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Neuroprotective Potential of Bioactive Natural Compounds in Oxidative Stress Conditions

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 28259

Special Issue Editors

Ruder Boskovic Institute, Zagreb, Croatia
Interests: model membranes; biodegradable nanomaterials; lipid peroxidation; natural products; antioxidants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxidative stress is one of the major causes of neuronal death in a variety of neurodegenerative diseases. Its contribution to neuropsychiatric disorders has been suggested as well. As the world’s population is getting older, neurodegenerative diseases, such as Alzheimer´s and Parkinson´s disease, represent a growing medical, economic, and social issue. Although the considerable progress has been made towards understanding the pathological mechanisms that underlie development and progression of these diseases at the molecular and cellular levels, this knowledge has not yet been successfully translated into the clinics.

Oxidative stress occurs when increased accumulation of reactive oxygen species (ROS) overwhelms the brain’s intrinsic capacity of oxidative defence, leading to detrimental effects on neuronal functioning and viability. Many evidences indicate that deregulation of metal homeostasis, accompanied with enhanced production of free radicals and increased oxidative stress, could be directly involved in the onset and progression of neurodegenerative diseases. On the other hand, natural products have potential to re-establish redox homeostasis and reduce or prevent metal-induced oxidative damage. They may act as antioxidants, metal chelators and modulators of intracellular signalling. Hence, bioactive natural molecules represent a promising multi-target drug option, particularly at the early stages of neurodegenerative processes.

Therefore, this Special Issue of Molecules is dedicated to research and review articles that cover the latest findings about the beneficial effects of bioactive natural compounds in the prevention and therapy of oxidative stress-driven neuronal injury. Studies devoted to investigation of efficacy and mechanisms of action of various bioactive molecules with the potential to regain metal homeostasis in the treatment of neurodegenerative diseases are particularly welcome.

Dr. Maja Jazvinšćak Jembrek
Dr. Suzana Šegota
Guest Editors

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Keywords

  • Oxidative stress
  • Natural antioxidants
  • Neuroprotection
  • Metal homeostasis

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Published Papers (8 papers)

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Research

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10 pages, 1056 KiB  
Article
Electrophysiological Activity and Survival Rate of Rats Nervous Tissue Cells Depends on D/H Isotopic Composition of Medium
Molecules 2021, 26(7), 2036; https://doi.org/10.3390/molecules26072036 - 02 Apr 2021
Cited by 6 | Viewed by 1990
Abstract
The deuterium content modification in an organism has a neuroprotective effect during the hypoxia model, affecting anxiety, memory and stress resistance. The aim of this work was to elucidate the possible mechanisms of the medium D/H composition modification on nerve cells. We studied [...] Read more.
The deuterium content modification in an organism has a neuroprotective effect during the hypoxia model, affecting anxiety, memory and stress resistance. The aim of this work was to elucidate the possible mechanisms of the medium D/H composition modification on nerve cells. We studied the effect of an incubation medium with a 50 ppm deuterium content compared to a medium with 150 ppm on: (1) the activity of Wistar rats’ hippocampus CA1 field neurons, (2) the level of cultured cerebellar neuron death during glucose deprivation and temperature stress, (3) mitochondrial membrane potential (MMP) and the generation of reactive oxygen species in cultures of cerebellar neurons. The results of the analysis showed that the incubation of hippocampal sections in a medium with a 50 ppm deuterium reduced the amplitude of the pop-spike. The restoration of neuron activity was observed when sections were returned to the incubation medium with a 150 ppm deuterium content. An environment with a 50 ppm deuterium did not significantly affect the level of reactive oxygen species in neuron cultures, while MMP decreased by 16–20%. In experiments with glucose deprivation and temperature stress, the medium with 50 ppm increased the death of neurons. Thus, a short exposure of nerve cells in the medium with 50 ppm deuterium acts as an additional stressful factor, which is possibly associated with the violation of the cell energy balance. The decrease in the mitochondrial membrane potential, which is known to be associated with ATP synthesis, indicates that this effect may be associated with the cell energy imbalance. The decrease in the activity of the CA1 field hippocampal neurons may reflect reversible adaptive changes in the operation of fast-reacting ion channels. Full article
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28 pages, 8059 KiB  
Article
Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper
Molecules 2021, 26(4), 845; https://doi.org/10.3390/molecules26040845 - 05 Feb 2021
Cited by 10 | Viewed by 3184
Abstract
Oxidative stress (OS) induced by the disturbed homeostasis of metal ions is one of the pivotal factors contributing to neurodegeneration. The aim of the present study was to investigate the effects of flavonoid myricetin on copper-induced toxicity in neuroblastoma SH-SY5Y cells. As determined [...] Read more.
Oxidative stress (OS) induced by the disturbed homeostasis of metal ions is one of the pivotal factors contributing to neurodegeneration. The aim of the present study was to investigate the effects of flavonoid myricetin on copper-induced toxicity in neuroblastoma SH-SY5Y cells. As determined by the MTT method, trypan blue exclusion assay and measurement of ATP production, myricetin heightened the toxic effects of copper and exacerbated cell death. It also increased copper-induced generation of reactive oxygen species, indicating the prooxidative nature of its action. Furthermore, myricetin provoked chromatin condensation and loss of membrane integrity without caspase-3 activation, suggesting the activation of both caspase-independent programmed cell death and necrosis. At the protein level, myricetin-induced upregulation of PARP-1 and decreased expression of Bcl-2, whereas copper-induced changes in the expression of p53, p73, Bax and NME1 were not further affected by myricetin. Inhibitors of ERK1/2 and JNK kinases, protein kinase A and L-type calcium channels exacerbated the toxic effects of myricetin, indicating the involvement of intracellular signaling pathways in cell death. We also employed atomic force microscopy (AFM) to evaluate the morphological and mechanical properties of SH-SY5Y cells at the nanoscale. Consistent with the cellular and molecular methods, this biophysical approach also revealed a myricetin-induced increase in cell surface roughness and reduced elasticity. Taken together, we demonstrated the adverse effects of myricetin, pointing out that caution is required when considering powerful antioxidants for adjuvant therapy in copper-related neurodegeneration. Full article
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18 pages, 2785 KiB  
Article
Melatonin Rescues the Dendrite Collapse Induced by the Pro-Oxidant Toxin Okadaic Acid in Organotypic Cultures of Rat Hilar Hippocampus
Molecules 2020, 25(23), 5508; https://doi.org/10.3390/molecules25235508 - 25 Nov 2020
Cited by 5 | Viewed by 2027
Abstract
The pro-oxidant compound okadaic acid (OKA) mimics alterations found in Alzheimer’s disease (AD) as oxidative stress and tau hyperphosphorylation, leading to neurodegeneration and cognitive decline. Although loss of dendrite complexity occurs in AD, the study of this post-synaptic domain in chemical-induced models remains [...] Read more.
The pro-oxidant compound okadaic acid (OKA) mimics alterations found in Alzheimer’s disease (AD) as oxidative stress and tau hyperphosphorylation, leading to neurodegeneration and cognitive decline. Although loss of dendrite complexity occurs in AD, the study of this post-synaptic domain in chemical-induced models remains unexplored. Moreover, there is a growing expectation for therapeutic adjuvants to counteract these brain dysfunctions. Melatonin, a free-radical scavenger, inhibits tau hyperphosphorylation, modulates phosphatases, and strengthens dendritic arbors. Thus, we determined if OKA alters the dendritic arbors of hilar hippocampal neurons and whether melatonin prevents, counteracts, or reverses these damages. Rat organotypic cultures were incubated with vehicle, OKA, melatonin, and combined treatments with melatonin either before, simultaneously, or after OKA. DNA breaks were assessed by TUNEL assay and nuclei were counterstained with DAPI. Additionally, MAP2 was immunostained to assess the dendritic arbor properties by the Sholl method. In hippocampal hilus, OKA increased DNA fragmentation and reduced the number of MAP2(+) cells, whereas melatonin protected against oxidation and apoptosis. Additionally, OKA decreased the dendritic arbor complexity and melatonin not only counteracted, but also prevented and reversed the dendritic arbor retraction, highlighting its role in post-synaptic domain integrity preservation against neurodegenerative events in hippocampal neurons. Full article
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20 pages, 5815 KiB  
Article
Synergistic Neuroprotective Effect of Endogenously-Produced Hydroxytyrosol and Synaptic Vesicle Proteins on Pheochromocytoma Cell Line against Salsolinol
Molecules 2020, 25(7), 1715; https://doi.org/10.3390/molecules25071715 - 08 Apr 2020
Cited by 6 | Viewed by 3363
Abstract
Oxidative stress triggers a lethal cascade, leading to Parkinson’s disease by causing degeneration of dopaminergic neurons. In this study, eight antioxidants were screened for their neuroprotective effect on PC12 cells (pheochromocytoma cell line) under oxidative stress induced by salsolinol (OSibS). Hydroxytyrosol was found [...] Read more.
Oxidative stress triggers a lethal cascade, leading to Parkinson’s disease by causing degeneration of dopaminergic neurons. In this study, eight antioxidants were screened for their neuroprotective effect on PC12 cells (pheochromocytoma cell line) under oxidative stress induced by salsolinol (OSibS). Hydroxytyrosol was found to be the strongest neuroprotective agent; it improved viability of PC12 cells by up to 81.69% under OSibS. Afterward, two synaptic vesicle proteins, synapsin-1 and septin-5, were screened for their neuroprotective role; the overexpression of synapsin-1 and the downregulation of septin-5 separately improved the viability of PC12 cells by up to 71.17% and 67.00%, respectively, compared to PC12 cells only treated with salsolinol (PoTwS) under OSibS. Subsequently, the PC12+syn++sep cell line was constructed and pretreated with 100 µM hydroxytyrosol, which improved its cell viability by up to 99.03% and led to 14.71- and 6.37-fold reductions in the levels of MDA and H2O2, respectively, and 6.8-, 12.97-, 10.57-, and 7.57-fold increases in the activity of catalase, glutathione reductase, superoxide dismutase, and glutathione peroxidase, respectively, compared to PoTwS under OSibS. Finally, alcohol dehydrogenase-6 from Saccharomyces cerevisiae was expressed in PC12+syn++sep cells to convert 3,4-dihydroxyphenylacetaldehyde (an endogenous neurotoxin) into hydroxytyrosol. The PC12+syn++sep+ADH6+ cell line also led to 22.38- and 12.33-fold decreases in the production of MDA and H2O2, respectively, and 7.15-, 13.93-, 12.08-, and 8.11-fold improvements in the activity of catalase, glutathione reductase, superoxide dismutase, and glutathione peroxidase, respectively, compared to PoTwS under OSibS. Herein, we report the endogenous production of a powerful antioxidant, hydroxytyrosol, from 3,4-dihydroxyphenylacetaldehyde, and evaluate its synergistic neuroprotective effect, along with synapsin-1 and septin-5, on PC12 cells under OSibS. Full article
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Review

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21 pages, 1095 KiB  
Review
Nutraceutical Approaches of Autophagy and Neuroinflammation in Alzheimer’s Disease: A Systematic Review
Molecules 2020, 25(24), 6018; https://doi.org/10.3390/molecules25246018 - 18 Dec 2020
Cited by 23 | Viewed by 4280
Abstract
Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer’s disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that [...] Read more.
Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer’s disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called “nutraceuticals” epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD. Full article
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16 pages, 614 KiB  
Review
Neuroprotective Effects of Quercetin in Pediatric Neurological Diseases
Molecules 2020, 25(23), 5597; https://doi.org/10.3390/molecules25235597 - 28 Nov 2020
Cited by 23 | Viewed by 4074
Abstract
Oxidative stress is a crucial event underlying several pediatric neurological diseases, such as the central nervous system (CNS) tumors, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Neuroprotective therapy with natural compounds used as antioxidants has the potential to delay, ameliorate or prevent [...] Read more.
Oxidative stress is a crucial event underlying several pediatric neurological diseases, such as the central nervous system (CNS) tumors, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Neuroprotective therapy with natural compounds used as antioxidants has the potential to delay, ameliorate or prevent several pediatric neurological diseases. The present review provides an overview of the most recent research outcomes following quercetin treatment for CNS tumors, ASD and ADHD as well as describes the potential in vitro and in vivo ameliorative effect on oxidative stress of bioactive natural compounds, which seems like a promising future therapy for these diseases. The neuroprotective effects of quercetin against oxidative stress can also be applied in the management of several neurodegenerative disorders with effects such as anti-cancer, anti-inflammatory, anti-viral, anti-obesity and anti-microbial. Therefore, quercetin appears to be a suitable adjuvant for therapy against pediatric neurological diseases. Full article
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20 pages, 917 KiB  
Review
The Potential Mechanisms of the Neuroprotective Actions of Oil Palm Phenolics: Implications for Neurodegenerative Diseases
Molecules 2020, 25(21), 5159; https://doi.org/10.3390/molecules25215159 - 05 Nov 2020
Cited by 8 | Viewed by 2999
Abstract
Neurodegenerative diseases (ND) can be characterized by degradation and subsequent loss of neurons. ND has been identified as the leading cause of disability-adjusted life years (DALYs) worldwide and is associated with various risk factors such as ageing, certain genetic polymorphisms, inflammation, immune and [...] Read more.
Neurodegenerative diseases (ND) can be characterized by degradation and subsequent loss of neurons. ND has been identified as the leading cause of disability-adjusted life years (DALYs) worldwide and is associated with various risk factors such as ageing, certain genetic polymorphisms, inflammation, immune and metabolic conditions that may induce elevated reactive oxygen species (ROS) release and subsequent oxidative stress. Presently, no specific cure or prevention is available for ND patients; the symptoms can be only alleviated via drug treatment or surgery. The existing pharmacological treatments are only available for partial treatment of the symptoms. A natural product known as oil palm phenolics (OPP), which is high in antioxidant, could become a potential supplementary antioxidant for neurodegenerative health. OPP is a water-soluble extract from palm fruit that demonstrated medicinal properties including anti-tumor, anti-diabetic and neuroprotective effects. In this review, OPP was proposed for its neuroprotective effects via several mechanisms including antioxidant and anti-inflammatory properties. Besides, OPP has been found to modulate the genes involved in neurotrophic activity. The evidence and proposed mechanism of OPP on the neuroprotective health may provide a comprehensive natural medicine approach to alleviate the symptoms of neurodegenerative diseases. Full article
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19 pages, 669 KiB  
Review
Anti-Apoptotic Effects of Carotenoids in Neurodegeneration
Molecules 2020, 25(15), 3453; https://doi.org/10.3390/molecules25153453 - 29 Jul 2020
Cited by 60 | Viewed by 5356
Abstract
Apoptosis, programmed cell death type I, is a critical part of neurodegeneration in cerebral ischemia, Parkinson’s, and Alzheimer’s disease. Apoptosis begins with activation of pro-death proteins Bax and Bak, release of cytochrome c and activation of caspases, loss of membrane integrity of intracellular [...] Read more.
Apoptosis, programmed cell death type I, is a critical part of neurodegeneration in cerebral ischemia, Parkinson’s, and Alzheimer’s disease. Apoptosis begins with activation of pro-death proteins Bax and Bak, release of cytochrome c and activation of caspases, loss of membrane integrity of intracellular organelles, and ultimately cell death. Approaches that block apoptotic pathways may prevent or delay neurodegenerative processes. Carotenoids are a group of pigments found in fruits, vegetables, and seaweeds that possess antioxidant properties. Over the last several decades, an increasing number of studies have demonstrated a protective role of carotenoids in neurodegenerative disease. In this review, we describe functions of commonly consumed carotenoids including lycopene, β-carotene, lutein, astaxanthin, and fucoxanthin and their roles in neurodegenerative disease models. We also discuss the underlying cellular mechanisms of carotenoid-mediated neuroprotection, including their antioxidant properties, role as signaling molecules, and as gene regulators that alleviate apoptosis-associated brain cell death. Full article
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