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Mechanisms of Neurotoxicity

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

Deadline for manuscript submissions: 30 August 2024 | Viewed by 5968

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Special Issue Editors

Dr. Paola Alberti

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Guest Editor

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Interests: neuropathy; ion channels; voltage gated ion channels; pain; chemotherapy

Dr. Eleonora Pozzi

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Guest Editor

Dipartimento di Medicina e Chirurgia, University of Milano-Bicocca, Monza, Italy
Interests: peripheral neuropathies

Special Issue Information

Dear Colleagues,

Neurons are a perennial cell population and, therefore, neurotoxicity understanding and management is a relevant challenge to treat/prevent neurological disorders. There are many different potentially neurotoxic agents which include chemotherapy drugs, environmental pollution, et cetera. This Special Issue explores mechanisms of damage that involve either the peripheral and/or central nervous system to provide a sound biological rational to potential treatment strategies.

Dr. Paola Alberti
Dr. Eleonora Pozzi
Guest Editors

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Keywords

neuropathy
ion channels
voltage gated ion channels
pain
chemotherapy

Published Papers (5 papers)

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Research

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12 pages, 2501 KiB

Open AccessArticle

Mild Oxidative Stress Induced by Sodium Arsenite Reduces Lipocalin-2 Expression Levels in Cortical Glial Cells

by Ye-Jin Cho, So-Hyun Park and Kwon-Yul Ryu

Int. J. Mol. Sci. 2023, 24(21), 15864; https://doi.org/10.3390/ijms242115864 - 01 Nov 2023

Cited by 1 | Viewed by 786

Abstract

Astrocytes and microglia, the most abundant glial cells in the central nervous system, are involved in maintaining homeostasis in the brain microenvironment and in the progression of various neurological disorders. Lipocalin-2 (LCN2) is a small secretory protein that can be transcriptionally upregulated via nuclear factor kappa B (NF-κB) signaling. It is synthesized and secreted by glial cells, resulting in either the restoration of damaged neural tissues or the induction of neuronal apoptosis in a context-dependent manner. It has recently been reported that when glial cells are under lipopolysaccharide-induced inflammatory stress, either reduced production or accelerated degradation of LCN2 can alleviate neurotoxicity. However, the regulatory mechanisms of LCN2 in glial cells are not yet fully understood. In this study, we used primary astroglial-enriched cells which produce LCN2 and found that the production of LCN2 could be reduced by sodium arsenite treatment. Surprisingly, the reduced LCN2 production was not due to the suppression of NF-κB signaling. Mild oxidative stress induced by sodium arsenite treatment activated antioxidant responses and downregulated Lcn2 expression without reducing the viability of astroglial-enriched cells. Intriguingly, reduced LCN2 production could not be achieved by simple activation of the nuclear factor erythroid-2-related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) pathway in astroglial-enriched cells. Thus, it appears that mild oxidative stress, occurring in an Nrf2-independent manner, is required for the downregulation of Lcn2 expression. Taken together, our findings provide new insights into the regulatory mechanisms of LCN2 and suggest that mild oxidative stress may alter LCN2 homeostasis, even under neuroinflammatory conditions. Full article

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

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19 pages, 4705 KiB

Open AccessArticle

Probing the Effect of Acidosis on Tether-Mode Mechanotransduction of Proprioceptors

by Yuan-Ren Cheng, Chih-Hung Chi, Cheng-Han Lee, Shing-Hong Lin, Ming-Yuan Min and Chih-Cheng Chen

Int. J. Mol. Sci. 2023, 24(16), 12783; https://doi.org/10.3390/ijms241612783 - 14 Aug 2023

Cited by 1 | Viewed by 938

Abstract

Proprioceptors are low-threshold mechanoreceptors involved in perceiving body position and strain bearing. However, the physiological response of proprioceptors to fatigue- and muscle-acidosis-related disturbances remains unknown. Here, we employed whole-cell patch-clamp recordings to probe the effect of mild acidosis on the mechanosensitivity of the proprioceptive neurons of dorsal root ganglia (DRG) in mice. We cultured neurite-bearing parvalbumin-positive (Pv+) DRG neurons on a laminin-coated elastic substrate and examined mechanically activated currents induced through substrate deformation-driven neurite stretch (SDNS). The SDNS-induced inward currents (I_SDNS) were indentation depth-dependent and significantly inhibited by mild acidification (pH 7.2~6.8). The acid-inhibiting effect occurred in neurons with an I_SDNS sensitive to APETx2 (an ASIC3-selective antagonist) inhibition, but not in those with an I_SNDS resistant to APETx2. Detailed subgroup analyses revealed I_SDNS was expressed in 59% (25/42) of Parvalbumin-positive (Pv+) DRG neurons, 90% of which were inhibited by APETx2. In contrast, an acid (pH 6.8)-induced current (I_Acid) was expressed in 76% (32/42) of Pv+ DRG neurons, 59% (21/32) of which were inhibited by APETx2. Together, ASIC3-containing channels are highly heterogenous and differentially contribute to the I_SNDS and I_Acid among Pv+ proprioceptors. In conclusion, our findings highlight the importance of ASIC3-containing ion channels in the physiological response of proprioceptors to acidic environments. Full article

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

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17 pages, 8110 KiB

Open AccessArticle

Sodium Leak Channel in Glutamatergic Neurons of the Lateral Parabrachial Nucleus Modulates Inflammatory Pain in Mice

by Lin Wu, Yujie Wu, Jin Liu, Jingyao Jiang, Cheng Zhou and Donghang Zhang

Int. J. Mol. Sci. 2023, 24(15), 11907; https://doi.org/10.3390/ijms241511907 - 25 Jul 2023

Cited by 2 | Viewed by 1176

Abstract

Elevated excitability of glutamatergic neurons in the lateral parabrachial nucleus (PBL) is associated with the pathogenesis of inflammatory pain, but the underlying molecular mechanisms are not fully understood. Sodium leak channel (NALCN) is widely expressed in the central nervous system and regulates neuronal excitability. In this study, chemogenetic manipulation was used to explore the association between the activity of PBL glutamatergic neurons and pain thresholds. Complete Freund’s adjuvant (CFA) was used to construct an inflammatory pain model in mice. Pain behaviour was tested using von Frey filaments and Hargreaves tests. Local field potential (LFP) was used to record the activity of PBL glutamatergic neurons. Gene knockdown techniques were used to investigate the role of NALCN in inflammatory pain. We further explored the downstream projections of PBL using cis-trans-synaptic tracer virus. The results showed that chemogenetic inhibition of PBL glutamatergic neurons increased pain thresholds in mice, whereas chemogenetic activation produced the opposite results. CFA plantar modelling increased the number of C-Fos protein and NALCN expression in PBL glutamatergic neurons. Knockdown of NALCN in PBL glutamatergic neurons alleviated CFA-induced pain. CFA injection induced C-Fos protein expression in central nucleus amygdala (CeA) neurons, which was suppressed by NALCN knockdown in PBL glutamatergic neurons. Therefore, elevated expression of NALCN in PBL glutamatergic neurons contributes to the development of inflammatory pain via PBL-CeA projections. Full article

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

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18 pages, 2502 KiB

Open AccessArticle

Sodium-Calcium Exchanger 2: A Pivotal Role in Oxaliplatin Induced Peripheral Neurotoxicity and Axonal Damage?

by Elisa Ballarini, Alessio Malacrida, Virginia Rodriguez-Menendez, Eleonora Pozzi, Annalisa Canta, Alessia Chiorazzi, Laura Monza, Sara Semperboni, Cristina Meregalli, Valentina Alda Carozzi, Maryamsadat Hashemi, Gabriella Nicolini, Arianna Scuteri, Stephen N. Housley, Guido Cavaletti and Paola Alberti

Int. J. Mol. Sci. 2022, 23(17), 10063; https://doi.org/10.3390/ijms231710063 - 02 Sep 2022

Cited by 8 | Viewed by 1992

Abstract

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na⁺ voltage-operated channels (Na⁺VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na⁺/Ca²⁺ exchanger 2 (NCX2), resulting in toxic Ca²⁺ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN. Full article

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

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Review

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21 pages, 851 KiB

Open AccessReview

HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology

by Landon John-Patrick Thompson, Jessica Genovese, Zhenzi Hong, Meera Vir Singh and Vir Bahadur Singh

Int. J. Mol. Sci. 2024, 25(9), 4697; https://doi.org/10.3390/ijms25094697 - 25 Apr 2024

Viewed by 284

Abstract

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood–brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND. Full article

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

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