Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.0
3.4
Journals
Brain Sciences
Special Issues
Toxic Mechanisms and Emerging Therapeutic Strategies in Brain Disorders
share announcement

Toxic Mechanisms and Emerging Therapeutic Strategies in Brain Disorders

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuropharmacology and Neuropathology".

Deadline for manuscript submissions: 28 August 2026 | Viewed by 5948

Editors

Dr. Alexandra Susana Latini

E-Mail Website
Guest Editor
Department of Biochemistry, Laboratory of Bioenergetics and Oxidative Stress, LABOX, Federal University of Santa Catarina, Florianópolis 88037-100, Brazil
Interests: mitochondria; tetrahydrobiopterin; mitochondrial disorders
Dr. Ana Lucia De Paul

E-Mail Website
Guest Editor
1. Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Instituto de Investigaciones en Ciencias de La Salud (INICSA), Córdoba, Argentina
2. Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
Interests: phenylketonuria; metabolic disorders; neonatal screening

Special Issue Information

Dear Colleagues,

Disorders impacting the nervous system often involve complex and multifactorial toxic mechanisms, including oxidative stress, mitochondrial dysfunction, excitotoxicity, protein aggregation, and neuroinflammation. These pathological processes contribute to neuronal damage and progression across a wide spectrum of neurological, neurodegenerative, and neurometabolic diseases. Understanding these toxic cascades is essential for identifying new therapeutic targets and improving clinical outcomes. This Special Issue aims to highlight recent advances in the characterization of neurotoxic mechanisms and to explore innovative therapeutic strategies, including pharmacological, gene-based, and metabolic interventions. We invite original research articles, reviews, and perspectives addressing molecular and cellular pathways of toxicity, biomarker development, and translational approaches for treatment. By bringing together cutting-edge studies from diverse neurological conditions, this issue seeks to foster a deeper understanding of shared mechanisms and promote the development of cross-cutting therapeutic strategies for disorders of the nervous system.

Dr. Alexandra Susana Latini
Dr. Ana Lucia De Paul
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurotoxicity
  • physiopathology
  • therapies
  • mitochondrial transplantation
  • oxidative stress
  • inflammation
  • mitochondrial dysfunction

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (4 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

16 pages, 2237 KB  
Article
Potential Biological Processes Related to Brain SLC13A5 Across the Lifespan: Weighted Gene Co-Expression Network Analysis from Large Human Transcriptomic Data
by Bruna Klippel Ferreira, Patricia Fernanda Schuck, Gustavo Costa Ferreira and Hércules Rezende Freitas
Brain Sci. 2026, 16(2), 163; https://doi.org/10.3390/brainsci16020163 - 30 Jan 2026
Viewed by 1038
Abstract
Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories [...] Read more.
Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho = 0.802, p = 8.62 × 10−6) and closely matched SLC13A5 abundance (rho = 0.884, p = 2.73 × 10−6), with a significant partial association after adjusting for developmental rank (rho = 0.672, p = 6.17 × 10−4). Functional enrichment converged on oxidative phosphorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mitochondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism. Full article
(This article belongs to the Special Issue Toxic Mechanisms and Emerging Therapeutic Strategies in Brain Disorders)
►▼ Show Figures

Figure 1

16 pages, 4297 KB  
Communication
Clomipramine Induced Oxidative Stress and Morphological Alterations in the Prefrontal Cortex and Limbic System of Neonatal Rats
by Norma Angélica Labra-Ruíz, Julieta Griselda Mendoza-Torreblanca, Norma Osnaya-Brizuela, Armando Valenzuela-Peraza, Maribel Ortiz-Herrera, Gerardo Barragán-Mejía, Noemí Cárdenas-Rodríguez and Daniel Santamaría-Del Ángel
Brain Sci. 2025, 15(10), 1068; https://doi.org/10.3390/brainsci15101068 - 30 Sep 2025
Viewed by 1338
Abstract
Although clomipramine (CLO) is widely used as a serotonin reuptake inhibitor, its subchronic administration during the early stages of brain development leads to depressive-like behaviors in adulthood. High doses of CLO have been linked to mitochondrial impairment and increased reactive oxygen species in [...] Read more.
Although clomipramine (CLO) is widely used as a serotonin reuptake inhibitor, its subchronic administration during the early stages of brain development leads to depressive-like behaviors in adulthood. High doses of CLO have been linked to mitochondrial impairment and increased reactive oxygen species in cells and adult animals. It is unknown whether subchronic administration of this drug at early ages can induce oxidative stress (OS) in adulthood. The objective of this study was to evaluate OS and cellular damage in the prefrontal cortex and limbic system (hippocampus and amygdala) of rats exposed to CLO neonatally. Methods: Forty male Wistar rats were divided into experimental (EXP) and control (CTRL) groups. The EXP animals received CLO (15 mg/kg, twice daily, subcutaneously, postnatal days 5–35); the CTRL animals received saline. At 55 and 85 days of age, the brains were collected for biochemical assays and histological analysis. Results: Rats exposed to neonatal CLO presented significant reductions in reduced glutathione (GSH) and increases in oxidized glutathione (GSSG) and malondialdehyde in both studied regions, especially on day 85. The GSH/GSSG ratio decreased, indicating persistent OS. Histology revealed neuronal degeneration, pyknotic nuclei, cell shrinkage, and disorganized tissue, which progressed from days 55 to 85. Conclusions: Early exposure to CLO can cause long-lasting neurochemical and structural alterations in the brain regions associated with the regulation of emotions and some behavioral responses that can persist over time and affect behavior in adulthood. Full article
(This article belongs to the Special Issue Toxic Mechanisms and Emerging Therapeutic Strategies in Brain Disorders)
►▼ Show Figures

Graphical abstract

19 pages, 1603 KB  
Article
Resolution of Lipopolysaccharide-Induced Inflammation Followed by DNA Hypomethylation and Increased Tetrahydrobiopterin Biosynthesis in Mouse Hippocampus
by Jennyffer Souza, Debora da Luz Scheffer, Alexandre Francisco Solano, Samantha Veloso, Luisa Cruz, Rodrigo Foganholi-Silva and Alexandra Latini
Brain Sci. 2025, 15(8), 880; https://doi.org/10.3390/brainsci15080880 - 18 Aug 2025
Cited by 1 | Viewed by 1609
Abstract
Background: Robust evidence supports the role of tetrahydrobiopterin (BH4) metabolism in sustaining inflammation; however, the mechanisms underlying the persistent upregulation of the BH4 pathway remain incompletely understood. This study investigated the epigenetic regulation of BH4 metabolism following a single injection of lipopolysaccharide [...] Read more.
Background: Robust evidence supports the role of tetrahydrobiopterin (BH4) metabolism in sustaining inflammation; however, the mechanisms underlying the persistent upregulation of the BH4 pathway remain incompletely understood. This study investigated the epigenetic regulation of BH4 metabolism following a single injection of lipopolysaccharide (LPS) in the mouse hippocampus. Methods: Male C57BL/6J mice received either saline or LPS (0.33 mg/kg, i.p.) and were sacrificed at 4 h or 24 h post injection. Behavioral assessments and analyses of hippocampal neurotransmitter metabolism, DNA methylation profile, oxidative stress, and inflammasome activation were performed. Neopterin levels, a marker of immune system activation, were measured in both the plasma and hippocampus. Results: LPS-treated mice exhibited sickness behavior, including reduced locomotor and exploratory activity at both 4 and 24 h. While exploratory behavior showed partial recovery by 24 h, locomotor activity remained impaired. Neopterin levels increased in both the plasma and hippocampus following LPS administration but returned to baseline in the hippocampus by 24 h. Despite the normalization of neopterin, a persistent pro-inflammatory state in the hippocampus was evident at 24 h, as shown by increased expression of Ikbkb and components of the NLRP3 inflammasome, along with elevated oxidative stress markers. Upregulation of Nrf-2 and Hmox1 suggested activation of a protective antioxidant response. Dopaminergic metabolism was disrupted, indicating impaired BH4-dependent dopamine turnover. Epigenetic analysis revealed increased expression of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) and Tet2, along with reduced expression of Tet1 and Tet3. Promoter hypomethylation of Gch1 and Ptps was observed, correlating with increased hippocampal expression and potentially elevated BH4 levels. Conclusions: Together, these findings show that a single LPS challenge was sufficient to induce the activation of the BH4 synthesis pathway during the late acute inflammatory phase, both systemically and in the hippocampus, potentially driven by epigenetic modifications such as promoter hypomethylation. This may contribute to the perpetuation of neuroinflammation. Full article
(This article belongs to the Special Issue Toxic Mechanisms and Emerging Therapeutic Strategies in Brain Disorders)
►▼ Show Figures

Figure 1

Review

Jump to: Research

15 pages, 832 KB  
Review
Malonyl-CoA Decarboxylase: A Spotlight on Brain Aspects
by Monique Fonseca-Teixeira, Elaine Silva Brito, Clara Beltrao-Valente, Bruna Klippel Ferreira, Patricia Fernanda Schuck and Gustavo Costa Ferreira
Brain Sci. 2026, 16(2), 220; https://doi.org/10.3390/brainsci16020220 - 12 Feb 2026
Viewed by 1434
Abstract
Malonyl-CoA decarboxylase (MCD) is an enzyme that controls malonyl-CoA levels and regulates fatty acid synthesis and oxidation. Although its physiological relevance in peripheral tissues is well known, the role of MCD in the central nervous system remains poorly understood. MCD is expressed in [...] Read more.
Malonyl-CoA decarboxylase (MCD) is an enzyme that controls malonyl-CoA levels and regulates fatty acid synthesis and oxidation. Although its physiological relevance in peripheral tissues is well known, the role of MCD in the central nervous system remains poorly understood. MCD is expressed in mitochondria, cytosol, and peroxisomes and may be regulated by PPAR-α, AMPK, and SIRT4 in tissues such as muscle, liver and kidney. In the brain, MCD expression varies during development and can respond to nutritional states. Inherited MCD deficiency (malonic aciduria) leads to the toxic accumulation of malonic acid and predominantly affects the central nervous system. The underlying mechanisms leading to brain damage in MCD patients remain unclear. Conversely, pharmacological modulation of MCD activity has been studied in obesity, diabetes, and ischemic injury, highlighting its therapeutic potential. There are still major gaps regarding MCD cellular distribution, regulatory pathways, and metabolic interaction with CPT1c (carnitine palmitoyltransferase 1c) in neural metabolism. A deeper understanding of the role of MCD in brain physiology and pathology may indicate novel therapeutic strategies targeting metabolic disorders that involve altered malonyl-CoA dynamics. Here, we discuss the current knowns and unknowns regarding MCD physiology, regulation, and pathophysiology, emphasizing brain aspects. Full article
(This article belongs to the Special Issue Toxic Mechanisms and Emerging Therapeutic Strategies in Brain Disorders)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-4
Back to TopTop