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Advance in Neurotoxicity Research from Development to Aging

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

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 24077

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Special Issue Editors

Dr. Debora Cutuli

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Guest Editor

Department of Psychology, Sapienza University of Rome, Rome, Italy
Interests: behavioral neuroscience; cognition; aging; neurodegenerative diseases; development; psychobiology

Dr. Laura Petrosini

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Guest Editor

Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
Interests: behavioral neuroscience; neurodegeneration; cognition; emotional behaviors; cerebellar physiology

Prof. Dr. Francesca Gelfo

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Guest Editor

Department of Human Sciences, Guglielmo Marconi University, Rome, Italy
Interests: behavioural neuroscience; psychopharmacology; neuroprotection; cerebral and cognitive reserve; neurodegenerative diseases; neuronal morphology; neurotrophic factors

Special Issue Information

Dear Colleagues,

A substance capable of inducing a consistent pattern of neural dysfunction or change in the chemistry or structure of the nervous system may be defined as neurotoxic. Even brief exposure to multiple substances can result in severe functional deficits, including abnormalities in relevant biochemical parameters, EEG findings, psychological and behavioral testing, neurological examinations, and axonopathy and cell death. The neurotoxins produce various effects in development and aging.

This Special Issue on the lifetime effects of neurotoxins on brain functioning will present new advances on some of the most common agents known to affect neural organization. Despite a growing body of preclinical studies demonstrating neurotoxic effects in both the developing and aging brain, the impact of neurotoxic agents on the human brain remains to be clarified. In particular, elderly subjects are at increased risk for adverse reactions given their physiological alterations that affect pharmacokinetic processes.

This Special Issue welcomes papers addressing the different effects that exposure to neurotoxic agents may elicit in both developmental and aging stages.

Dr. Debora Cutuli
Dr. Laura Petrosini
Prof. Dr. Francesca Gelfo
Guest Editors

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Keywords

neurodevelopment
aging
neurotoxicity mechanisms
neurotoxic agents
immunotoxic agents
animal models
neurodegenerative diseases

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Published Papers (9 papers)

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Editorial

Jump to: Research, Review

9 pages, 292 KiB

Open AccessEditorial

Advance in Neurotoxicity Research from Development to Aging

by Debora Cutuli, Laura Petrosini and Francesca Gelfo

Int. J. Mol. Sci. 2023, 24(20), 15112; https://doi.org/10.3390/ijms242015112 - 12 Oct 2023

Viewed by 910

Abstract

A substance capable of inducing a consistent pattern of neural dysfunction in the chemistry or structure of the nervous system may be defined as neurotoxic [...] Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

Research

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18 pages, 2230 KiB

Open AccessArticle

Zinc Inhibits the GABA_AR/ATPase during Postnatal Rat Development: The Role of Cysteine Residue

by Sergey A. Menzikov, Danila M. Zaichenko, Aleksey A. Moskovtsev, Sergey G. Morozov and Aslan A. Kubatiev

Int. J. Mol. Sci. 2023, 24(3), 2764; https://doi.org/10.3390/ijms24032764 - 1 Feb 2023

Cited by 3 | Viewed by 1600

Abstract

Zinc ions (Zn²⁺) are concentrated in various brain regions and can act as a neuromodulator, targeting a wide spectrum of postsynaptic receptors and enzymes. Zn²⁺ inhibits the GABA_ARs, and its potency is profoundly affected by the subunit composition and neuronal developmental stage. Although the extracellular amino acid residues of the receptor’s hetero-oligomeric structure are preferred for Zn²⁺ binding, there are intracellular sites that, in principle, could coordinate its potency. However, their role in modulating the receptor function during postembryonic development remains unclear. The GABA_AR possesses an intracellular ATPase that enables the energy-dependent anion transport via a pore. Here, we propose a mechanistic and molecular basis for the inhibition of intracellular GABA_AR/ATPase function by Zn²⁺ in neonatal and adult rats. The enzymes within the scope of GABA_AR performance as Cl⁻ATPase and then as Cl⁻, HCO₃⁻ATPase form during the first week of postnatal rat development. In addition, we have shown that the Cl⁻ATPase form belongs to the β1 subunit, whereas the β3 subunit preferably possesses the Cl⁻, HCO₃⁻ATPase activity. We demonstrated that a Zn²⁺ with variable efficacy inhibits the GABA_AR as well as the ATPase activities of immature or mature neurons. Using fluorescence recording in the cortical synaptoneurosomes (SNs), we showed a competitive association between Zn²⁺ and NEM in parallel changes both in the ATPase activity and the GABA_AR-mediated Cl⁻ and HCO₃⁻ fluxes. Finally, by site-directed mutagenesis, we identified in the M3 domain of β subunits the cysteine residue (C313) that is essential for the manifestation of Zn²⁺ potency. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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23 pages, 2745 KiB

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Near-Infrared Photothermally Enhanced Photo-Oxygenation for Inhibition of Amyloid-β Aggregation Based on RVG-Conjugated Porphyrinic Metal–Organic Framework and Indocyanine Green Nanoplatform

by Jiuhai Wang, Yutian Gu, Xu Liu, Yadi Fan, Yu Zhang, Changqing Yi, Changming Cheng and Mo Yang

Int. J. Mol. Sci. 2022, 23(18), 10885; https://doi.org/10.3390/ijms231810885 - 17 Sep 2022

Cited by 13 | Viewed by 2727

Abstract

Amyloid aggregation is associated with many neurodegenerative diseases such as Alzheimer’s disease (AD). The current technologies using phototherapy for amyloid inhibition are usually photodynamic approaches based on evidence that reactive oxygen species can inhibit Aβ aggregation. Herein, we report a novel combinational photothermally assisted photo-oxygenation treatment based on a nano-platform of the brain-targeting peptide RVG conjugated with the 2D porphyrinic PCN−222 metal–organic framework and indocyanine green (PCN−222@ICG@RVG) with enhanced photo-inhibition in Alzheimer’s Aβ aggregation. A photothermally assisted photo-oxygenation treatment based on PCN@ICG could largely enhance the photo-inhibition effect on Aβ₄₂ aggregation and lead to much lower neurotoxicity upon near-infrared (NIR) irradiation at 808 nm compared with a single modality of photo-treatment in both cell-free and in vitro experiments. Generally, local photothermal heat increases the instability of Aβ aggregates and keeps Aβ in the status of monomers, which facilitates the photo-oxygenation process of generating oxidized Aβ monomers with low aggregation capability. In addition, combined with the brain-targeting peptide RVG, the PCN−222@ICG@RVG nanoprobe shows high permeability of the human blood–brain barrier (BBB) on a human brain-on-a-chip platform. The ex vivo study also demonstrates that NIR-activated PCN−222@ICG@RVG could efficiently dissemble Aβ plaques. Our work suggests that the combination of photothermal treatment with photo-oxygenation can synergistically enhance the inhibition of Aβ aggregation, which may boost NIR-based combinational phototherapy of AD in the future. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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14 pages, 1788 KiB

Open AccessArticle

Sevoflurane Induces Neurotoxicity in the Animal Model with Alzheimer’s Disease Neuropathology via Modulating Glutamate Transporter and Neuronal Apoptosis

by Chunxia Huang, John Man Tak Chu, Yan Liu, Vivian Suk Wai Kwong, Raymond Chuen Chung Chang and Gordon Tin Chun Wong

Int. J. Mol. Sci. 2022, 23(11), 6250; https://doi.org/10.3390/ijms23116250 - 2 Jun 2022

Cited by 5 | Viewed by 2123

Abstract

Perioperative neurocognitive disorders are frequently observed in postoperative patients and previous reports have shown that pre-existing mild cognitive impairment with accumulated neuropathology may be a risk factor. Sevoflurane is a general anesthetic agent which is commonly used in clinical practice. However, the effects of sevoflurane in postoperative subjects are still controversial, as both neurotoxic or neuroprotective effects were reported. The purpose of this study is to investigate the effects of sevoflurane in 3 × Tg mice, a specific animal model with pre-existing Alzheimer’s disease neuropathology. 3 × Tg mice and wild-type mice were exposed to 2 h of sevoflurane respectively. Cognitive function, glutamate transporter expression, MAPK kinase pathways, and neuronal apoptosis were accessed on day 7 post-exposure. Our findings indicate that sevoflurane-induced cognitive deterioration in 3 × Tg mice, which was accompanied with the modulation of glutamate transporter, MAPK signaling, and neuronal apoptosis in the cortical and hippocampal regions. Meanwhile, no significant impact was observed in wild-type mice. Our results demonstrated that prolonged inhaled sevoflurane results in the exacerbation of neuronal and cognitive dysfunction which depends on the neuropathology background. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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20 pages, 2325 KiB

Open AccessArticle

Coating-Dependent Neurotoxicity of Silver Nanoparticles—An In Vivo Study on Hippocampal Oxidative Stress and Neurosteroids

by Katarzyna Dziendzikowska, Jacek Wilczak, Wojciech Grodzicki, Joanna Gromadzka-Ostrowska, Małgorzata Węsierska and Marcin Kruszewski

Int. J. Mol. Sci. 2022, 23(3), 1365; https://doi.org/10.3390/ijms23031365 - 25 Jan 2022

Cited by 16 | Viewed by 3101

Abstract

Silver nanoparticles (AgNPs) are one of the most widely used nanomaterials. The level of exposure to nanosilver is constantly raising, and a growing body of research highlights that it is harmful to the health, especially the nervous system, of humans. The potential pathways through which nanosilver affects neurons include the release of silver ions and the associated induction of oxidative stress. To better understand the mechanisms underlying the neurotoxicity of nanosilver, in this study we exposed male Wistar rats to 0.5 mg/kg body weight of AgNPs coated with bovine serum albumin (BSA), polyethylene glycol (PEG), or citrate, or to AgNO₃ as a source of silver ions for 28 days and assessed the expression of antioxidant defense markers in the hippocampus of the exposed animals after 1 week of spatial memory training. We also evaluated the influence of AgNPs coating on neurosteroidogenesis in the rat hippocampus. The results showed that AgNPs disrupted the antioxidant system in the hippocampus and induced oxidative stress in a coating-dependent manner, which could potentially be responsible for neurodegeneration and cognitive disorders. The analysis of the influence of AgNPs on neurosteroids also indicated coating-dependent modulation of steroid levels with a significant decrease in the concentrations of progesterone and 17α-progesterone in AgNPs(BSA), AgNPs(PEG), and Ag⁺ groups. Furthermore, exposure to AgNPs or Ag⁺ resulted in the downregulation of selected genes involved in antioxidant defense (Cat), neurosteroid synthesis (Star, Hsd3b3, Hsd17b1, and Hsd17b10), and steroid metabolism (Ar, Er1, and Er2). In conclusion, depending on the coating material used for their stabilization, AgNPs induced oxidative stress and modulated the concentrations of steroids as well as the expression of genes involved in steroid synthesis and metabolism. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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Review

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23 pages, 935 KiB

Open AccessReview

Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer’s Disease Animal Models of Lipopolysaccharide-Induced Inflammation

by Davide Decandia, Francesca Gelfo, Eugenia Landolfo, Francesca Balsamo, Laura Petrosini and Debora Cutuli

Int. J. Mol. Sci. 2023, 24(6), 5921; https://doi.org/10.3390/ijms24065921 - 21 Mar 2023

Cited by 13 | Viewed by 3519

Abstract

Alzheimer’s disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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29 pages, 1460 KiB

Open AccessReview

Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview

by Eugenia Landolfo, Debora Cutuli, Davide Decandia, Francesca Balsamo, Laura Petrosini and Francesca Gelfo

Int. J. Mol. Sci. 2023, 24(6), 5404; https://doi.org/10.3390/ijms24065404 - 11 Mar 2023

Cited by 5 | Viewed by 1698

Abstract

Neuroinflammation is a pathophysiological condition associated with damage to the nervous system. Maternal immune activation and early immune activation have adverse effects on the development of the nervous system and cognitive functions. Neuroinflammation during adulthood leads to neurodegenerative diseases. Lipopolysaccharide (LPS) is used in preclinical research to mimic neurotoxic effects leading to systemic inflammation. Environmental enrichment (EE) has been reported to cause a wide range of beneficial changes in the brain. Based on the above, the purpose of the present review is to describe the effects of exposure to EE paradigms in counteracting LPS-induced neuroinflammation throughout the lifespan. Up to October 2022, a methodical search of studies in the literature, using the PubMed and Scopus databases, was performed, focusing on exposure to LPS, as an inflammatory mediator, and to EE paradigms in preclinical murine models. On the basis of the inclusion criteria, 22 articles were considered and analyzed in the present review. EE exerts sex- and age-dependent neuroprotective and therapeutic effects in animals exposed to the neurotoxic action of LPS. EE’s beneficial effects are present throughout the various ages of life. A healthy lifestyle and stimulating environments are essential to counteract the damages induced by neurotoxic exposure to LPS. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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11 pages, 806 KiB

Open AccessReview

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

by Yuhai Zhao, Vivian R. Jaber, Aileen I. Pogue, Nathan M. Sharfman, Christopher Taylor and Walter J. Lukiw

Int. J. Mol. Sci. 2022, 23(20), 12671; https://doi.org/10.3390/ijms232012671 - 21 Oct 2022

Cited by 23 | Viewed by 3556

Abstract

Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In Homo sapiens, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including Bacteroides fragilis and Escherichia coli. LPSs have been abundantly detected in aged human brain by multiple independent research investigators, and an increased abundance of LPSs around and within Alzheimer’s disease (AD)-affected neurons has been found. Microbiome-generated LPSs and other endotoxins cross GI-tract biophysiological barriers into the systemic circulation and across the blood–brain barrier into the brain, a pathological process that increases during aging and in vascular disorders, including ‘leaky gut syndrome’. Further evidence indicates that LPSs up-regulate pro-inflammatory transcription factor complex NF-kB (p50/p65) and subsequently a set of NF-kB-sensitive microRNAs, including miRNA-30b, miRNA-34a, miRNA-146a and miRNA-155. These up-regulated miRNAs in turn down-regulate a family of neurodegeneration-associated messenger RNA (mRNA) targets, including the mRNA encoding the neuron-specific neurofilament light (NF-L) chain protein. While NF-L has been reported to be up-regulated in peripheral biofluids in AD and other progressive and lethal pro-inflammatory neurodegenerative disorders, NF-L is significantly down-regulated within neocortical neurons, and this may account for neuronal atrophy, loss of axonal caliber and alterations in neuronal cell shape, modified synaptic architecture and network deficits in neuronal signaling capacity. This paper reviews and reveals the most current findings on the neurotoxic aspects of LPSs and how these pro-inflammatory glycolipids contribute to the biological mechanism of progressive, age-related and ultimately lethal neurodegenerative disorders. This recently discovered gut-microbiota-derived LPS–NF-kB–miRNA-30b–NF-L pathological signaling network: (i) underscores a direct positive pathological link between the LPSs of GI-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic-signaling of the AD brain and stressed human brain cells in primary culture; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-mediated actions on the expression of NF-L, an abundant filamentous protein known to be important in the maintenance of neuronal and synaptic homeostasis. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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15 pages, 1754 KiB

Open AccessReview

Iron Deposition in Brain: Does Aging Matter?

by Eleonora Ficiarà, Ilaria Stura and Caterina Guiot

Int. J. Mol. Sci. 2022, 23(17), 10018; https://doi.org/10.3390/ijms231710018 - 2 Sep 2022

Cited by 14 | Viewed by 3180

Abstract

The alteration of iron homeostasis related to the aging process is responsible for increased iron levels, potentially leading to oxidative cellular damage. Iron is modulated in the Central Nervous System in a very sensitive manner and an abnormal accumulation of iron in the brain has been proposed as a biomarker of neurodegeneration. However, contrasting results have been presented regarding brain iron accumulation and the potential link with other factors during aging and neurodegeneration. Such uncertainties partly depend on the fact that different techniques can be used to estimate the distribution of iron in the brain, e.g., indirect (e.g., MRI) or direct (post-mortem estimation) approaches. Furthermore, recent evidence suggests that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their anatomical location. This review aims to collect the available data on the association between iron concentration in the brain and aging, shedding light on potential mechanisms that may be helpful in the detection of physiological neurodegeneration processes and neurodegenerative diseases such as Alzheimer’s disease. Full article

(This article belongs to the Special Issue Advance in Neurotoxicity Research from Development to Aging)

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