Antioxidants

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11 pages, 737 KiB

Open AccessArticle

Assessment of the Telomere Length and Its Effect on the Symptomatology of Parkinson’s Disease

by Tina Levstek, Sara Redenšek, Maja Trošt, Vita Dolžan and Katarina Trebušak Podkrajšek

Antioxidants 2021, 10(1), 137; https://doi.org/10.3390/antiox10010137 - 19 Jan 2021

Cited by 9 | Viewed by 3497

Abstract

Telomeres, which are repetitive sequences that cap the end of the chromosomes, shorten with each cell division. Besides cellular aging, there are several other factors that influence telomere length (TL), in particular, oxidative stress and inflammation, which play an important role in the [...] Read more.

Telomeres, which are repetitive sequences that cap the end of the chromosomes, shorten with each cell division. Besides cellular aging, there are several other factors that influence telomere length (TL), in particular, oxidative stress and inflammation, which play an important role in the pathogenesis of neurodegenerative brain diseases including Parkinson’s disease (PD). So far, the majority of studies have not demonstrated a significant difference in TL between PD patients and healthy individuals. However, studies investigating the effect of TL on the symptomatology and disease progression of PD are scarce, and thus, warranted. We analyzed TL of peripheral blood cells in a sample of 204 PD patients without concomitant autoimmune diseases and analyzed its association with several PD related phenotypes. Monochrome multiplex quantitative PCR (mmqPCR) was used to determine relative TL given as a ratio of the amount of DNA between the telomere and albumin as the housekeeping gene. We found a significant difference in the relative TL between PD patients with and without dementia, where shorter TL presented higher risk for dementia (p = 0.024). However, the correlation was not significant after adjustment for clinical factors (p = 0.509). We found no correlations between TLs and the dose of dopaminergic therapy when the analysis was adjusted for genetic variability in inflammatory or oxidative factors. In addition, TL influenced time to onset of motor complications after levodopa treatment initiation (p = 0.0134), but the association did not remain significant after adjustment for age at inclusion and disease duration (p = 0.0781). Based on the results of our study we conclude that TL contributes to certain PD-related phenotypes, although it may not have a major role in directing the course of the disease. Nevertheless, this expends currently limited knowledge regarding the association of the telomere attrition and the disease severity or motor complications in Parkinson’s disease. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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13 pages, 1827 KiB

Open AccessArticle

Investigations into the Role of Metabolism in the Inflammatory Response of BV2 Microglial Cells

by Pamela Maher

Antioxidants 2021, 10(1), 109; https://doi.org/10.3390/antiox10010109 - 14 Jan 2021

Cited by 4 | Viewed by 3376

Abstract

Although the hallmarks of Alzheimer’s disease (AD) are amyloid beta plaques and neurofibrillary tangles, there is growing evidence that neuroinflammation, mitochondrial dysfunction and oxidative stress play important roles in disease development and progression. A major risk factor for the development of AD is [...] Read more.

Although the hallmarks of Alzheimer’s disease (AD) are amyloid beta plaques and neurofibrillary tangles, there is growing evidence that neuroinflammation, mitochondrial dysfunction and oxidative stress play important roles in disease development and progression. A major risk factor for the development of AD is diabetes, which is also characterized by oxidative stress and mitochondrial dysfunction along with chronic, low-grade inflammation. Increasing evidence indicates that in immune cells, the induction of a pro-inflammatory phenotype is associated with a shift from oxidative phosphorylation (OXPHOS) to glycolysis. However, whether hyperglycemia also contributes to this shift is not clear. Several different approaches including culturing BV2 microglial cells in different carbon sources, using enzyme inhibitors and knocking down key pathway elements were used in conjunction with bacterial lipopolysaccharide (LPS) activation to address this question. The results indicate that while high glucose favors NO production, pro-inflammatory cytokine production is highest in the presence of carbon sources that drive OXPHOS. In addition, among the carbon sources that drive OXPHOS, glutamine is a very potent inducer of IL6 production. This effect is dampened in the presence of glucose. Together, these results may provide new prospects for the therapeutic manipulation of neuroinflammation in the context of diabetes and AD. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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13 pages, 1941 KiB

Open AccessArticle

Counteracting Effects of Glutathione on the Glutamate-Driven Excitation/Inhibition Imbalance in First-Episode Schizophrenia: A 7T MRS and Dynamic Causal Modeling Study

by Roberto Limongi, Peter Jeon, Jean Théberge and Lena Palaniyappan

Antioxidants 2021, 10(1), 75; https://doi.org/10.3390/antiox10010075 - 8 Jan 2021

Cited by 24 | Viewed by 4336

Abstract

Oxidative stress plays a key role in the pathophysiology of schizophrenia. While free radicals produced by glutamatergic excess and oxidative metabolism have damaging effects on brain tissue, antioxidants such as glutathione (GSH) counteract these effects. The interaction between glutamate (GLU) and GSH is [...] Read more.

Oxidative stress plays a key role in the pathophysiology of schizophrenia. While free radicals produced by glutamatergic excess and oxidative metabolism have damaging effects on brain tissue, antioxidants such as glutathione (GSH) counteract these effects. The interaction between glutamate (GLU) and GSH is centered on N-Methyl-D-aspartate (NMDA) receptors. GSH levels increase during glutamate-mediated excitatory neuronal activity, which serves as a checkpoint to protect neurons from oxidative damage and reduce excitatory overdrive. We studied the possible influence of GSH on the glutamate-mediated dysconnectivity in 19 first-episode schizophrenia (FES) patients and 20 healthy control (HC) subjects. Using ultra-high field (7 Tesla) magnetic resonance spectroscopy (MRS) and resting state functional magnetic resonance imaging (fMRI), we measured GSH and GLU levels in the dorsal anterior cingulate cortex (dACC) and blood-oxygenation level-dependent activity in both the dACC and the anterior insula (AI). Using spectral dynamic causal modeling, we found that when compared to HCs, in FES patients inhibitory activity within the dACC decreased with GLU levels whereas inhibitory activity in both the dACC and AI increased with GSH levels. Our model explains how higher levels of GSH can reverse the downstream pathophysiological effects of a hyperglutamatergic state in FES. This provides an initial insight into the possible mechanistic effect of antioxidant system on the excitatory overdrive in the salience network (dACC-AI). Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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21 pages, 2762 KiB

Open AccessArticle

Age-Dependent Vulnerability to Oxidative Stress of Postnatal Rat Pyramidal Motor Cortex Neurons

by Livia Carrascal, Ella Gorton, Ricardo Pardillo-Díaz, Patricia Perez-García, Ricardo Gómez-Oliva, Carmen Castro and Pedro Nunez-Abades

Antioxidants 2020, 9(12), 1307; https://doi.org/10.3390/antiox9121307 - 19 Dec 2020

Cited by 5 | Viewed by 3061

Abstract

Oxidative stress is one of the main proposed mechanisms involved in neuronal degeneration. To evaluate the consequences of oxidative stress on motor cortex pyramidal neurons during postnatal development, rats were classified into three groups: Newborn (P2–P7); infantile (P11–P15); and young adult (P20–P40). Oxidative [...] Read more.

Oxidative stress is one of the main proposed mechanisms involved in neuronal degeneration. To evaluate the consequences of oxidative stress on motor cortex pyramidal neurons during postnatal development, rats were classified into three groups: Newborn (P2–P7); infantile (P11–P15); and young adult (P20–P40). Oxidative stress was induced by 10 µM of cumene hydroperoxide (CH) application. In newborn rats, using the whole cell patch-clamp technique in brain slices, no significant modifications in membrane excitability were found. In infantile rats, the input resistance increased and rheobase decreased due to the blockage of GABAergic tonic conductance. Lipid peroxidation induced by CH resulted in a noticeable increase in protein-bound 4-hidroxynonenal in homogenates in only infantile and young adult rat slices. Interestingly, homogenates of newborn rat brain slices showed the highest capacity to respond to oxidative stress by dramatically increasing their glutathione and free thiol content. This increase correlated with a time-dependent increase in the glutathione reductase activity, suggesting a greater buffering capacity of newborn rats to resist oxidative stress. Furthermore, pre-treatment of the slices with glutathione monoethyl ester acted as a neuroprotector in pyramidal neurons of infantile rats. We conclude that during maturation, the vulnerability to oxidative stress in rat motor neurons increases with age. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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11 pages, 2350 KiB

Open AccessArticle

Ethanol Induces Microglial Cell Death via the NOX/ROS/PARP/TRPM2 Signalling Pathway

by Muhammad Syahreel Azhad Sha’fie, Sharani Rathakrishnan, Iffa Nadhira Hazanol, Mohd Haziq Izzazuddin Dali, Mohd Ezuan Khayat, Syahida Ahmad, Yazmin Hussin, Noorjahan Banu Alitheen, Lin-Hua Jiang and Sharifah Alawieyah Syed Mortadza

Antioxidants 2020, 9(12), 1253; https://doi.org/10.3390/antiox9121253 - 9 Dec 2020

Cited by 17 | Viewed by 4515

Abstract

Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to [...] Read more.

Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to support generation of oxidative stress due to NADPH oxidases (NOX_-mediated production of reactive oxygen species (ROS). Here, we investigated the role of the oxidative stress-sensitive Ca²⁺-permeable transient receptor potential melastatin-related 2 (TRPM2) channel in ethanol (EtOH)-induced microglial cell death using BV2 microglial cells. Like H₂O₂, exposure to EtOH induced concentration-dependent cell death, assessed using a propidium iodide assay. H₂O₂/EtOH-induced cell death was inhibited by treatment with TRPM2 channel inhibitors and also treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, demonstrating the critical role of PARP and the TRPM2 channel in EtOH-induced cell death. Exposure to EtOH, as expected, led to an increase in ROS production, shown using imaging of 2’,7’-dichlorofluorescein fluorescence. Consistently, EtOH-induced microglial cell death was suppressed by inhibition of NADPH oxidase (NOX) as well as inhibition of protein kinase C. Taken together, our results suggest that exposure to high doses of ethanol can induce microglial cell death via the NOX/ROS/PARP/TRPM2 signaling pathway, providing novel and potentially important insights into alcohol-induced brain pathologies. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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16 pages, 2910 KiB

Open AccessArticle

Synthetic Secoisolariciresinol Diglucoside Attenuates Established Pain, Oxidative Stress and Neuroinflammation in a Rodent Model of Painful Radiculopathy

by Sonia Kartha, Christine L. Weisshaar, Ralph A. Pietrofesa, Melpo Christofidou-Solomidou and Beth A. Winkelstein

Antioxidants 2020, 9(12), 1209; https://doi.org/10.3390/antiox9121209 - 30 Nov 2020

Cited by 7 | Viewed by 2754

Abstract

Painful cervical radiculopathy is characterized by chronic neuroinflammation that lowers endogenous antioxidant responses leading to the development of oxidative stress and pain after neural trauma. Therefore, antioxidants such as secoisolariciresinol diglucoside (SDG), that promote antioxidant signaling and reduce oxidative damage may also provide [...] Read more.

Painful cervical radiculopathy is characterized by chronic neuroinflammation that lowers endogenous antioxidant responses leading to the development of oxidative stress and pain after neural trauma. Therefore, antioxidants such as secoisolariciresinol diglucoside (SDG), that promote antioxidant signaling and reduce oxidative damage may also provide pain relief. This study investigated if repeated systemic administration of synthetic SDG after a painful root compression reduces the established pain, oxidative stress and spinal glial activation that are typically evident. SDG was administered on days 1–3 after compression and the extent of oxidative damage in the dorsal root ganglia (DRG) and spinal cord was measured at day 7 using the oxidative stress markers 8-hydroxguanosine (8-OHG) and nitrotyrosine. Spinal microglial and astrocytic activation were also separately evaluated at day 7 after compression. In addition to reducing pain, SDG treatment reduced both spinal 8-OHG and nitrotyrosine, as well as peripheral 8-OHG in the DRG. Moreover, SDG selectively reduced glial activation by decreasing the extent of astrocytic but not microglial activation. These findings suggest that synthetic SDG may attenuate existing radicular pain by suppressing the oxidative stress and astrocytic activation that develop after painful injury, possibly identifying it as a potent therapeutic for painful radiculopathies. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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20 pages, 2069 KiB

Open AccessArticle

Memory-Enhancing Effects of Origanum majorana Essential Oil in an Alzheimer’s Amyloid beta1-42 Rat Model: A Molecular and Behavioral Study

by Paula Alexandra Postu, Dragos Lucian Gorgan, Oana Cioanca, Manuela Russ, Stefan Mikkat, Michael Otto Glocker and Lucian Hritcu

Antioxidants 2020, 9(10), 919; https://doi.org/10.3390/antiox9100919 - 26 Sep 2020

Cited by 20 | Viewed by 9006

Abstract

Origanum L. (Lamiaceae) is an important genus of medicinal and aromatic plants used in traditional medicine since ancient times as culinary herbs and remedies. The aim of the present study was to evaluate the chemical composition, as well as the biochemical and cellular [...] Read more.

Origanum L. (Lamiaceae) is an important genus of medicinal and aromatic plants used in traditional medicine since ancient times as culinary herbs and remedies. The aim of the present study was to evaluate the chemical composition, as well as the biochemical and cellular activities of freshly prepared Origanum majorana L. essential oil (OmEO) in an Alzheimer’s disease (AD) amyloid beta1-42 (Aβ1-42) rat model. OmEO (1% and 3%) was inhaled for 21 consecutive days, while Aβ1-42 was administered intracerebroventricularly to induce AD-like symptoms. Our data demonstrate that OmEO increased antioxidant activity and enhanced brain-derived neurotrophic factor (BDNF) expression, which in concert contributed to the improvement of cognitive function of animals. Moreover, OmEO presented beneficial effects on memory performance in Y-maze and radial arm-maze tests in the Aβ1-42 rat AD model. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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29 pages, 4022 KiB

Open AccessArticle

Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ_25-35-Induced Rat Model of Alzheimer’s Disease

by Razvan Stefan Boiangiu, Marius Mihasan, Dragos Lucian Gorgan, Bogdan Alexandru Stache, Brindusa Alina Petre and Lucian Hritcu

Antioxidants 2020, 9(8), 768; https://doi.org/10.3390/antiox9080768 - 18 Aug 2020

Cited by 17 | Viewed by 4924

Abstract

The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ_25-35-induced rat model of Alzheimer’s disease [...] Read more.

The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ_25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ_25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ_25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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17 pages, 4389 KiB

Open AccessArticle

Integrated Hypoxia Signaling and Oxidative Stress in Developmental Neurotoxicity of Benzo[a]Pyrene in Zebrafish Embryos

by Yi-Chen Lin, Chang-Yi Wu, Chin-Hwa Hu, Tun-Wen Pai, Yet-Ran Chen and Wen-Der Wang

Antioxidants 2020, 9(8), 731; https://doi.org/10.3390/antiox9080731 - 11 Aug 2020

Cited by 31 | Viewed by 4431

Abstract

Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon formed by the incomplete combustion of organic matter. Environmental B[a]P contamination poses a serious health risk to many organisms because the pollutant may negatively affect many physiological systems. As such, chronic exposure to B[a]P is known [...] Read more.

Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon formed by the incomplete combustion of organic matter. Environmental B[a]P contamination poses a serious health risk to many organisms because the pollutant may negatively affect many physiological systems. As such, chronic exposure to B[a]P is known to lead to locomotor dysfunction and neurodegeneration in several organisms. In this study, we used the zebrafish model to delineate the acute toxic effects of B[a]P on the developing nervous system. We found that embryonic exposure of B[a]P downregulates shh and isl1, causing morphological hypoplasia in the telencephalon, ventral thalamus, hypothalamus, epiphysis and posterior commissure. Moreover, hypoxia-inducible factors (hif1a and hif2a) are repressed upon embryonic exposure of B[a]P, leading to reduced expression of the Hif-target genes, epo and survivin, which are associated with neural differentiation and maintenance. During normal embryogenesis, low-level oxidative stress regulates neuronal development and function. However, our experiments revealed that embryonic oxidative stress is greatly increased in B[a]P-treated embryos. The expression of catalase was decreased and sod1 expression increased in B[a]P-treated embryos. These transcriptional changes were coincident with increased embryonic levels of H₂O₂ and malondialdehyde, with the levels in B[a]P-treated fish similar to those in embryos treated with 120-μM H₂O₂. Together, our data suggest that reduced Hif signaling and increased oxidative stress are involved in B[a]P-induced acute neurotoxicity during embryogenesis. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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14 pages, 1333 KiB

Open AccessArticle

Ameliorative Effects of Rhoifolin in Scopolamine-Induced Amnesic Zebrafish (Danio rerio) Model

by Ion Brinza, Ahmed M. Abd-Alkhalek, Mohamed A. El-Raey, Razvan Stefan Boiangiu, Omayma A. Eldahshan and Lucian Hritcu

Antioxidants 2020, 9(7), 580; https://doi.org/10.3390/antiox9070580 - 3 Jul 2020

Cited by 39 | Viewed by 4819

Abstract

Rhoifolin (Rho) exerts many biological activities such as anticancer, antidiabetic, hepatoprotective, antirheumatic, antibacterial, and antiviral properties. The neuroprotective action of this compound has not been studied. The goal of this study was to investigate the improvement impact of Rho on scopolamine (Sco)-induced zebrafish [...] Read more.

Rhoifolin (Rho) exerts many biological activities such as anticancer, antidiabetic, hepatoprotective, antirheumatic, antibacterial, and antiviral properties. The neuroprotective action of this compound has not been studied. The goal of this study was to investigate the improvement impact of Rho on scopolamine (Sco)-induced zebrafish anxiety, amnesia, and brain oxidative stress and to elucidate the underlying mechanisms involved. Zebrafish were treated with Rho (1, 3, and 5 μg/L) for nine consecutive days and were subsequently subjected to Sco (100 μM) 30 min before behavioral tests (novel tank diving test, Y-maze, and novel object recognition tests). Rho was isolated from Chorisia crispiflora (Malvaceae) leaves and identified by different spectroscopic techniques. To further assess the possible mechanisms of Rho in enhancing the memory capacities in zebrafish, the in vivo antioxidant status and acetylcholinesterase (AChE) activity was also evaluated. Rho from Chorisia crispiflora leaves was identified. Rho could alleviate anxiety, memory deficits, and brain oxidative stress in Sco-treated zebrafish and could regulate the cholinergic function by inhibiting the AChE activity. Our results demonstrated that Rho could be a promising candidate compound against anxiety and amnesia by restoring the cholinergic activity and the amelioration of brain oxidative stress. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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19 pages, 2148 KiB

Open AccessArticle

Zinc Concentration Dynamics Indicate Neurological Impairment Odds after Traumatic Spinal Cord Injury

by Raban Arved Heller, André Sperl, Julian Seelig, Patrick Haubruck, Tobias Bock, Theresa Werner, Albert Besseling, Qian Sun, Lutz Schomburg, Arash Moghaddam and Bahram Biglari

Antioxidants 2020, 9(5), 421; https://doi.org/10.3390/antiox9050421 - 13 May 2020

Cited by 17 | Viewed by 5234

Abstract

Traumatic Spinal Cord Injury (TSCI) is debilitating and often results in a loss of motor and sensory function caused by an interwoven set of pathological processes. Oxidative stress and inflammatory processes are amongst the critical factors in the secondary injury phase after TSCI. [...] Read more.

Traumatic Spinal Cord Injury (TSCI) is debilitating and often results in a loss of motor and sensory function caused by an interwoven set of pathological processes. Oxidative stress and inflammatory processes are amongst the critical factors in the secondary injury phase after TSCI. The essential trace element Zinc (Zn) plays a crucial role during this phase as part of the antioxidant defense system. The study aims to determine dynamic patterns in serum Zn concentration in patients with TSCI and test for a correlation with neurological impairment. A total of 42 patients with TSCI were enrolled in this clinical observational study. Serum samples were collected at five different points in time after injury (at admission, and after 4 h, 9 h, 12 h, 24 h, and 3 days). The analysis of the serum Zn concentrations was conducted by total reflection X-ray fluorescence (TXRF). The patients were divided into two groups—a study group S (n = 33) with neurological impairment, including patients with remission (G1, n = 18) and no remission (G0, n = 15) according to a positive AIS (American Spinal Injury Association (ASIA) Impairment Scale) conversion within 3 months after the trauma; and a control group C (n = 9), consisting of subjects with vertebral fractures without neurological impairment. The patient data and serum concentrations were examined and compared by non-parametric test methods to the neurological outcome. The median Zn concentrations in group S dropped within the first 9 h after injury (964 µg/L at admission versus 570 µg/L at 9 h, p < 0.001). This decline was stronger than in control subjects (median of 751 µg/L versus 729 µg/L, p = 0.023). A binary logistic regression analysis including the difference in serum Zn concentration from admission to 9 h after injury yielded an area under the curve (AUC) of 82.2% (CI: 64.0–100.0%) with respect to persistent neurological impairment. Early Zn concentration dynamics differed in relation to the outcome and may constitute a helpful diagnostic indicator for patients with spinal cord trauma. The fast changes in serum Zn concentrations allow an assessment of neurological impairment risk on the first day after trauma. This finding supports strategies for improving patient care by avoiding strong deficits via adjuvant nutritive measures, e.g., in unresponsive patients after trauma. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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Review

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25 pages, 11441 KiB

Open AccessReview

Beyond Antioxidant Effects: Nature-Based Templates Unveil New Strategies for Neurodegenerative Diseases

by Andrea Bacci, Massimiliano Runfola, Simona Sestito and Simona Rapposelli

Antioxidants 2021, 10(3), 367; https://doi.org/10.3390/antiox10030367 - 28 Feb 2021

Cited by 16 | Viewed by 3568

Abstract

The complex network of malfunctioning pathways occurring in the pathogenesis of neurodegenerative diseases (NDDs) represents a huge hurdle in the development of new effective drugs to be used in therapy. In this context, redox reactions act as crucial regulators in the maintenance of [...] Read more.

The complex network of malfunctioning pathways occurring in the pathogenesis of neurodegenerative diseases (NDDs) represents a huge hurdle in the development of new effective drugs to be used in therapy. In this context, redox reactions act as crucial regulators in the maintenance of neuronal microenvironment homeostasis. Particularly, their imbalance results in the severe compromising of organism’s natural defense systems and subsequently, in the instauration of deleterious OS, that plays a fundamental role in the insurgence and progress of NDDs. Despite the huge efforts in drug discovery programs, the identification process of new therapeutic agents able to counteract the relentless progress of neurodegenerative processes has produced low or no effective therapies. Consequently, a paradigm-shift in the drug discovery approach for these diseases is gradually occurring, paving the way for innovative therapeutical approaches, such as polypharmacology. The aim of this review is to provide an overview of the main pharmacological features of most promising nature-based scaffolds for a possible application in drug discovery, especially for NDDs, highlighting their multifaceted effects against OS and neuronal disorders. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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16 pages, 1593 KiB

Open AccessReview

Two Distinct Faces of Vitamin C: AA vs. DHA

by Luciano Ferrada, Rocío Magdalena, María Jose Barahona, Eder Ramírez, Cristian Sanzana, José Gutiérrez and Francisco Nualart

Antioxidants 2021, 10(2), 215; https://doi.org/10.3390/antiox10020215 - 1 Feb 2021

Cited by 18 | Viewed by 4239

Abstract

Historically, vitamin C has been associated with many regulatory processes that involve specific signaling pathways. Among the most studied signaling pathways are those involved in the regulation of aging, differentiation, neurotransmission, proliferation, and cell death processes in cancer. This wide variety of regulatory [...] Read more.

Historically, vitamin C has been associated with many regulatory processes that involve specific signaling pathways. Among the most studied signaling pathways are those involved in the regulation of aging, differentiation, neurotransmission, proliferation, and cell death processes in cancer. This wide variety of regulatory effects is due to the fact that vitamin C has a dual mechanism of action. On the one hand, it regulates the expression of genes associated with proliferation (Ccnf and Ccnb1), differentiation (Sox-2 and Oct-4), and cell death (RIPK1 and Bcl-2). At the same time, vitamin C can act as a regulator of kinases, such as MAPK and p38, or by controlling the activation of the NF-kB pathway, generating chronic responses related to changes in gene expression or acute responses associated with the regulation of signal transduction processes. To date, data from the literature show a permanent increase in processes regulated by vitamin C. In this review, we critically examine how vitamin C regulates these different cellular programs in normal and tumor cells. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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27 pages, 1967 KiB

Open AccessReview

Inflaming the Brain with Iron

by Pamela J. Urrutia, Daniel A. Bórquez and Marco Tulio Núñez

Antioxidants 2021, 10(1), 61; https://doi.org/10.3390/antiox10010061 - 6 Jan 2021

Cited by 71 | Viewed by 7758

Abstract

Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, [...] Read more.

Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain. Secreted inflammatory mediators include cytokines and reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin and nitric oxide (·NO). Hepcidin is a small cationic peptide with a central role in regulating systemic iron homeostasis. Also present in the cerebrospinal fluid (CSF), hepcidin can reduce iron export from neurons and decreases iron entry through the blood–brain barrier (BBB) by binding to the iron exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) into the iron regulatory protein 1 (IRP1), which regulates cellular iron homeostasis through its binding to iron response elements (IRE) located in the mRNAs of iron-related proteins. Nitric oxide-activated IRP1 can impair cellular iron homeostasis during neuroinflammation, triggering iron accumulation, especially in the mitochondria, leading to neuronal death. In this review, we will summarize findings that connect neuroinflammation and iron accumulation, which support their causal association in the neurodegenerative processes observed in AD and PD. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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17 pages, 275 KiB

Open AccessReview

Role of Oxidative Stress and Neuroinflammation in Attention-Deficit/Hyperactivity Disorder

by Juan Carlos Corona

Antioxidants 2020, 9(11), 1039; https://doi.org/10.3390/antiox9111039 - 23 Oct 2020

Cited by 66 | Viewed by 9703

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood. Although abnormalities in several brain regions and disturbances of the catecholaminergic pathway have been demonstrated, the pathophysiology of ADHD is not completely understood, but as a multifactorial disorder, has been associated with an increase [...] Read more.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood. Although abnormalities in several brain regions and disturbances of the catecholaminergic pathway have been demonstrated, the pathophysiology of ADHD is not completely understood, but as a multifactorial disorder, has been associated with an increase in oxidative stress and neuroinflammation. This review presents an overview of factors that increase oxidative stress and neuroinflammation. The imbalance between oxidants and antioxidants and also the treatment with medications are two factors that can increase oxidative damage, whereas the comorbidity between ADHD and inflammatory disorders, altered immune response, genetic and environmental associations, and polymorphisms in inflammatory-related genes can increase neuroinflammation. Evidence of an association with these factors has become valuable for research on ADHD. Such evidence opens up new intervention routes for the use of natural products as antioxidants that could have potential as a treatment against oxidative stress and neuroinflammation in ADHD. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

16 pages, 1469 KiB

Open AccessReview

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

by Elena Obrador, Rosario Salvador, Rafael López-Blanch, Ali Jihad-Jebbar, Soraya L. Vallés and José M. Estrela

Antioxidants 2020, 9(9), 901; https://doi.org/10.3390/antiox9090901 - 22 Sep 2020

Cited by 76 | Viewed by 6533

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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22 pages, 2417 KiB

Open AccessReview

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

by Masamichi Ikawa, Hidehiko Okazawa, Yasunari Nakamoto and Makoto Yoneda

Antioxidants 2020, 9(9), 861; https://doi.org/10.3390/antiox9090861 - 14 Sep 2020

Cited by 27 | Viewed by 4801

Abstract

Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission [...] Read more.

Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with ⁶²Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. ⁶²Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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26 pages, 1920 KiB

Open AccessReview

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

by Pablo Berríos-Cárcamo, Mauricio Quezada, María Elena Quintanilla, Paola Morales, Marcelo Ezquer, Mario Herrera-Marschitz, Yedy Israel and Fernando Ezquer

Antioxidants 2020, 9(9), 830; https://doi.org/10.3390/antiox9090830 - 4 Sep 2020

Cited by 48 | Viewed by 6748

Abstract

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain [...] Read more.

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system X_c⁻ activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)

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