Antioxidants

Research

23 pages, 4635 KiB

Open AccessArticle

Oral Feeding of an Antioxidant Cocktail as a Therapeutic Strategy in a Mouse Model of Rett Syndrome: Merits and Limitations of Long-Term Treatment

by Laura Baroncelli, Stefanie Auel, Lena Rinne, Ann-Kathrin Schuster, Victoria Brand, Belinda Kempkes, Katharina Dietrich and Michael Müller

Antioxidants 2022, 11(7), 1406; https://doi.org/10.3390/antiox11071406 - 20 Jul 2022

Cited by 4 | Viewed by 2412

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder that typically arises from spontaneous germline mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene. For the first 6–18 months of life, the development of the mostly female patients appears normal. Subsequently, [...] Read more.

Rett syndrome (RTT) is a severe neurodevelopmental disorder that typically arises from spontaneous germline mutations in the X-chromosomal methyl-CpG binding protein 2 (MECP2) gene. For the first 6–18 months of life, the development of the mostly female patients appears normal. Subsequently, cognitive impairment, motor disturbances, hand stereotypies, epilepsy, and irregular breathing manifest, with previously learned skills being lost. Early mitochondrial impairment and a systemic oxidative burden are part of the complex pathogenesis, and contribute to disease progression. Accordingly, partial therapeutic merits of redox-stabilizing and antioxidant (AO) treatments were reported in RTT patients and Mecp2-mutant mice. Pursuing these findings, we conducted a full preclinical trial on male and female mice to define the therapeutic value of an orally administered AO cocktail composed of vitamin E, N-acetylcysteine, and α-lipoic acid. AO treatment ameliorated some of the microcephaly-related aspects. Moreover, the reduced growth, lowered blood glucose levels, and the hippocampal synaptic plasticity of Mecp2^−/y mice improved. However, the first-time detected intensified oxidative DNA damage in Mecp2-mutant cortex persisted. The behavioral performance, breathing regularity, and life expectancy of Mecp2-mutant mice did not improve upon AO treatment. Long-term-treated Mecp2^+/− mice eventually became obese. In conclusion, the AO cocktail ameliorated a subset of symptoms of the complex RTT-related phenotype, thereby further confirming the potential merits of AO-based pharmacotherapies. Yet, it also became evident that long-term AO treatment may lose efficacy and even aggravate the metabolic disturbances in RTT. This emphasizes the importance of a constantly well-balanced redox balance for systemic well-being. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

19 pages, 5074 KiB

Open AccessArticle

Neuroprotective Effects of Myrtenal in an Experimental Model of Dementia Induced in Rats

by Stela Dragomanova, Stoyan Pavlov, Desislava Marinova, Yordan Hodzev, Maria Cristina Petralia, Paolo Fagone, Ferdinando Nicoletti, Maria Lazarova, Elina Tzvetanova, Albena Alexandrova, Reni Kalfin and Lyubka Tancheva

Antioxidants 2022, 11(2), 374; https://doi.org/10.3390/antiox11020374 - 12 Feb 2022

Cited by 9 | Viewed by 2652

Abstract

There is growing attention on natural substances capable of stimulating the cholinergic system and of exerting antioxidant effects, as potential therapeutic agents in Alzheimer’s disease (AD). The aim of the present study is to evaluate the expected neuroprotective mechanisms of myrtenal (M) in [...] Read more.

There is growing attention on natural substances capable of stimulating the cholinergic system and of exerting antioxidant effects, as potential therapeutic agents in Alzheimer’s disease (AD). The aim of the present study is to evaluate the expected neuroprotective mechanisms of myrtenal (M) in an experimental model of dementia in rats. Dementia was induced in male Wistar rats by scopolamine (Sc) administration (0.1 mg/kg for 8 days and 20.0 mg/kg on day 9). The animals were divided into 5 groups (1) Controls; (2) Sc; (3) Sc + Myrtenal (40 mg/kg), (4) Sc + Galantamine (1 mg/kg); (5) Sc + Lipoic acid (30 mg/kg). Changes in recognition memory and habituation were evaluated via the Novel Object Recognition and Open Field tests. Acetylcholinesterase (AChE) activity, ACh levels, and changes in oxidative status of the brain were measured biochemically. The histological changes in two brain regions—cortex and hippocampus, were evaluated qualitatively and quantitatively. Myrtenal improved recognition memory and habituation, exerted antioxidant effects and significantly increased ACh brain levels. Histologically, the neuroprotective capacity of myrtenal was also confirmed. For the first time, we have demonstrated the neuroprotective potential of myrtenal in an experimental model of dementia. Our study provides proof-of-concept for the testing of myrtenal, in association with standard of care treatments, in patients affected by cognitive decline. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

27 pages, 3484 KiB

Open AccessArticle

Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial

by Kirsten M. Wright, Melissa Bollen, Jason David, Alex B. Speers, Mikah S. Brandes, Nora E. Gray, Armando Alcázar Magaña, Christine McClure, Jan F. Stevens, Claudia S. Maier, Joseph F. Quinn and Amala Soumyanath

Antioxidants 2022, 11(2), 215; https://doi.org/10.3390/antiox11020215 - 23 Jan 2022

Cited by 16 | Viewed by 5929

Abstract

Centella asiatica is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of C. asiatica improve cognition in mouse models of aging and Alzheimer’s disease (AD) through the modulation of mitochondrial biogenesis and nuclear factor-erythroid-2-related [...] Read more.

Centella asiatica is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of C. asiatica improve cognition in mouse models of aging and Alzheimer’s disease (AD) through the modulation of mitochondrial biogenesis and nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response genes. This randomized, double-blind, crossover Phase I trial explored the oral bioavailability and pharmacokinetics of key compounds from two doses (2 g and 4 g) of a standardized C. asiatica aqueous extract product (CAP), over 10 h, in four mildly demented older adults on cholinesterase inhibitor therapy. The analysis focused on triterpenes (TTs) and caffeoylquinic acids (CQAs), which are known to contribute to C. asiatica’s neurological activity. The acute safety of CAP and the effects on NRF2 gene expression in peripheral blood mononuclear cells were evaluated. Single administration of 2 g or 4 g of CAP was safe and well-tolerated. The TT aglycones, asiatic acid and madecassic acid, were identified in plasma and urine, while the parent glycosides, asiaticoside and madecassoside, although abundant in CAP, were absent in plasma and had limited renal excretion. Similarly, mono- and di-CQAs showed delayed absorption and limited presence in plasma or urine, while the putative metabolites of these compounds showed detectable plasma pharmacokinetic profiles and urinary excretion. CAP elicited a temporal change in NRF2 gene expression, mirroring the TT aglycone’s pharmacokinetic curve in a paradoxical dose-dependent manner. The oral bioavailability of active compounds or their metabolites, NRF2 target engagement, and the acute safety and tolerability of CAP support the validity of using CAP in future clinical studies. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

16 pages, 1990 KiB

Open AccessArticle

Withania somnifera and Centella asiatica Extracts Ameliorate Behavioral Deficits in an In Vivo Drosophila melanogaster Model of Oxidative Stress

by Kadine Cabey, Dani M. Long, Alexander Law, Nora E. Gray, Christine McClure, Maya Caruso, Parnian Lak, Kirsten M. Wright, Jan F. Stevens, Claudia S. Maier, Amala Soumyanath and Doris Kretzschmar

Antioxidants 2022, 11(1), 121; https://doi.org/10.3390/antiox11010121 - 6 Jan 2022

Cited by 9 | Viewed by 3014

Abstract

Due to an increase in the aging population, age-related diseases and age-related changes, such as diminished cognition and sleep disturbances, are an increasing health threat. It has been suggested that an increase in oxidative stress underlies many of these changes. Current treatments for [...] Read more.

Due to an increase in the aging population, age-related diseases and age-related changes, such as diminished cognition and sleep disturbances, are an increasing health threat. It has been suggested that an increase in oxidative stress underlies many of these changes. Current treatments for these diseases and changes either have low efficacy or have deleterious side effects preventing long-time use. Therefore, alternative treatments that promote healthy aging and provide resilience against these health threats are needed. The herbs Withania somnifera and Centella asiatica may be two such alternatives because both have been connected with reducing oxidative stress and could therefore ameliorate age-related impairments. To test the effects of these herbs on behavioral phenotypes induced by oxidative stress, we used the Drosophila melanogaster sniffer mutant which has high levels of oxidative stress due to reduced carbonyl reductase activity. Effects on cognition and mobility were assessed using phototaxis assays and both, W. somnifera and C. asiatica water extracts improved phototaxis in sniffer mutants. In addition, W. somnifera improved nighttime sleep in male and female sniffer flies and promoted a less fragmented sleep pattern in male sniffer flies. This suggests that W. somnifera and C. asiatica can ameliorate oxidative stress-related changes in behavior and that by doing so they might promote healthy aging in humans. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Graphical abstract

20 pages, 3232 KiB

Open AccessArticle

Acacia catechu Willd. Extract Protects Neuronal Cells from Oxidative Stress-Induced Damage

by Elda Chiaino, Roberto Stella, Caterina Peggion, Matteo Micucci, Roberta Budriesi, Laura Beatrice Mattioli, Carla Marzetti, Federica Pessina, Massimo Valoti and Maria Frosini

Antioxidants 2022, 11(1), 81; https://doi.org/10.3390/antiox11010081 - 29 Dec 2021

Cited by 6 | Viewed by 3427

Abstract

Oxidative stress (OS) and the resulting reactive oxygen species (ROS) generation and inflammation play a pivotal role in the neuronal loss occurring during the onset of neurodegenerative diseases. Therefore, promising future drugs that would prevent or slow down the progression of neurodegeneration should [...] Read more.

Oxidative stress (OS) and the resulting reactive oxygen species (ROS) generation and inflammation play a pivotal role in the neuronal loss occurring during the onset of neurodegenerative diseases. Therefore, promising future drugs that would prevent or slow down the progression of neurodegeneration should possess potent radical-scavenging activity. Acacia catechu Willd. heartwood extract (AC), already characterized for its high catechin content, is endowed with antioxidant properties. The aim of the present study was to assess AC neuroprotection in both human neuroblastoma SH-SY5Y cells and rat brain slices treated with hydrogen peroxide. In SH-SY5Y cells, AC prevented a decrease in viability, as well as an increase in sub-diploid-, DAPI positive cells, reduced ROS formation, and recovered the mitochondrial potential and caspase-3 activation. AC related neuroprotective effects also occurred in rat brain slices as a reversal prevention in the expression of the main proteins involved in apoptosis and signalling pathways related to calcium homeostasis following OS-mediated injury. Additionally, unbiased quantitative mass spectrometry allowed for assessing that AC partially prevented the hydrogen peroxide-induced altered proteome, including proteins belonging to the synaptic vesicle fusion apparatus. In conclusion, the present results suggest the possibility of AC as a nutraceutical useful in preventing neurodegenerative diseases. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

32 pages, 12848 KiB

Open AccessArticle

Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

by Meghan Gage, Marson Putra, Logan Wachter, Kylie Dishman, Megan Gard, Crystal Gomez-Estrada and Thimmasettappa Thippeswamy

Antioxidants 2022, 11(1), 61; https://doi.org/10.3390/antiox11010061 - 28 Dec 2021

Cited by 17 | Viewed by 5308

Abstract

Diisopropylfluorophosphate (DFP), an organophosphate nerve agent (OPNA), exposure causes status epilepticus (SE) and epileptogenesis. In this study, we tested the protective effects of saracatinib (AZD0530), a Src kinase inhibitor, in mixed-sex or male-only Sprague Dawley rats exposed to 4–5 mg/kg DFP followed by [...] Read more.

Diisopropylfluorophosphate (DFP), an organophosphate nerve agent (OPNA), exposure causes status epilepticus (SE) and epileptogenesis. In this study, we tested the protective effects of saracatinib (AZD0530), a Src kinase inhibitor, in mixed-sex or male-only Sprague Dawley rats exposed to 4–5 mg/kg DFP followed by 2 mg/kg atropine and 25 mg/kg 2-pralidoxime. Midazolam (3 mg/kg) was given to the mixed-sex cohort (1 h post-DFP) and male-only cohort (~30 min post-DFP). Saracatinib (20 mg/kg, oral, daily for 7 days) or vehicle was given two hours later and euthanized eight days or ten weeks post-DFP. Brain immunohistochemistry (IHC) showed increased microgliosis, astrogliosis, and neurodegeneration in DFP-treated animals. In the 10-week post-DFP male-only group, there were no significant differences between groups in the novel object recognition, Morris water maze, rotarod, or forced swim test. Brain IHC revealed significant mitigation by saracatinib in contrast to vehicle-treated DFP animals in microgliosis, astrogliosis, neurodegeneration, and nitro-oxidative stressors, such as inducible nitric oxide synthase, GP91^phox, and 3-Nitrotyrosine. These findings suggest the protective effects of saracatinib on brain pathology seem to depend on the initial SE severity. Further studies on dose optimization, including extended treatment regimen depending on the SE severity, are required to determine its disease-modifying potential in OPNA models. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

25 pages, 2989 KiB

Open AccessArticle

Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation

by Ángel Cores, Noelia Carmona-Zafra, Olmo Martín-Cámara, Juan Domingo Sánchez, Pablo Duarte, Mercedes Villacampa, Paloma Bermejo-Bescós, Sagrario Martín-Aragón, Rafael León and J. Carlos Menéndez

Antioxidants 2022, 11(1), 28; https://doi.org/10.3390/antiox11010028 - 24 Dec 2021

Cited by 8 | Viewed by 3487

Abstract

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as [...] Read more.

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Graphical abstract

19 pages, 3454 KiB

Open AccessArticle

Anti-Amnesic Effects of Epigallocatechin Gallate on Scopolamine-Induced Learning and Memory Dysfunction in Sprague-Dawley Rats

by Min-Jeong Kim, Eun-Sang Hwang, Kwan Joong Kim, Sungho Maeng, Ho Jin Heo, Ji-Ho Park and Dae-Ok Kim

Antioxidants 2022, 11(1), 1; https://doi.org/10.3390/antiox11010001 - 21 Dec 2021

Cited by 16 | Viewed by 3368

Abstract

Epigallocatechin gallate (EGCG) is a major flavan-3-ol of green tea polyphenols that exhibits various beneficial health effects, including antioxidant, anti-bacterial, and anti-inflammatory properties. This study aimed to evaluate whether EGCG prevents scopolamine-induced learning and memory impairment in in vivo and ex vivo models. [...] Read more.

Epigallocatechin gallate (EGCG) is a major flavan-3-ol of green tea polyphenols that exhibits various beneficial health effects, including antioxidant, anti-bacterial, and anti-inflammatory properties. This study aimed to evaluate whether EGCG prevents scopolamine-induced learning and memory impairment in in vivo and ex vivo models. Male Sprague-Dawley (SD) rats were pre-treated with EGCG (5 mg/kg/day; intraperitoneal injection (i.p.)) for 10 days. Then, EGCG and scopolamine (1 mg/kg/day; i.p.) were applied 60 and 30 min before the behavioral tests, respectively, for another 9 days. EGCG alleviated the cognitive deficits in the Y-maze, passive avoidance, and Morris water maze tests. EGCG showed improved cholinergic functions by decreasing acetylcholinesterase activity in hippocampi dissected from the brain of the rats after the behavioral tests. EGCG also reduced oxidative stress, partly due to increased superoxide dismutase activity and decreased malondialdehyde level in the hippocampi of the rat brains after the behavioral tests. Furthermore, EGCG attenuated the scopolamine-induced blockade of long-term potentiation in organotypic hippocampal tissue of seven-day-old SD rats. Taken together, these results suggested that EGCG is a potential therapeutic agent for alleviating cognitive dysfunction. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

13 pages, 6284 KiB

Open AccessArticle

Hibiscus Flower and Olive Leaf Extracts Activate Apoptosis in SH-SY5Y Cells

by Elda Chiaino, Matteo Micucci, Roberta Budriesi, Laura Beatrice Mattioli, Carla Marzetti, Maddalena Corsini and Maria Frosini

Antioxidants 2021, 10(12), 1962; https://doi.org/10.3390/antiox10121962 - 7 Dec 2021

Cited by 7 | Viewed by 3088

Abstract

Compounds of natural origin may constitute an interesting tool for the treatment of neuroblastoma, the most prevalent extracranial solid tumor in children. PRES is a commercially available food supplement, composed of a 13:2 (w/w) extracts mix of Olea europaea L. leaves [...] Read more.

Compounds of natural origin may constitute an interesting tool for the treatment of neuroblastoma, the most prevalent extracranial solid tumor in children. PRES is a commercially available food supplement, composed of a 13:2 (w/w) extracts mix of Olea europaea L. leaves (OE) and Hibiscus sabdariffa L. flowers (HS). Its potential towards neuroblastoma is still unexplored and was thus investigated in human neuroblastoma SH-SY5Y cells. PRES decreased the viability of cells in a concentration-dependent fashion (24 h IC₅₀ 247.2 ± 31.8 µg/mL). Cytotoxicity was accompanied by an increase in early and late apoptotic cells (AV-PI assay) and sub G0/G1 cells (cell cycle analysis), ROS formation, reduction in mitochondrial membrane potential, and caspases activities. The ROS scavenger N-acetyl-L-cysteine reverted the cytotoxic effects of PRES, suggesting a key role played by ROS in PRES-mediated SH-SY5Y cell death. Finally, the effects of OE and HS extracts were singularly tested and compared to those of the corresponding mixture. OE- or HS-mediated cytotoxicity was always significantly lower than that caused by PRES, suggesting a synergic effect. In conclusion, the present findings highlight the potential of PRES for the treatment of neuroblastoma and offers the basis for a further characterization of the mechanisms underlying its effects. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

27 pages, 5365 KiB

Open AccessArticle

Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress

by Ahmed Elkamhawy, Jiyu Woo, Noha A. Gouda, Jushin Kim, Hossam Nada, Eun Joo Roh, Ki Duk Park, Jungsook Cho and Kyeong Lee

Antioxidants 2021, 10(10), 1604; https://doi.org/10.3390/antiox10101604 - 12 Oct 2021

Cited by 24 | Viewed by 4577

Abstract

Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson’s disease (PD). Herein, 24 melatonin analogues (3a–x [...] Read more.

Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells. MAO-B inhibitors are a promising therapeutical approach for Parkinson’s disease (PD). Herein, 24 melatonin analogues (3a–x) were synthesized as novel MAO-B inhibitors with the potential to counteract oxidative stress in neuronal PC12 cells. Structure elucidation, characterization, and purity of the synthesized compounds were performed using ¹H-NMR, ¹³C-NMR, HRMS, and HPLC. At 10 µM, 12 compounds showed >50% MAO-B inhibition. Among them, compounds 3n, 3r, and 3u–w showed >70% inhibition of MAO-B and IC₅₀ values of 1.41, 0.91, 1.20, 0.66, and 2.41 µM, respectively. When compared with the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), compounds 3n, 3r, 3u, and 3v demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively). Furthermore, compounds 3n and 3r exhibited safe neurotoxicity profiles in PC12 cells and reversed 6-OHDA- and rotenone-induced neuronal oxidative stress. Both compounds significantly up-regulated the expression of the anti-oxidant enzyme, heme oxygenase (HO)-1. Treatment with Zn(II)-protoporphyrin IX (ZnPP), a selective HO-1 inhibitor, abolished the neuroprotective effects of the tested compounds, suggesting a critical role of HO-1 up-regulation. Both compounds increased the nuclear translocation of Nrf2, which is a key regulator of the antioxidative response. Taken together, these data show that compounds 3n and 3r could be further exploited for their multi-targeted role in oxidative stress-related PD therapy. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

15 pages, 5113 KiB

Open AccessArticle

Polyphenols and IUGR Pregnancies: Intrauterine Growth Restriction and Hydroxytyrosol Affect the Development and Neurotransmitter Profile of the Hippocampus in a Pig Model

by Natalia Yeste, Néstor Gómez, Marta Vázquez-Gómez, Consolación García-Contreras, Martí Pumarola, Antonio González-Bulnes and Anna Bassols

Antioxidants 2021, 10(10), 1505; https://doi.org/10.3390/antiox10101505 - 22 Sep 2021

Cited by 7 | Viewed by 2912

Abstract

Intrauterine growth restriction (IUGR) refers to poor growth of a fetus during pregnancy due to deficient maternal nutrition or oxygen supply. Supplementation of a mother’s diet with antioxidants, such as hydroxytyrosol (HTX), has been proposed to ameliorate the adverse phenotypes of IUGR. In [...] Read more.

Intrauterine growth restriction (IUGR) refers to poor growth of a fetus during pregnancy due to deficient maternal nutrition or oxygen supply. Supplementation of a mother’s diet with antioxidants, such as hydroxytyrosol (HTX), has been proposed to ameliorate the adverse phenotypes of IUGR. In the present study, sows were treated daily with or without 1.5 mg of HTX per kilogram of feed from day 35 of pregnancy (at 30% of the total gestational period), and fetuses were sampled at day 100 of gestation. Fetuses were classified as normal body weight (NBW) or low body weight (LBW) as a consequence of IUGR, constituting four groups: NBW-Control, NBW-HTX, LBW-Control, and LBW-HTX. The brain was removed, and the hippocampus, amygdala, and prefrontal cortex were rapidly dissected. Neuronal markers were studied by immunohistochemistry, and a decrease in the number of mature neurons in the hippocampal Cornu Ammonis subfield 1 (CA1) and the Dentate Gyrus (DG) regions was observed in LBW fetuses together with a higher number of immature neurons and other alterations in neuronal morphology. Furthermore, IUGR conditions altered the neurotransmitter (NT) profile, since an increase in the serotonin (5-HT) pathway was observed in LBW fetuses. Supplementation with HTX was able to reverse the morphological and neurochemical changes, leading both characteristics to values similar to those of NBW fetuses. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

24 pages, 37848 KiB

Open AccessArticle

Nutraceutical Strategy to Counteract Eye Neurodegeneration and Oxidative Stress in Drosophila melanogaster Fed with High-Sugar Diet

by Elisabetta Catalani, Giuseppina Fanelli, Federica Silvestri, Agnese Cherubini, Simona Del Quondam, Silvia Bongiorni, Anna Rita Taddei, Marcello Ceci, Clara De Palma, Cristiana Perrotta, Sara Rinalducci, Giorgio Prantera and Davide Cervia

Antioxidants 2021, 10(8), 1197; https://doi.org/10.3390/antiox10081197 - 27 Jul 2021

Cited by 14 | Viewed by 3519

Abstract

Aberrant production of reactive oxygen species (ROS) is a common feature of damaged retinal neurons in diabetic retinopathy, and antioxidants may exert both preventive and therapeutic action. To evaluate the beneficial and antioxidant properties of food supplementation with Lisosan G, a powder of [...] Read more.

Aberrant production of reactive oxygen species (ROS) is a common feature of damaged retinal neurons in diabetic retinopathy, and antioxidants may exert both preventive and therapeutic action. To evaluate the beneficial and antioxidant properties of food supplementation with Lisosan G, a powder of bran and germ of grain (Triticum aestivum) obtained by fermentation with selected lactobacillus and natural yeast strains, we used an in vivo model of hyperglycemia-induced retinal damage, the fruit fly Drosophila melanogaster fed with high-sucrose diet. Lisosan G positively affected the visual system of hyperglycemic flies at structural/functional level, decreased apoptosis, and reactivated protective autophagy at the retina internal network. Also, in high sucrose-fed Drosophila, Lisosan G reduced the levels of brain ROS and retina peroxynitrite. The analysis of oxidative stress-related metabolites suggested 7,8-dihydrofolate, uric acid, dihydroorotate, γ-L-glutamyl-L-cysteine, allantoin, cysteinyl-glycine, and quinolate as key mediators of Lisosan G-induced inhibition of neuronal ROS, along with the upregulation of glutathione system. Of note, Lisosan G may impact oxidative stress and the ensuing retinal cell death, also independently from autophagy, although the autophagy-ROS cross-talk is critical. This study demonstrated that the continuous supplementation with the alimentary integrator Lisosan G exerts a robust and multifaceted antioxidant effect on retinal neurons, thus providing efficacious neuroprotection of hyperglycemic eye. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

19 pages, 2394 KiB

Open AccessArticle

Study of the Antioxidant Effects of Coffee Phenolic Metabolites on C6 Glioma Cells Exposed to Diesel Exhaust Particles

by Laura Botto, Alessandra Bulbarelli, Elena Lonati, Emanuela Cazzaniga, Michele Tassotti, Pedro Mena, Daniele Del Rio and Paola Palestini

Antioxidants 2021, 10(8), 1169; https://doi.org/10.3390/antiox10081169 - 23 Jul 2021

Cited by 5 | Viewed by 3499

Abstract

The contributing role of environmental factors to the development of neurodegenerative diseases has become increasingly evident. Here, we report that exposure of C6 glioma cells to diesel exhaust particles (DEPs), a major constituent of urban air pollution, causes intracellular reactive oxygen species (ROS) [...] Read more.

The contributing role of environmental factors to the development of neurodegenerative diseases has become increasingly evident. Here, we report that exposure of C6 glioma cells to diesel exhaust particles (DEPs), a major constituent of urban air pollution, causes intracellular reactive oxygen species (ROS) production. In this scenario, we suggest employing the possible protective role that coffee phenolic metabolites may have. Coffee is a commonly consumed hot beverage and a major contributor to the dietary intake of (poly) phenols. Taking into account physiological concentrations, we analysed the effects of two different coffee phenolic metabolites mixes consisting of compounds derived from bacterial metabolization reactions or phase II conjugations, as well as caffeic acid. The results showed that these mixes were able to counteract DEP-induced oxidative stress. The cellular components mediating the downregulation of ROS included extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and uncoupling protein 2 (UCP2). Contrary to coffee phenolic metabolites, the treatment with N-acetylcysteine (NAC), a known antioxidant, was found to be ineffective in preventing the DEP exposure oxidant effect. These results revealed that coffee phenolic metabolites could be promising candidates to protect against some adverse health effects of daily exposure to air pollution. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Graphical abstract

16 pages, 2977 KiB

Open AccessArticle

Hydroxytyrosol Selectively Affects Non-Enzymatic Glycation in Human Insulin and Protects by AGEs Cytotoxicity

by Ivana Sirangelo, Margherita Borriello, Maria Liccardo, Marika Scafuro, Paola Russo and Clara Iannuzzi

Antioxidants 2021, 10(7), 1127; https://doi.org/10.3390/antiox10071127 - 15 Jul 2021

Cited by 16 | Viewed by 2755

Abstract

Hydroxytyrosol (HT), the major phenolic compound in olive oil, is attracting increasing interest for its beneficial properties including a notable antioxidant and anti-inflammatory power. In this study, using a combination of biophysical and cell biology techniques, we have tested the role of HT [...] Read more.

Hydroxytyrosol (HT), the major phenolic compound in olive oil, is attracting increasing interest for its beneficial properties including a notable antioxidant and anti-inflammatory power. In this study, using a combination of biophysical and cell biology techniques, we have tested the role of HT in the formation of advanced glycation end-products (AGEs). AGEs have a key role in clinical sciences as they have been associated to diabetes, neurodegenerative and cardiovascular diseases. In addition, as the incidence of Alzheimer’s disease (AD) is strongly increased in diabetic patients, AGE formation is supposed to be involved in the development of the pathological hallmarks of AD. Our data show that HT selectively inhibits protein glycation reaction in human insulin, and it is able to counteract the AGE-induced cytotoxicity in human neurotypical cells by acting on SIRT1 level and oxidative stress, as well as on inflammatory response. This study identifies new beneficial properties for HT and suggests it might be a promising molecule in protecting against the AGE-induced toxicity, a key mechanism underlying the development and progression of neurodegenerative disorders. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

22 pages, 4420 KiB

Open AccessArticle

Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

by Shruti Shandilya, Kavindra Kumar Kesari and Janne Ruokolainen

Antioxidants 2021, 10(6), 983; https://doi.org/10.3390/antiox10060983 - 20 Jun 2021

Cited by 11 | Viewed by 4756

Abstract

Vitamin K2, known for its antioxidative and anti-inflammatory properties, can act as a potent neuroprotective molecule. Despite its action against mitochondrial dysfunction, the mechanism underlying the links between the protective effects of vitamin K2 and endoplasmic reticulum (ER) stress along with basal levels [...] Read more.

Vitamin K2, known for its antioxidative and anti-inflammatory properties, can act as a potent neuroprotective molecule. Despite its action against mitochondrial dysfunction, the mechanism underlying the links between the protective effects of vitamin K2 and endoplasmic reticulum (ER) stress along with basal levels of total tau protein and amyloid-beta 42 (Aβ42) has not been elucidated yet. To understand the neuroprotective effect of vitamin K2 during metabolic complications, SH-SY5Y cells were treated with streptozotocin for 24 h and menadione for 2 h in a dose-dependent manner, followed by post-treatment of vitamin K2 for 5 h. The modulating effects of vitamin K2 on cell viability, lactate dehydrogenase release, reactive oxygen species (ROS), mitochondrial membrane potential, ER stress marker (CHOP), an indicator of unfolded protein response (UPR), inositol requiring enzyme 1 (p-IRE1α), glycogen synthase kinase 3 (GSK3α/β), total tau and Aβ42 were studied. Results showed that vitamin K2 significantly reduces neuronal cell death by inhibiting cytotoxicity and ROS levels and helps in the retainment of mitochondrial membrane potential. Moreover, vitamin K2 significantly decreased the expression of CHOP protein along with the levels and the nuclear localization of p-IRE1α, thus showing its significant role in inhibiting chronic ER stress-mediated UPR and eventually cell death. In addition, vitamin K2 significantly down-regulated the expression of GSK3α/β together with the levels of total tau protein, with a petite effect on secreted Aβ42 levels. These results suggested that vitamin K2 alleviated mitochondrial damage, ER stress and tauopathy-mediated neuronal cell death, which highlights its role as new antioxidative therapeutics targeting related cellular processes. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

16 pages, 3599 KiB

Open AccessArticle

Neuroprotective Effects of Coreopsis lanceolata Flower Extract against Oxidative Stress-Induced Apoptosis in Neuronal Cells and Mice

by Hyung Don Kim, Ji Yeon Lee, Jeong-Yong Park, Dong Hwi Kim, Min Hye Kang, Hyun-A Seong, Kyung Hye Seo and Yun-Jeong Ji

Antioxidants 2021, 10(6), 951; https://doi.org/10.3390/antiox10060951 - 12 Jun 2021

Cited by 6 | Viewed by 3358

Abstract

Coreopsis lanceolata L. is a perennial plant of the family Asteraceae, and its flower is known to contain flavonoids with various bioactivities. We evaluated the effect of Coreopsis lanceolata L. flower (CLF) extracts on H₂O₂-induced oxidative stress (OS) in [...] Read more.

Coreopsis lanceolata L. is a perennial plant of the family Asteraceae, and its flower is known to contain flavonoids with various bioactivities. We evaluated the effect of Coreopsis lanceolata L. flower (CLF) extracts on H₂O₂-induced oxidative stress (OS) in neuronal cells and mouse neurons. The flowering part of CL was used as CLF1 (70% ethanol extract) and CLF2 (water extract), and 10 types of phenolic compounds were quantified using high-performance liquid chromatography. To evaluate the neuroprotective effects of CLF, the antioxidant activities of the extracts were measured, and the expression levels of antioxidant enzymes and proteins related to OS-induced apoptosis in neuronal cells and mouse neurons treated with the extracts were investigated. In the in vitro study, CLF ameliorated H₂O₂-induced oxidative stress and induced the expression of antioxidant enzymes in PC12 cells. Furthermore, CLF1 enhanced the expression of the Bcl-xL protein but reduced the expression of Bax and the cleavage of caspase-3. In the same manner, CLF1 showed neuroprotective effects against OS in vivo. Pretreatment with CLF1 (200 mg/kg) increased the Bcl-2 protein and decreased Bax compared with the 1-methyl-4-phenylpyridinium ion (MPP+)-treated C57BL/6 mice model group. Our results suggest that the protective effects of CLF1 on MPP+-induced apoptosis may be due to its anti-apoptotic activity, through regulating the expression of the Bcl-2 family. CLF1 exerts neuroprotective effects against OS-induced apoptosis in PC12 cells in a Parkinson’s disease model mouse. This effect may be attributable to the upregulation of Bcl-2 protein expression, downregulation of Bax expression, and inhibition of caspase-3 activation. These data indicate that CLF may provide therapeutic value for the treatment of progressive neurodegenerative diseases. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

22 pages, 3478 KiB

Open AccessArticle

Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation

by Ángel Cores, Sheila Abril, Patrycja Michalska, Pablo Duarte, Ana I. Olives, M. Antonia Martín, Mercedes Villacampa, Rafael León and J. Carlos Menéndez

Antioxidants 2021, 10(6), 941; https://doi.org/10.3390/antiox10060941 - 10 Jun 2021

Cited by 16 | Viewed by 2862

Abstract

Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary [...] Read more.

Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants. Most members of the library showed low cytotoxicity and good activity as inductors of Nrf2, a transcription factor that acts as the master regulator of the antioxidant response associated with activation of the antioxidant response element (ARE). Nrf2-dependent protein expression was also proved by the significant increase in the levels of the HMOX1 and NQO1 proteins. Some compounds exerted neuroprotective properties in oxidative stress situations, such as rotenone/oligomycin-induced toxicity, and also against protein hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. Compound 3i, which can be considered a good candidate for further hit-to-lead development against neurodegenerative diseases due to its well-balanced multitarget profile, was further characterized by proving its ability to reduce phosphorylated Tau levels. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Graphical abstract

25 pages, 13109 KiB

Open AccessArticle

Hericium erinaceus and Coriolus versicolor Modulate Molecular and Biochemical Changes after Traumatic Brain Injury

by Ramona D’Amico, Angela Trovato Salinaro, Roberta Fusco, Marika Cordaro, Daniela Impellizzeri, Maria Scuto, Maria Laura Ontario, Gianluigi Lo Dico, Salvatore Cuzzocrea, Rosanna Di Paola, Rosalba Siracusa and Vittorio Calabrese

Antioxidants 2021, 10(6), 898; https://doi.org/10.3390/antiox10060898 - 2 Jun 2021

Cited by 40 | Viewed by 8381

Abstract

Traumatic brain injury (TBI) is a major health and socioeconomic problem affecting the world. This condition results from the application of external physical force to the brain which leads to transient or permanent structural and functional impairments. TBI has been shown to be [...] Read more.

Traumatic brain injury (TBI) is a major health and socioeconomic problem affecting the world. This condition results from the application of external physical force to the brain which leads to transient or permanent structural and functional impairments. TBI has been shown to be a risk factor for neurodegeneration which can lead to Parkinson’s disease (PD) for example. In this study, we wanted to explore the development of PD-related pathology in the context of an experimental model of TBI and the potential ability of Coriolus versicolor and Hericium erinaceus to prevent neurodegenerative processes. Traumatic brain injury was induced in mice by controlled cortical impact. Behavioral tests were performed at various times: the animals were sacrificed 30 days after the impact and the brain was processed for Western blot and immunohistochemical analyzes. After the head injury, a significant decrease in the expression of tyrosine hydroxylase and the dopamine transporter in the substantia nigra was observed, as well as significant behavioral alterations that were instead restored following daily oral treatment with Hericium erinaceus and Coriolus versicolor. Furthermore, a strong increase in neuroinflammation and oxidative stress emerged in the vehicle groups. Treatment with Hericium erinaceus and Coriolus versicolor was able to prevent both the neuroinflammatory and oxidative processes typical of PD. This study suggests that PD-related molecular events may be triggered on TBI and that nutritional fungi such as Hericium erinaceus and Coriolus versicolor may be important in redox stress response mechanisms and neuroprotection, preventing the progression of neurodegenerative diseases such as PD. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

21 pages, 5091 KiB

Open AccessArticle

Polyphenols and IUGR Pregnancies: Effects of the Antioxidant Hydroxytyrosol on Brain Neurochemistry and Development in a Porcine Model

by Natalia Yeste, Daniel Valent, Laura Arroyo, Marta Vázquez-Gómez, Consolación García-Contreras, Martí Pumarola, Antonio González-Bulnes and Anna Bassols

Antioxidants 2021, 10(6), 884; https://doi.org/10.3390/antiox10060884 - 31 May 2021

Cited by 7 | Viewed by 3268

Abstract

Supplementation of a mother’s diet with antioxidants, such as hydroxytyrosol (HTX), has been proposed to ameliorate the adverse phenotypes of fetuses at risk of intrauterine growth restriction. In the present study, sows were treated daily with or without 1.5 mg of HTX per [...] Read more.

Supplementation of a mother’s diet with antioxidants, such as hydroxytyrosol (HTX), has been proposed to ameliorate the adverse phenotypes of fetuses at risk of intrauterine growth restriction. In the present study, sows were treated daily with or without 1.5 mg of HTX per kilogram of feed from day 35 of pregnancy (at 30% of total gestational period), and individuals were sampled at three different ages: 100-day-old fetuses and 1-month- and 6-month-old piglets. After euthanasia, the brain was removed and the hippocampus, amygdala, and prefrontal cortex were dissected. The profile of the catecholaminergic and serotoninergic neurotransmitters (NTs) was characterized and an immunohistochemical study of the hippocampus was performed. The results indicated that maternal supplementation with HTX during pregnancy affected the NT profile in a brain-area-dependant mode and it modified the process of neuron differentiation in the hippocampal CA1 and GD areas, indicating that cell differentiation occurred more rapidly in the HTX group. These effects were specific to the fetal period, concomitantly with HTX maternal supplementation, since no major differences remained between the control and treated groups in 1-month- and 6-month-old pigs. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Graphical abstract

18 pages, 3444 KiB

Open AccessArticle

New Neuroprotective Effect of Lemon IntegroPectin on Neuronal Cellular Model

by Domenico Nuzzo, Pasquale Picone, Costanza Giardina, Miriana Scordino, Giuseppa Mudò, Mario Pagliaro, Antonino Scurria, Francesco Meneguzzo, Laura M. Ilharco, Alexandra Fidalgo, Rosa Alduina, Alessandro Presentato, Rosaria Ciriminna and Valentina Di Liberto

Antioxidants 2021, 10(5), 669; https://doi.org/10.3390/antiox10050669 - 25 Apr 2021

Cited by 23 | Viewed by 5023

Abstract

Lemon IntegroPectin obtained via hydrodynamic cavitation of organic lemon processing waste in water shows significant neuroprotective activity in vitro, as first reported in this study investigating the effects of both lemon IntegroPectin and commercial citrus pectin on cell viability, cell morphology, reactive oxygen [...] Read more.

Lemon IntegroPectin obtained via hydrodynamic cavitation of organic lemon processing waste in water shows significant neuroprotective activity in vitro, as first reported in this study investigating the effects of both lemon IntegroPectin and commercial citrus pectin on cell viability, cell morphology, reactive oxygen species (ROS) production, and mitochondria perturbation induced by treatment of neuronal SH-SY5Y human cells with H₂O₂. Mediated by ROS, including H₂O₂ and its derivatives, oxidative stress alters numerous cellular processes, such as mitochondrial regulation and cell signaling, propagating cellular injury that leads to incurable neurodegenerative diseases. These results, and the absence of toxicity of this new pectic substance rich in adsorbed flavonoids and terpenes, suggest further studies to investigate its activity in preventing, retarding, or even curing neurological diseases. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

16 pages, 2505 KiB

Open AccessArticle

A Flavonoid-Rich Extract of Mandarin Juice Counteracts 6-OHDA-Induced Oxidative Stress in SH-SY5Y Cells and Modulates Parkinson-Related Genes

by Santa Cirmi, Alessandro Maugeri, Giovanni Enrico Lombardo, Caterina Russo, Laura Musumeci, Sebastiano Gangemi, Gioacchino Calapai, Davide Barreca and Michele Navarra

Antioxidants 2021, 10(4), 539; https://doi.org/10.3390/antiox10040539 - 30 Mar 2021

Cited by 34 | Viewed by 5424

Abstract

Parkinson’s disease (PD) is a degenerative disorder of the nervous system due to unceasing impairment of dopaminergic neurons situated in the substantia nigra. At present, anti-PD drugs acting on dopamine receptors are mainly symptomatic and have only very limited neuroprotective effects, whereas drugs [...] Read more.

Parkinson’s disease (PD) is a degenerative disorder of the nervous system due to unceasing impairment of dopaminergic neurons situated in the substantia nigra. At present, anti-PD drugs acting on dopamine receptors are mainly symptomatic and have only very limited neuroprotective effects, whereas drugs slowing down neurodegeneration of dopaminergic neurons and deterioration of clinical symptoms are not yet available. Given that, the development of more valuable pharmacological strategies is highly demanded. Comprehensive research on innovative neuroprotective drugs has proven that anti-inflammatory and antioxidant molecules from food sources may prevent and/or counteract neurodegenerative diseases, such as PD. The present study was aimed at the evaluation the protective effect of mandarin juice extract (MJe) against 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma cell death. Treatment of differentiated SH-SY5Y cells with 6-OHDA brought cell death, and specifically, apoptosis, which was significantly inhibited by the preincubation with MJe through caspase 3 blockage and the modulation of p53, Bax, and Bcl-2 genes. In addition, it showed antioxidant properties in abiotic models as well as in vitro, where it reduced both reactive oxygen and nitrogen species induced by 6-OHDA, along with restored mitochondrial membrane potential, and prevented the oxidative DNA damage evoked by 6-OHDA. Furthermore, MJe restored the impaired balance of SNCA, LRRK2, PINK1, parkin, and DJ-1 gene levels, PD-related factors, caused by 6-OHDA oxidative stress. Overall, these results indicate that MJe exerts neuroprotective effects against 6-OHDA-induced cell death in SH-SY5Y cells by mechanisms involving both the specific interaction with intracellular pathways and its antioxidant capability. Our study suggests a novel possible strategy to prevent and/or ameliorate neurodegenerative diseases, such as PD. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

17 pages, 2755 KiB

Open AccessArticle

Icaritin Provides Neuroprotection in Parkinson’s Disease by Attenuating Neuroinflammation, Oxidative Stress, and Energy Deficiency

by Hao Wu, Xi Liu, Ze-Yu Gao, Ming Lin, Xin Zhao, Yi Sun and Xiao-Ping Pu

Antioxidants 2021, 10(4), 529; https://doi.org/10.3390/antiox10040529 - 29 Mar 2021

Cited by 33 | Viewed by 4259

Abstract

Neuroinflammation, oxidative stress, and mitochondrial dysfunction are all important pathogenic mechanisms underlying motor dysfunction and dopaminergic neuronal damage observed in patients with Parkinson’s disease (PD). However, despite extensive efforts, targeting inflammation and oxidative stress using various approaches has not led to meaningful clinical [...] Read more.

Neuroinflammation, oxidative stress, and mitochondrial dysfunction are all important pathogenic mechanisms underlying motor dysfunction and dopaminergic neuronal damage observed in patients with Parkinson’s disease (PD). However, despite extensive efforts, targeting inflammation and oxidative stress using various approaches has not led to meaningful clinical outcomes, and mitochondrial enhancers have also failed to convincingly achieve disease-modifying effects. We tested our hypothesis that treatment approaches in PD should simultaneously reduce neuroinflammation, oxidative stress, and improve alterations in neuronal energy metabolism using the flavonoid icaritin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Using matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI-MSI), coupled with biochemical analyses and behavioral tests, we demonstrate that icaritin improves PD by attenuating the the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activity and stabilizing mitochondrial function, based on our extensive analyses showing the inhibition of NLRP3 inflammasome, reduction of NLRP3-mediated IL-1β secretion, and improvements in the levels of antioxidant molecules. Our data also indicated that icaritin stabilized the levels of proteins related to mitochondrial function, such as voltage-dependent anion channel (VDAC) and ATP synthase subunit beta (ATP5B), as well as those of molecules related to energy metabolism, such as ATP and ADP, ultimately improving mitochondrial dysfunction. By employing molecular docking, we also discovered that icaritin can interact with NLRP3, VDAC, ATP5B, and several blood–brain barrier (BBB)-related proteins. These data provide insights into the promising therapeutic potential of icaritin in PD. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Graphical abstract

Review

Jump to: Research, Other

50 pages, 3718 KiB

Open AccessReview

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

by Marcos Martinez-Banaclocha

Antioxidants 2022, 11(2), 416; https://doi.org/10.3390/antiox11020416 - 18 Feb 2022

Cited by 18 | Viewed by 5717

Abstract

In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the [...] Read more.

In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

36 pages, 2502 KiB

Open AccessEditor’s ChoiceReview

Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation

by Anushruti Ashok, Syed Suhail Andrabi, Saffar Mansoor, Youzhi Kuang, Brian K. Kwon and Vinod Labhasetwar

Antioxidants 2022, 11(2), 408; https://doi.org/10.3390/antiox11020408 - 17 Feb 2022

Cited by 86 | Viewed by 13743

Abstract

Free radicals are formed as a part of normal metabolic activities but are neutralized by the endogenous antioxidants present in cells/tissue, thus maintaining the redox balance. This redox balance is disrupted in certain neuropathophysiological conditions, causing oxidative stress, which is implicated in several [...] Read more.

Free radicals are formed as a part of normal metabolic activities but are neutralized by the endogenous antioxidants present in cells/tissue, thus maintaining the redox balance. This redox balance is disrupted in certain neuropathophysiological conditions, causing oxidative stress, which is implicated in several progressive neurodegenerative diseases. Following neuronal injury, secondary injury progression is also caused by excessive production of free radicals. Highly reactive free radicals, mainly the reactive oxygen species (ROS) and reactive nitrogen species (RNS), damage the cell membrane, proteins, and DNA, which triggers a self-propagating inflammatory cascade of degenerative events. Dysfunctional mitochondria under oxidative stress conditions are considered a key mediator in progressive neurodegeneration. Exogenous delivery of antioxidants holds promise to alleviate oxidative stress to regain the redox balance. In this regard, natural and synthetic antioxidants have been evaluated. Despite promising results in preclinical studies, clinical translation of antioxidants as a therapy to treat neurodegenerative diseases remains elusive. The issues could be their low bioavailability, instability, limited transport to the target tissue, and/or poor antioxidant capacity, requiring repeated and high dosing, which cannot be administered to humans because of dose-limiting toxicity. Our laboratory is investigating nanoparticle-mediated delivery of antioxidant enzymes to address some of the above issues. Apart from being endogenous, the main advantage of antioxidant enzymes is their catalytic mechanism of action; hence, they are significantly more effective at lower doses in detoxifying the deleterious effects of free radicals than nonenzymatic antioxidants. This review provides a comprehensive analysis of the potential of antioxidant therapy, challenges in their clinical translation, and the role nanoparticles/drug delivery systems could play in addressing these challenges. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

18 pages, 736 KiB

Open AccessReview

Endoplasmic Reticulum Stress in Chemotherapy-Induced Peripheral Neuropathy: Emerging Role of Phytochemicals

by Yugal Goel, Raghda Fouda and Kalpna Gupta

Antioxidants 2022, 11(2), 265; https://doi.org/10.3390/antiox11020265 - 28 Jan 2022

Cited by 7 | Viewed by 3926

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting long-term sequela in cancer patients undergoing treatment, often leading to discontinuation of treatment. No established therapy exists to prevent and/or ameliorate CIPN. Reactive oxygen species (ROS) and mitochondrial dysregulation have been proposed to underlie the [...] Read more.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting long-term sequela in cancer patients undergoing treatment, often leading to discontinuation of treatment. No established therapy exists to prevent and/or ameliorate CIPN. Reactive oxygen species (ROS) and mitochondrial dysregulation have been proposed to underlie the pathobiology of CIPN. However, interventions to prevent and treat CIPN are largely ineffective. Additional factors and mechanism-based targets need to be identified to develop novel strategies to target CIPN. The role of oxidative stress appears to be central, but the contribution of endoplasmic reticulum (ER) stress remains under-examined in the pathobiology of CIPN. This review describes the significance of ER stress and its contribution to CIPN, the protective role of herbal agents in countering ER stress in nervous system-associated disorders, and their possible repurposing for preventing CIPN. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

11 pages, 1320 KiB

Open AccessReview

Antitumor Effects of Natural Compounds Derived from Allium sativum on Neuroblastoma: An Overview

by Carlos César Patiño-Morales, Ricardo Jaime-Cruz, Concepción Sánchez-Gómez, Juan Carlos Corona, Estefani Yaquelin Hernández-Cruz, Ivia Kalinova-Jelezova, José Pedraza-Chaverri, Perla D. Maldonado, Carlos Alfredo Silva-Islas and Marcela Salazar-García

Antioxidants 2022, 11(1), 48; https://doi.org/10.3390/antiox11010048 - 27 Dec 2021

Cited by 20 | Viewed by 4076

Abstract

Garlic (Allium sativum) has been used in alternative medicine to treat several diseases, such as cardiovascular and neurodegenerative diseases, cancer, and hepatic diseases. Several publications have highlighted other features of garlic, including its antibacterial, antioxidative, antihypertensive, and antithrombotic properties. The properties [...] Read more.

Garlic (Allium sativum) has been used in alternative medicine to treat several diseases, such as cardiovascular and neurodegenerative diseases, cancer, and hepatic diseases. Several publications have highlighted other features of garlic, including its antibacterial, antioxidative, antihypertensive, and antithrombotic properties. The properties of garlic result from the combination of natural compounds that act synergistically and cause different effects. Some garlic-derived compounds have been studied for the treatment of several types of cancer; however, reports on the effects of garlic on neuroblastoma are scarce. Neuroblastoma is a prevalent childhood tumor for which the search for therapeutic alternatives to improve treatment without affecting the patients’ quality of life continues. Garlic-derived compounds hold potential for the treatment of this type of cancer. A review of articles published to date on some garlic compounds and their effect on neuroblastoma was undertaken to comprehend the possible therapeutic role of these compounds. This review aimed to analyze the impact of some garlic compounds on cells derived from neuroblastoma. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

16 pages, 1524 KiB

Open AccessReview

The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer’s Disease

by Janine Mett

Antioxidants 2021, 10(12), 1991; https://doi.org/10.3390/antiox10121991 - 14 Dec 2021

Cited by 17 | Viewed by 3765

Abstract

Alzheimer’s disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is [...] Read more.

Alzheimer’s disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

26 pages, 2093 KiB

Open AccessReview

Two Birds One Stone: The Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease—Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

by Kai-Jung Lin, Tzu-Jou Wang, Shang-Der Chen, Kai-Lieh Lin, Chia-Wei Liou, Min-Yu Lan, Yao-Chung Chuang, Jiin-Haur Chuang, Pei-Wen Wang, Jong-Jer Lee, Feng-Sheng Wang, Hung-Yu Lin and Tsu-Kung Lin

Antioxidants 2021, 10(12), 1935; https://doi.org/10.3390/antiox10121935 - 2 Dec 2021

Cited by 31 | Viewed by 5851

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease affecting more than 1% of the population over 65 years old. The etiology of the disease is unknown and there are only symptomatic managements available with no known disease-modifying treatment. [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease affecting more than 1% of the population over 65 years old. The etiology of the disease is unknown and there are only symptomatic managements available with no known disease-modifying treatment. Aging, genes, and environmental factors contribute to PD development and key players involved in the pathophysiology of the disease include oxidative stress, mitochondrial dysfunction, autophagic–lysosomal imbalance, and neuroinflammation. Recent epidemiology studies have shown that type-2 diabetes (T2DM) not only increased the risk for PD, but also is associated with PD clinical severity. A higher rate of insulin resistance has been reported in PD patients and is suggested to be a pathologic driver in this disease. Oral diabetic drugs including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to provide neuroprotective effects in both PD patients and experimental models; additionally, antidiabetic drugs have been demonstrated to lower incidence rates of PD in DM patients. Among these, the most recently developed drugs, SGLT2 inhibitors may provide neuroprotective effects through improving mitochondrial function and antioxidative effects. In this article, we will discuss the involvement of mitochondrial-related oxidative stress in the development of PD and potential benefits provided by antidiabetic agents especially focusing on sglt2 inhibitors. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

12 pages, 1168 KiB

Open AccessReview

Oxidative Stress in the Brain: Basic Concepts and Treatment Strategies in Stroke

by Matyas Jelinek, Michal Jurajda and Kamil Duris

Antioxidants 2021, 10(12), 1886; https://doi.org/10.3390/antiox10121886 - 25 Nov 2021

Cited by 99 | Viewed by 6686

Abstract

The production of free radicals is inevitably associated with metabolism and other enzymatic processes. Under physiological conditions, however, free radicals are effectively eliminated by numerous antioxidant mechanisms. Oxidative stress occurs due to an imbalance between the production and elimination of free radicals under [...] Read more.

The production of free radicals is inevitably associated with metabolism and other enzymatic processes. Under physiological conditions, however, free radicals are effectively eliminated by numerous antioxidant mechanisms. Oxidative stress occurs due to an imbalance between the production and elimination of free radicals under pathological conditions. Oxidative stress is also associated with ageing. The brain is prone to oxidative damage because of its high metabolic activity and high vulnerability to ischemic damage. Oxidative stress, thus, plays a major role in the pathophysiology of both acute and chronic pathologies in the brain, such as stroke, traumatic brain injury or neurodegenerative diseases. The goal of this article is to summarize the basic concepts of oxidative stress and its significance in brain pathologies, as well as to discuss treatment strategies for dealing with oxidative stress in stroke. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

26 pages, 5532 KiB

Open AccessReview

DHA and Its Elaborated Modulation of Antioxidant Defenses of the Brain: Implications in Aging and AD Neurodegeneration

by Mario Díaz, Fátima Mesa-Herrera and Raquel Marín

Antioxidants 2021, 10(6), 907; https://doi.org/10.3390/antiox10060907 - 3 Jun 2021

Cited by 46 | Viewed by 6602

Abstract

DHA (docosahexaenoic acid) is perhaps the most pleiotropic molecule in nerve cell biology. This long-chain highly unsaturated fatty acid has evolved to accomplish essential functions ranging from structural components allowing fast events in nerve cell membrane physiology to regulation of neurogenesis and synaptic [...] Read more.

DHA (docosahexaenoic acid) is perhaps the most pleiotropic molecule in nerve cell biology. This long-chain highly unsaturated fatty acid has evolved to accomplish essential functions ranging from structural components allowing fast events in nerve cell membrane physiology to regulation of neurogenesis and synaptic function. Strikingly, the plethora of DHA effects has to take place within the hostile pro-oxidant environment of the brain parenchyma, which might suggest a molecular suicide. In order to circumvent this paradox, different molecular strategies have evolved during the evolution of brain cells to preserve DHA and to minimize the deleterious effects of its oxidation. In this context, DHA has emerged as a member of the “indirect antioxidants” family, the redox effects of which are not due to direct redox interactions with reactive species, but to modulation of gene expression within thioredoxin and glutathione antioxidant systems and related pathways. Weakening or deregulation of these self-protecting defenses orchestrated by DHA is associated with normal aging but also, more worryingly, with the development of neurodegenerative diseases. In the present review, we elaborate on the essential functions of DHA in the brain, including its role as indirect antioxidant, the selenium connection for proper antioxidant function and their changes during normal aging and in Alzheimer’s disease. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Graphical abstract

Other

Jump to: Research, Review

5 pages, 395 KiB

Open AccessComment

Comment on Yeste et al. Polyphenols and IUGR Pregnancies: Intrauterine Growth Restriction and Hydroxytyrosol Affect the Development and Neurotransmitter Profile of the Hippocampus in a Pig Model. Antioxidants 2021, 10, 1505

by Glòria Garrabou, Ana Sandra Hernández, Mariona Guitart-Mampel, Elena Escalada-Casellas, Gemma Malats-Revelles, Sara Castro-Barquero, Ana María Ruiz-León, Kilian Vellvé, Rosa Casas, Francesc Cardellach, Fàtima Crispi and Francesc Josep García-García

Antioxidants 2022, 11(5), 833; https://doi.org/10.3390/antiox11050833 - 25 Apr 2022

Viewed by 2008

Abstract

Intrauterine growth restriction (IUGR) affects 5–10% of newborns and increases the risks of intrauterine demise, neonatal morbidity, and death. In their recent publication, Yeste et al. found the benefits of hydroxytyrosol supplementation on brain remodeling from an IUGR pig model. Additionally, we found [...] Read more.

Intrauterine growth restriction (IUGR) affects 5–10% of newborns and increases the risks of intrauterine demise, neonatal morbidity, and death. In their recent publication, Yeste et al. found the benefits of hydroxytyrosol supplementation on brain remodeling from an IUGR pig model. Additionally, we found a significant decrease in phenolic alcohol (tyrosol and hydroxytyrosol) intake in IUGR pregnant women. Altogether, these findings support the notion that dietetic interventions, through supplementation but mostly via a balanced diet, can ameliorate IUGR complications. Furthermore, diet intervention combined with early biomarkers may allow clinicians to eventually anticipate IUGR diagnosis and help avoid one of the most frequent causes of newborn mortality and morbidity. Full article

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (31 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI