-F_4t-Neuroprostane and 10-F_4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome

by Cinzia Signorini, Silvia Leoncini, Thierry Durand, Jean-Marie Galano, Alexandre Guy, Valérie Bultel-Poncé, Camille Oger, Jetty Chung-Yung Lee, Lucia Ciccoli, Joussef Hayek and Claudio De Felice

Int. J. Mol. Sci. 2021, 22(8), 4240; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084240 - 19 Apr 2021

Cited by 1 | Viewed by 2097

Abstract

Neuroprostanes, a family of non-enzymatic metabolites of the docosahexaenoic acid, have been suggested as potential biomarkers for neurological diseases. Objective biological markers are strongly needed in Rett syndrome (RTT), which is a progressive X-linked neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene with a predominant multisystemic phenotype. The aim of the study is to assess a possible association between MECP2 mutations or RTT disease progression and plasma levels of 4(RS)-4-F_4t-neuroprostane (4-F_4t-NeuroP) and 10(RS)-10-F_4t-neuroprostane (10-F_4t-NeuroP) in typical RTT patients with proven MECP2 gene mutation. Clinical severity and disease progression were assessed using the Rett clinical severity scale (RCSS) in n = 77 RTT patients. The 4-F_4t-NeuroP and 10-F_4t-NeuroP molecules were totally synthesized and used to identify the contents of the plasma of the patients. Neuroprostane levels were related to MECP2 mutation category (i.e., early truncating, gene deletion, late truncating, and missense), specific hotspot mutations (i.e., R106W, R133C, R168X, R255X, R270X, R294X, R306C, and T158M), and disease stage (II through IV). Circulating 4-F_4t-NeuroP and 10-F_4t-NeuroP were significantly related to (i) the type of MECP2 mutations where higher levels were associated to gene deletions (p ≤ 0.001); (ii) severity of common hotspot MECP2 mutation (large deletions, R168X, R255X, and R270X); (iii) disease stage, where higher concentrations were observed at stage II (p ≤ 0.002); and (iv) deficiency in walking (p ≤ 0.0003). This study indicates the biological significance of 4-F_4t-NeuroP and 10-F_4t-NeuroP as promising molecules to mark the disease progression and potentially gauge genotype–phenotype associations in RTT. Full article

(This article belongs to the Special Issue Updates on Mechanisms and Markers of Oxidative Stress in Neurological Diseases)

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14 pages, 2308 KiB

Open AccessArticle

18F-Fluorodeoxyglucose Positron Emission Tomography Tracks the Heterogeneous Brain Susceptibility to the Hyperglycemia-Related Redox Stress

by Alberto Miceli, Vanessa Cossu, Cecilia Marini, Patrizia Castellani, Stefano Raffa, Maria Isabella Donegani, Silvia Bruno, Silvia Ravera, Laura Emionite, Anna Maria Orengo, Federica Grillo, Flavio Nobili, Silvia Morbelli, Antonio Uccelli, Gianmario Sambuceti and Matteo Bauckneht

Int. J. Mol. Sci. 2020, 21(21), 8154; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218154 - 31 Oct 2020

Cited by 6 | Viewed by 1913

Abstract

In cognitively normal patients, mild hyperglycemia selectively decreases 18F-Fluorodeoxyglucose (FDG) uptake in the posterior brain, reproducing Alzheimer disease pattern, hampering the diagnostic accuracy of this widely used tool. This phenomenon might involve either a heterogeneous response of glucose metabolism or a different sensitivity to hyperglycemia-related redox stress. Indeed, previous studies reported a close link between FDG uptake and activation of a specific pentose phosphate pathway (PPP), triggered by hexose-6P-dehydrogenase (H6PD) and contributing to fuel NADPH-dependent antioxidant responses in the endoplasmic reticulum (ER). To clarify this issue, dynamic positron emission tomography was performed in 40 BALB/c mice four weeks after administration of saline (n = 17) or 150 mg/kg streptozotocin (n = 23, STZ). Imaging data were compared with biochemical and histological indexes of glucose metabolism and redox balance. Cortical FDG uptake was homogeneous in controls, while it was selectively decreased in the posterior brain of STZ mice. This difference was independent of the activity of enzymes regulating glycolysis and cytosolic PPP, while it was paralleled by a decreased H6PD catalytic function and enhanced indexes of oxidative damage. Thus, the relative decrease in FDG uptake of the posterior brain reflects a lower activation of ER-PPP in response to hyperglycemia-related redox stress in these areas. Full article

(This article belongs to the Special Issue Updates on Mechanisms and Markers of Oxidative Stress in Neurological Diseases)

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16 pages, 2650 KiB

Open AccessArticle

p-Cresol Sulfate Caused Behavior Disorders and Neurodegeneration in Mice with Unilateral Nephrectomy Involving Oxidative Stress and Neuroinflammation

by Chiao-Yin Sun, Jian-Ri Li, Ya-Yu Wang, Shih-Yi Lin, Yen-Chuan Ou, Cheng-Jui Lin, Jiaan-Der Wang, Su-Lan Liao and Chun-Jung Chen

Int. J. Mol. Sci. 2020, 21(18), 6687; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186687 - 12 Sep 2020

Cited by 31 | Viewed by 3736

Abstract

Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles in the pathogenesis of neurological disorders, the CNS effects of PCS were investigated in unilateral nephrectomized C57/BL/6 mice. Unlike intact mice, unilateral nephrectomized mice showed increased circulating levels of PCS after exogenous administration. Upon PCS exposure, the unilateral nephrectomized mice developed depression-like, anxiety-like, and cognitive impairment behaviors with brain PCS accumulation in comparison with the nephrectomy-only group. In the prefrontal cortical tissues, neuronal cell survival and neurogenesis were impaired along with increased apoptosis, oxidative stress, and neuroinflammation. Circulating brain-derived neurotrophic factors (BDNF) and serotonin were decreased in association with increased corticosterone and repressor element-1 silencing transcription factor (REST), regulators involved in neurological disorders. On the contrary, these PCS-induced changes were alleviated by uremic toxin absorbent AST-120. Taken together, PCS administration in mice with nephrectomy contributed to neurological disorders with increased oxidative stress and neuroinflammation, which were alleviated by PCS chelation. It is suggested that PCS may be a therapeutic target for chronic kidney disease-associated CNS diseases. Full article

(This article belongs to the Special Issue Updates on Mechanisms and Markers of Oxidative Stress in Neurological Diseases)

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20 pages, 2593 KiB

Open AccessArticle

Neutralization of Lipocalin-2 Diminishes Stroke-Reperfusion Injury

by Guona Wang, Yi-Chinn Weng, I-Chen Chiang, Yu-Ting Huang, Yi-Chu Liao, Yi-Chun Chen, Cheng-Yuan Kao, Yu-Li Liu, Tsong-Hai Lee and Wen-Hai Chou

Int. J. Mol. Sci. 2020, 21(17), 6253; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176253 - 29 Aug 2020

Cited by 27 | Viewed by 3890

Abstract

Oxidative stress is a key contributor to the pathogenesis of stroke-reperfusion injury. Neuroinflammatory peptides released after ischemic stroke mediate reperfusion injury. Previous studies, including ours, have shown that lipocalin-2 (LCN2) is secreted in response to cerebral ischemia to promote reperfusion injury. Genetic deletion of LCN2 significantly reduces brain injury after stroke, suggesting that LCN2 is a mediator of reperfusion injury and a potential therapeutic target. Immunotherapy has the potential to harness neuroinflammatory responses and provides neuroprotection against stroke. Here we report that LCN2 was induced on the inner surface of cerebral endothelial cells, neutrophils, and astrocytes that gatekeep the blood–brain barrier (BBB) after stroke. LCN2 monoclonal antibody (mAb) specifically targeted LCN2 in vitro and in vivo, attenuating the induction of LCN2 and pro-inflammatory mediators (iNOS, IL-6, CCL2, and CCL9) after stroke. Administration of LCN2 mAb at 4 h after stroke significantly reduced neurological deficits, cerebral infarction, edema, BBB leakage, and infiltration of neutrophils. The binding epitope of LCN2 mAb was mapped to the β3 and β4 strands, which are responsible for maintaining the integrity of LCN2 cup-shaped structure. These data indicate that LCN2 can be pharmacologically targeted using a specific mAb to reduce reperfusion injury after stroke. Full article

(This article belongs to the Special Issue Updates on Mechanisms and Markers of Oxidative Stress in Neurological Diseases)

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22 pages, 2698 KiB

Open AccessArticle

The Dual-Active Histamine H₃ Receptor Antagonist and Acetylcholine Esterase Inhibitor E100 Alleviates Autistic-Like Behaviors and Oxidative Stress in Valproic Acid Induced Autism in Mice

by Nermin Eissa, Sheikh Azimullah, Petrilla Jayaprakash, Richard L. Jayaraj, David Reiner, Shreesh K. Ojha, Rami Beiram, Holger Stark, Dorota Łażewska, Katarzyna Kieć-Kononowicz and Bassem Sadek

Int. J. Mol. Sci. 2020, 21(11), 3996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113996 - 03 Jun 2020

Cited by 24 | Viewed by 4319

Abstract

The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer’s disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: K_i = 203 nM) and balanced AChE inhibitory effect (EeAChE: IC₅₀ = 2 µM and EqBuChE: IC₅₀ = 2 µM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all p < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all p < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels (p < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all p < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice (p < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours. Full article

(This article belongs to the Special Issue Updates on Mechanisms and Markers of Oxidative Stress in Neurological Diseases)

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