International Journal of Molecular Sciences

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14 pages, 2351 KiB

Open AccessArticle

Mechanisms of Toxicity of Industrially Relevant Silicomanganese Dust on Human 1321N1 Astrocytoma Cells: An In Vitro Study

by Yke Jildouw Arnoldussen, Torunn Kringlen Ervik, Johanna Samulin Erdem, Ida Kero, Mina Baarnes Eriksen, Vidar Skaug and Shanbeh Zienolddiny

Int. J. Mol. Sci. 2019, 20(3), 740; https://doi.org/10.3390/ijms20030740 - 10 Feb 2019

Cited by 4 | Viewed by 3117

Abstract

Tremendous efforts are applied in the ferroalloy industry to control and reduce exposure to dust generated during the production process, as inhalable Mn-containing particulate matter has been linked to neurodegenerative diseases. This study aimed to investigate the toxicity and biological effects of dust [...] Read more.

Tremendous efforts are applied in the ferroalloy industry to control and reduce exposure to dust generated during the production process, as inhalable Mn-containing particulate matter has been linked to neurodegenerative diseases. This study aimed to investigate the toxicity and biological effects of dust particles from laboratory-scale processes where molten silicomanganese (SiMn) was exposed to air, using a human astrocytoma cell line, 1321N1, as model system. Characterization of the dust indicated presence of both nano-sized and larger particles averaging between 100 and 300 nm. The dust consisted mainly of Si, Mn and O. Investigation of cellular mechanisms showed a dose- and time-dependent effect on cell viability, with only minor changes in the expression of proteins involved in apoptosis. Moreover, gene expression of the neurotoxic biomarker amyloid precursor protein (APP) increased, whereas APP protein expression decreased. Finally, induction of gap junctional intercellular communication (GJIC) increased with higher doses and correlated with the other endpoints. Thus, the effects of SiMn dust on 1321N1 cells are highly dependent on the dose of exposure and involves changes in APP, apoptosis-related proteins and intercellular communication. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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14 pages, 3499 KiB

Open AccessArticle

Cellular Responses of Industrially Relevant Silica Dust on Human Glial Cells In Vitro

by Yke Jildouw Arnoldussen, Torunn Kringlen Ervik, Mina Baarnes Eriksen, Ida Kero, Vidar Skaug and Shanbeh Zienolddiny

Int. J. Mol. Sci. 2019, 20(2), 358; https://doi.org/10.3390/ijms20020358 - 16 Jan 2019

Cited by 7 | Viewed by 3492

Abstract

Despite the rigorous emission control measures in the ferroalloy industry, there are still emissions of dust during the production of various alloys. Dust particles were collected from laboratory scale processes where oxide particulate matter was formed from liquid silicon (metallurgical grade). The dust [...] Read more.

Despite the rigorous emission control measures in the ferroalloy industry, there are still emissions of dust during the production of various alloys. Dust particles were collected from laboratory scale processes where oxide particulate matter was formed from liquid silicon (metallurgical grade). The dust was produced in a dry air atmosphere to mimic industrial conditions. To investigate possible effects of ultrafine dust on the central nervous system, a human astrocytic cell line was employed to investigate inflammatory effects of particles as astrocytes play a number of active and neuron supporting roles in the brain. Toxicity on the astrocytes by amorphous silica generated in laboratory scale was compared to crystalline macro-sized silica using several doses to determine toxicological dose response curves. The cell viability experiments indicated that low particle doses of amorphous silica induced a small nonsignificant reduction in cell viability compared to crystalline silica which led to increased levels of toxicity. The gene expression of amyloid precursor protein (APP), a biomarker of neurodegenerative disease, was affected by particle exposure. Furthermore, particle exposure, in a dose-and time-dependent manner, affected the ability of the cells to communicate through gap junction channels. In conclusion, in vitro studies using low doses of particles are important to understand mechanisms of toxicity of occupational exposure to silica particles. However, these studies cannot be extrapolated to real exposure scenarios at work place, therefore, controlling and keeping the particle exposure levels low at the work place, would prevent potential negative health effects. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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12 pages, 6066 KiB

Open AccessArticle

Dysregulation of Dopaminergic Regulatory Factors TH, Nurr1, and Pitx3 in the Ventral Tegmental Area Associated with Neuronal Injury Induced by Chronic Morphine Dependence

by Weibo Shi, Yaxing Zhang, Guoting Zhao, Songjun Wang, Guozhong Zhang, Chunling Ma, Yingmin Li and Bin Cong

Int. J. Mol. Sci. 2019, 20(2), 250; https://doi.org/10.3390/ijms20020250 - 10 Jan 2019

Cited by 9 | Viewed by 4865

Abstract

The ventral tegmental area (VTA), a critical portion of the mesencephalic dopamine system, is thought to be involved in the development and maintenance of addiction. It has been proposed that the dopaminergic regulatory factors TH, Nurr1, and Pitx3 are crucial for determining the [...] Read more.

The ventral tegmental area (VTA), a critical portion of the mesencephalic dopamine system, is thought to be involved in the development and maintenance of addiction. It has been proposed that the dopaminergic regulatory factors TH, Nurr1, and Pitx3 are crucial for determining the survival and maintenance of dopaminergic neurons. Thus, the present study investigated whether abnormalities in these dopaminergic regulatory factors in the VTA were associated with neuronal injury induced by chronic morphine dependence. Rat models with different durations of morphine dependence were established. Thionine staining was used to observe morphological changes in the VTA neurons. Immunohistochemistry and western blot were used to observe changes in the expression of the dopaminergic regulatory proteins TH, Nurr1, and Pitx3. Thionine staining revealed that prolonged morphine dependence resulted in dopaminergic neurons with edema, a lack of Nissl bodies, and pyknosis. Immunohistochemistry showed that the number of TH⁺, Nurr1⁺, and Pitx3⁺ cells, and the number of TH⁺ cells expressing Nurr1 or Pitx3, significantly decreased in the VTA after a long period of morphine dependence. Western blot results were consistent with the immunohistochemistry findings. Chronic morphine exposure resulted in abnormalities in dopaminergic regulatory factors and pathological changes in dopaminergic neurons in the VTA. These results suggest that dysregulation of dopaminergic regulatory factors in the VTA are associated with neuronal injury induced by chronic morphine dependence. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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9 pages, 1712 KiB

Open AccessArticle

Antioxidant Properties and the Formation of Iron Coordination Complexes of 8-Hydroxyquinoline

by Vladimir Chobot, Franz Hadacek, Gert Bachmann, Wolfram Weckwerth and Lenka Kubicova

Int. J. Mol. Sci. 2018, 19(12), 3917; https://doi.org/10.3390/ijms19123917 - 7 Dec 2018

Cited by 22 | Viewed by 6198

Abstract

Background: The alkaloid 8-hydroxyquinoline (8HQ) is well-known for various biological activities, including antioxidant effects and especially for the formation of coordination complexes with various transition metals, such as iron, amongst others. Therefore, 8HQ was extensively explored as a promising antineurodegenerative agent. However, other [...] Read more.

Background: The alkaloid 8-hydroxyquinoline (8HQ) is well-known for various biological activities, including antioxidant effects and especially for the formation of coordination complexes with various transition metals, such as iron, amongst others. Therefore, 8HQ was extensively explored as a promising antineurodegenerative agent. However, other authors noted pro-oxidant effects of 8HQ. Here, we explore the pro- and antioxidant properties of 8HQ, especially in context of coordination complexes with iron (II) and iron (III). Methods: Nano-electrospray−mass spectrometry, differential pulse voltammetry, deoxyribose degradation, iron (II) autoxidation, and brine shrimp mortality assays were used. Results: 8HQ formed a complex mixture of coordination complexes with iron (II) and iron (III). Furthermore, 8HQ showed antioxidant effects but no pro-oxidant ones. In the brine shrimp mortality assay, 8HQ demonstrated toxicity that decreased in the presence of iron (III). Conclusions: 8HQ is a potent antioxidant whose effects depend not only on the formation of the coordination complexes with iron ions, but surely on the scavenging activities due to the redox properties of the 8-hydroxyl group. No pro-oxidant effects were observed in the set of the used assays. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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19 pages, 4568 KiB

Open AccessArticle

β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP⁺ Toxicity in Human Neuroblastoma SH-SY5Y Cells

by Jesus Fernandez-Abascal, Mariantonia Ripullone, Aurora Valeri, Cosima Leone and Massimo Valoti

Int. J. Mol. Sci. 2018, 19(11), 3369; https://doi.org/10.3390/ijms19113369 - 28 Oct 2018

Cited by 15 | Viewed by 4637

Abstract

Cytochrome P450 (CYP) isozymes vary their expression depending on the brain area, the cell type, and the presence of drugs. Some isoforms are involved in detoxification and/or toxic activation of xenobiotics in central nervous system. However, their role in brain metabolism and neurodegeneration [...] Read more.

Cytochrome P450 (CYP) isozymes vary their expression depending on the brain area, the cell type, and the presence of drugs. Some isoforms are involved in detoxification and/or toxic activation of xenobiotics in central nervous system. However, their role in brain metabolism and neurodegeneration is still a subject of debate. We have studied the inducibility of CYP isozymes in human neuroblastoma SH-SY5Y cells, treated with β-naphtoflavone (β-NF) or ethanol (EtOH) as inducers, by qRT-PCR, Western blot (WB), and metabolic activity assays. Immunohistochemistry was used to localize the isoforms in mitochondria and/or endoplasmic reticulum (ER). Tetrazolium (MTT) assay was performed to study the role of CYPs during methylphenyl pyridine (MPP⁺) exposure. EtOH increased mRNA and protein levels of CYP2D6 by 73% and 60% respectively. Both β-NF and EtOH increased CYP2E1 mRNA (4- and 1.4-fold, respectively) and protein levels (64% both). The 7-ethoxycoumarin O-deethylation and dextromethorphan O-demethylation was greater in treatment samples than in controls. Furthermore, both treatments increased by 22% and 18%, respectively, the cell viability in MPP⁺-treated cells. Finally, CYP2D6 localized at mitochondria and ER. These data indicate that CYP is inducible in SH-SY5Y cells and underline this in vitro system for studying the role of CYPs in neurodegeneration. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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12 pages, 2321 KiB

Open AccessArticle

Humanin Attenuates NMDA-Induced Excitotoxicity by Inhibiting ROS-dependent JNK/p38 MAPK Pathway

by Xiaorong Yang, Hongmei Zhang, Jinzi Wu, Litian Yin, Liang-Jun Yan and Ce Zhang

Int. J. Mol. Sci. 2018, 19(10), 2982; https://doi.org/10.3390/ijms19102982 - 29 Sep 2018

Cited by 35 | Viewed by 4578

Abstract

Humanin (HN) is a novel 24-amino acid peptide that protects neurons against N-methyl-d-aspartate (NMDA)-induced toxicity. However, the contribution of the different mitogen-activated protein kinases (MAPKs) signals to HN neuroprotection against NMDA neurotoxicity remains unclear. The present study was therefore aimed to [...] Read more.

Humanin (HN) is a novel 24-amino acid peptide that protects neurons against N-methyl-d-aspartate (NMDA)-induced toxicity. However, the contribution of the different mitogen-activated protein kinases (MAPKs) signals to HN neuroprotection against NMDA neurotoxicity remains unclear. The present study was therefore aimed to investigate neuroprotective mechanisms of HN. We analyzed intracellular Ca²⁺ levels, reactive oxygen species (ROS) production, and the MAPKs signal transduction cascade using an in vitro NMDA-mediated excitotoxicity of cortical neurons model. Results showed that: (1) HN attenuated NMDA-induced neuronal insults by increasing cell viability, decreasing lactate dehydrogenase (LDH) release, and increasing cell survival; (2) HN reversed NMDA-induced increase in intracellular calcium; (3) pretreatment by HN or 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, decreased ROS generation after NMDA exposure; (4) administration of HN or N-Acetyl-l-cysteine (NAC), a ROS scavenger, inhibited NMDA-induced JNK and p38 MAPK activation. These results indicated that HN reduced intracellular elevation of Ca²⁺ levels, which, in turn, inhibited ROS generation and subsequent JNK and p38 MAPK activation that are involved in promoting cell survival in NMDA-induced excitotoxicity. Therefore, the present study suggests that inhibition of ROS-dependent JNK/p38 MAPK signaling pathway serves an effective strategy for HN neuroprotection against certain neurological diseases. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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16 pages, 2532 KiB

Open AccessArticle

Systemic Lipopolysaccharide-Induced Pain Sensitivity and Spinal Inflammation Were Reduced by Minocycline in Neonatal Rats

by Cheng-Ta Hsieh, Yih-Jing Lee, Xiaoli Dai, Norma Beatriz Ojeda, Hyun Joon Lee, Lu-Tai Tien and Lir-Wan Fan

Int. J. Mol. Sci. 2018, 19(10), 2947; https://doi.org/10.3390/ijms19102947 - 27 Sep 2018

Cited by 28 | Viewed by 6028

Abstract

In this study, we investigated the effects of minocycline, a putative suppressor of microglial activation, on systemic lipopolysaccharide (LPS)-induced spinal cord inflammation, allodynia, and hyperalgesia in neonatal rats. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) or sterile saline was performed in postnatal day [...] Read more.

In this study, we investigated the effects of minocycline, a putative suppressor of microglial activation, on systemic lipopolysaccharide (LPS)-induced spinal cord inflammation, allodynia, and hyperalgesia in neonatal rats. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) or sterile saline was performed in postnatal day 5 (P5) rat pups and minocycline (45 mg/kg) or vehicle (phosphate buffer saline; PBS) was administered (i.p.) 5 min after LPS injection. The von Frey filament and tail-flick tests were performed to determine mechanical allodynia (a painful sensation caused by innocuous stimuli, e.g., light touch) and thermal hyperalgesia (a condition of altered perception of temperature), respectively, and spinal cord inflammation was examined 24 h after the administration of drugs. Systemic LPS administration resulted in a reduction of tactile threshold in the von Frey filament tests and pain response latency in the tail-flick test of neonatal rats. The levels of microglia and astrocyte activation, pro-inflammatory cytokine interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) in the spinal cord of neonatal rats were increased 24 h after the administration of LPS. Treatment with minocycline significantly attenuated LPS-induced allodynia, hyperalgesia, the increase in spinal cord microglia, and astrocyte activation, and elevated levels of IL-1β, COX-2, and PGE2 in neonatal rats. These results suggest that minocycline provides protection against neonatal systemic LPS exposure-induced enhanced pain sensitivity (allodynia and hyperalgesia), and that the protective effects may be associated with its ability to attenuate LPS-induced microglia activation, and the levels of IL-1β, COX-2, and PGE2 in the spinal cord of neonatal rats. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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15 pages, 6360 KiB

Open AccessArticle

Developmental Exposure to Atrazine Impairs Spatial Memory and Downregulates the Hippocampal D1 Dopamine Receptor and cAMP-Dependent Signaling Pathway in Rats

by Jianan Li, Xueting Li, Haoran Bi, Kun Ma and Baixiang Li

Int. J. Mol. Sci. 2018, 19(8), 2241; https://doi.org/10.3390/ijms19082241 - 31 Jul 2018

Cited by 26 | Viewed by 4743

Abstract

Atrazine (ATR) is a widely used herbicide that has been implicated as a neurotoxicant. Recent experimental evidence has implicated that ATR exposure also appears to have adverse effects on the hippocampus, which is a critical region for learning and memory. The aim of [...] Read more.

Atrazine (ATR) is a widely used herbicide that has been implicated as a neurotoxicant. Recent experimental evidence has implicated that ATR exposure also appears to have adverse effects on the hippocampus, which is a critical region for learning and memory. The aim of the present study was to investigate the effects of ATR toxicity on the hippocampus of developing rats. Postnatal day (PND) 28 male Sprague–Dawley (SD) rats received ATR by oral gavage at 10 or 100 mg/kg bodyweight (BW) for 30 consecutive days and were sacrificed at PND 90. Behavioral test results indicated that spatial learning and memory were affected by ATR treatment. Electron microscopy analysis showed that the ultrastructures of the hippocampus were altered in the ATR-treated groups, as compared to the control group. Additionally, ATR treatment impacted dopamine and D1 dopamine receptor (D1DR) contents through different mechanisms. Reduced mRNA and protein expression levels of factors involved in the cAMP-dependent signaling pathway were also detected. These results indicate that the developmental exposure of rats to ATR can damage the hippocampus and spatial memory, which might be related to the downregulation of expression levels of the D1DR and its downstream signaling pathway. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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Review

Jump to: Research

9 pages, 957 KiB

Open AccessReview

NURR1 Impairment in Multiple Sclerosis

by Francesca Montarolo, Serena Martire, Simona Perga and Antonio Bertolotto

Int. J. Mol. Sci. 2019, 20(19), 4858; https://doi.org/10.3390/ijms20194858 - 30 Sep 2019

Cited by 16 | Viewed by 3954

Abstract

The transcription factor NURR1 is a constitutively active orphan receptor belonging to the steroid hormone receptor class NR4A. Although a genetic association between NURR1 and autoimmune inflammatory diseases has never emerged from genome-wide association studies (GWAS), alterations in the expression of NURR1 have [...] Read more.

The transcription factor NURR1 is a constitutively active orphan receptor belonging to the steroid hormone receptor class NR4A. Although a genetic association between NURR1 and autoimmune inflammatory diseases has never emerged from genome-wide association studies (GWAS), alterations in the expression of NURR1 have been observed in various autoimmune diseases. Specifically, its role in autoimmune inflammatory diseases is mainly related to its capability to counteract inflammation. In fact, NURR1 exerts anti-inflammatory functions inhibiting the transcription of the molecules involved in proinflammatory pathways, not only in the peripheral blood compartment, but also in the cerebral parenchyma acting in microglial cells and astrocytes. In parallel, NURR1 has been also linked to dopamine-associated brain disorders, such as Parkinson’s disease (PD) and schizophrenia, since it is involved in the development and in the maintenance of midbrain dopaminergic neurons (mDA). Considering its role in neuro- and systemic inflammatory processes, here we review the evidences supporting its contribution to multiple sclerosis (MS), a chronic inflammatory autoimmune disease affecting the central nervous system (CNS). To date, the specific role of NURR1 in MS is still debated and few authors have studied this topic. Here, we plan to clarify this issue analyzing the reported association between NURR1 and MS in human and murine model studies. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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23 pages, 1008 KiB

Open AccessReview

Recent Topics on The Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities

by Wei Zhang, Nobuaki Egashira and Satohiro Masuda

Int. J. Mol. Sci. 2019, 20(13), 3210; https://doi.org/10.3390/ijms20133210 - 29 Jun 2019

Cited by 36 | Viewed by 8505

Abstract

Although transplantation procedures have been developed for patients with end-stage hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin [...] Read more.

Although transplantation procedures have been developed for patients with end-stage hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity commonly occurs in clinical practice, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms through which CNIs cause neurotoxicity include increasing the permeability or injury of the blood–brain barrier, alterations of mitochondrial function, and alterations in the electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures, mycophenolate mofetil induces depression and headaches, methotrexate affects the central nervous system, the mouse monoclonal immunoglobulin G2 antibody (used against the cluster of differentiation 3) also induces headaches, and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms help reduce neurotoxic events considerably. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, combination therapy with drugs used to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize recent topics on the mechanisms of immunosuppressive drug-related neurotoxicity. In addition, information about the neuroprotective effects of several immunosuppressants is also discussed. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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32 pages, 1778 KiB

Open AccessReview

Purinergic Signaling and Cochlear Injury-Targeting the Immune System?

by László Köles, Judit Szepesy, Eszter Berekméri and Tibor Zelles

Int. J. Mol. Sci. 2019, 20(12), 2979; https://doi.org/10.3390/ijms20122979 - 18 Jun 2019

Cited by 14 | Viewed by 8301

Abstract

Hearing impairment is the most common sensory deficit, affecting more than 400 million people worldwide. Sensorineural hearing losses currently lack any specific or efficient pharmacotherapy largely due to the insufficient knowledge of the pathomechanism. Purinergic signaling plays a substantial role in cochlear (patho)physiology. [...] Read more.

Hearing impairment is the most common sensory deficit, affecting more than 400 million people worldwide. Sensorineural hearing losses currently lack any specific or efficient pharmacotherapy largely due to the insufficient knowledge of the pathomechanism. Purinergic signaling plays a substantial role in cochlear (patho)physiology. P2 (ionotropic P2X and the metabotropic P2Y) as well as adenosine receptors expressed on cochlear sensory and non-sensory cells are involved mostly in protective mechanisms of the cochlea. They are implicated in the sensitivity adjustment of the receptor cells by a K⁺ shunt and can attenuate the cochlear amplification by modifying cochlear micromechanics. Cochlear blood flow is also regulated by purines. Here, we propose to comprehend this field with the purine-immune interactions in the cochlea. The role of harmful immune mechanisms in sensorineural hearing losses has been emerging in the horizon of cochlear pathologies. In addition to decreasing hearing sensitivity and increasing cochlear blood supply, influencing the immune system can be the additional avenue for pharmacological targeting of purinergic signaling in the cochlea. Elucidating this complexity of purinergic effects on cochlear functions is necessary and it can result in development of new therapeutic approaches in hearing disabilities, especially in the noise-induced ones. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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23 pages, 893 KiB

Open AccessReview

Chemotherapy-Induced Peripheral Neuropathy and Changes in Cytoskeleton

by Alessio Malacrida, Cristina Meregalli, Virginia Rodriguez-Menendez and Gabriella Nicolini

Int. J. Mol. Sci. 2019, 20(9), 2287; https://doi.org/10.3390/ijms20092287 - 9 May 2019

Cited by 33 | Viewed by 8176

Abstract

Despite the different antineoplastic mechanisms of action, peripheral neurotoxicity induced by all chemotherapy drugs (anti-tubulin agents, platinum compounds, proteasome inhibitors, thalidomide) is associated with neuron morphological changes ascribable to cytoskeleton modifications. The “dying back” degeneration of distal terminals (sensory nerves) of dorsal root [...] Read more.

Despite the different antineoplastic mechanisms of action, peripheral neurotoxicity induced by all chemotherapy drugs (anti-tubulin agents, platinum compounds, proteasome inhibitors, thalidomide) is associated with neuron morphological changes ascribable to cytoskeleton modifications. The “dying back” degeneration of distal terminals (sensory nerves) of dorsal root ganglia sensory neurons, observed in animal models, in in vitro cultures and biopsies of patients is the most evident hallmark of the perturbation of the cytoskeleton. On the other hand, in highly polarized cells like neurons, the cytoskeleton carries out its role not only in axons but also has a fundamental role in dendrite plasticity and in the organization of soma. In the literature, there are many studies focused on the antineoplastic-induced alteration of microtubule organization (and consequently, fast axonal transport defects) while very few studies have investigated the effect of the different classes of drugs on microfilaments, intermediate filaments and associated proteins. Therefore, in this review, we will focus on: (1) Highlighting the fundamental role of the crosstalk among the three filamentous subsystems and (2) investigating pivotal cytoskeleton-associated proteins. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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16 pages, 4733 KiB

Open AccessReview

EDTA Chelation Therapy for the Treatment of Neurotoxicity

by Alessandro Fulgenzi and Maria Elena Ferrero

Int. J. Mol. Sci. 2019, 20(5), 1019; https://doi.org/10.3390/ijms20051019 - 26 Feb 2019

Cited by 35 | Viewed by 12333

Abstract

Neurotoxicity can be caused by numerous direct agents, of which toxic metals, organophosphorus pesticides, air pollution, radiation and electromagnetic fields, neurotoxins, chemotherapeutic and anesthetic drugs, and pathogens are the most important. Other indirect causes of neurotoxicity are cytokine and/or reactive oxygen species production [...] Read more.

Neurotoxicity can be caused by numerous direct agents, of which toxic metals, organophosphorus pesticides, air pollution, radiation and electromagnetic fields, neurotoxins, chemotherapeutic and anesthetic drugs, and pathogens are the most important. Other indirect causes of neurotoxicity are cytokine and/or reactive oxygen species production and adoptive immunotherapy. The development of neurodegenerative diseases has been associated with neurotoxicity. Which arms are useful to prevent or eliminate neurotoxicity? The chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA)—previously used to treat cardiovascular diseases—is known to be useful for the treatment of neurodegenerative diseases. This review describes how EDTA functions as a therapeutic agent for these diseases. Some case studies are reported to confirm our findings. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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13 pages, 1686 KiB

Open AccessReview

An Animal Model for Assessing the Effects of Hydroxyurea Exposure Suggests That the Administration of This Agent to Pregnant Women and Young Infants May Not Be as Safe as We Thought

by Lucía Rodríguez-Vázquez and Joaquín Martí

Int. J. Mol. Sci. 2018, 19(12), 3986; https://doi.org/10.3390/ijms19123986 - 11 Dec 2018

Cited by 3 | Viewed by 3247

Abstract

The cytostatic agent hydroxyurea (HU) has proven to be beneficial for a variety of conditions in the disciplines of oncology, hematology, infectious disease and dermatology. It disrupts the S phase of the cell cycle by inhibiting the ribonucleotide reductase enzyme, thus blocking the [...] Read more.

The cytostatic agent hydroxyurea (HU) has proven to be beneficial for a variety of conditions in the disciplines of oncology, hematology, infectious disease and dermatology. It disrupts the S phase of the cell cycle by inhibiting the ribonucleotide reductase enzyme, thus blocking the transformation of ribonucleotides into deoxyribonucleotides, a rate limiting step in DNA synthesis. HU is listed as an essential medicine by the World Health Organization. Several studies have indicated that HU is well tolerated and safe in pregnant women and very young pediatric patients. To our knowledge, only a few controlled studies on the adverse effects of HU therapy have been done in humans. Despite this, the prevalence of central nervous system abnormalities, including ischemic lesions and stenosis have been reported. This review will summarize and present the effects of HU exposure on the prenatal and perinatal development of the rat cerebellar cortex and deep cerebellar nuclei neurons. Our results call for the necessity to better understand HU effects and define the administration of this drug to gestating women and young pediatric patients. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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23 pages, 1153 KiB

Open AccessReview

Potential Role of Fluoride in the Etiopathogenesis of Alzheimer’s Disease

by Marta Goschorska, Irena Baranowska-Bosiacka, Izabela Gutowska, Emilia Metryka, Marta Skórka-Majewicz and Dariusz Chlubek

Int. J. Mol. Sci. 2018, 19(12), 3965; https://doi.org/10.3390/ijms19123965 - 9 Dec 2018

Cited by 28 | Viewed by 17017

Abstract

The etiopathogenesis of Alzheimer’s disease has not been fully explained. Now, the disease is widely attributed both to genetic and environmental factors. It is believed that only a small percentage of new AD cases result solely from genetic mutations, with most cases attributed [...] Read more.

The etiopathogenesis of Alzheimer’s disease has not been fully explained. Now, the disease is widely attributed both to genetic and environmental factors. It is believed that only a small percentage of new AD cases result solely from genetic mutations, with most cases attributed to environmental factors or to the interaction of environmental factors with preexistent genetic determinants. Fluoride is widespread in the environment and it easily crosses the blood–brain barrier. In the brain fluoride affects cellular energy metabolism, synthesis of inflammatory factors, neurotransmitter metabolism, microglial activation, and the expression of proteins involved in neuronal maturation. Finally, and of specific importance to its role in Alzheimer’s disease, studies report fluoride-induced apoptosis and inflammation within the central nervous system. This review attempts to elucidate the potential relationship between the effects of fluoride exposure and the pathogenesis of Alzheimer’s disease. We describe the impact of fluoride-induced oxidative stress and inflammation in the pathogenesis of AD and demonstrate a role for apoptosis in disease progression, as well as a mechanism for its initiation by fluoride. The influence of fluoride on processes of AD initiation and progression is complex and warrants further investigation, especially considering growing environmental fluoride pollution. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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11 pages, 1955 KiB

Open AccessReview

The Pathophysiology of Post-Traumatic Glioma

by Donata Simińska, Klaudyna Kojder, Dariusz Jeżewski, Ireneusz Kojder, Marta Skórka, Izabela Gutowska, Dariusz Chlubek and Irena Baranowska-Bosiacka

Int. J. Mol. Sci. 2018, 19(8), 2445; https://doi.org/10.3390/ijms19082445 - 19 Aug 2018

Cited by 13 | Viewed by 5874

Abstract

Malignant glioma is a brain tumor with a very high mortality rate resulting from the specific morphology of its infiltrative growth and poor early detection rates. The causes of one of its very specific types, i.e., post-traumatic glioma, have been discussed for many [...] Read more.

Malignant glioma is a brain tumor with a very high mortality rate resulting from the specific morphology of its infiltrative growth and poor early detection rates. The causes of one of its very specific types, i.e., post-traumatic glioma, have been discussed for many years, with some studies providing evidence for mechanisms where the reaction to an injury may in some cases lead to the onset of carcinogenesis in the brain. In this review of the available literature, we discuss the consequences of breaking the blood–brain barrier and consequences of the influx of immune-system cells to the site of injury. We also analyze the influence of inflammatory mediators on the expression of genes controlling the process of apoptosis and the effect of chemical mutagenic factors on glial cells in the brain. We present the results of experimental studies indicating a relationship between injury and glioma development. However, epidemiological studies on post-traumatic glioma, of which only a few confirm the conclusions of experimental research, indicate that any potential relationship between injury and glioma, if any, is indirect. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neurotoxicity)

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