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Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment

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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: 20 September 2026 | Viewed by 6192

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Special Issue Editors

Dr. Barbara Miziak

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Guest Editor

Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland
Interests: epilepsy; epileptogenesis; status epilepticus; neuroprotection; antiepileptic drugs; seizures
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Stanisław Jerzy Czuczwar

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Guest Editor

Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland
Interests: Alzheimer; epilepsy; stroke
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurological diseases constitute a large, heterogeneous group of disorders whose common feature is damage to the central nervous system. Their etiology includes mechanisms such as neurodegeneration, vascular changes, autoimmune processes, synaptic transmission disorders, and genetic defects. Frequently, the development of secondary chronic neuroglial inflammation, oxidative stress, and ion and energy homeostasis disorders can also be observed. In the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, the main role is played by the abnormal accumulation and aggregation of proteins and their toxic effect on nerve cells. In demyelinating diseases, such as multiple sclerosis, pathogenesis is mainly based on autoimmune damage to myelin sheaths. In the case of stroke, cerebral circulation disorders and cell death are observed. The etiology of epilepsy is multifactorial and includes neurotransmitter dysfunction and genetic mutations, as well as metabolic and electrolyte disorders, neurodegenerative processes, and inflammation in the brain.

Thorough knowledge and understanding of the above mechanisms also offer great opportunities for the development of therapies focusing on the pathomechanisms of neurological diseases. Currently, the most dominant form of therapy is pharmacotherapy, but newer strategies also include gene therapies, microRNA expression modulation, monoclonal antibodies, immunotherapies, and regenerative therapies.

Dr. Barbara Miziak
Prof. Dr. Stanisław Jerzy Czuczwar
Guest Editors

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Keywords

Alzheimer's disease
Parkinson's disease
Huntington's disease
epilepsy
stroke
neurological diseases
treatment of neurological diseases

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Published Papers (10 papers)

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Research

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18 pages, 8006 KB

Open AccessArticle

The RhoG-Binding Domain of ELMO1 Rescues the PTENopathy-like Phenotype in Oligodendroglial FBD-102b Cells

by Mikito Takahashi, Mei Tanaka, Hideji Yako, Yuki Miyamoto and Junji Yamauchi

Int. J. Mol. Sci. 2026, 27(8), 3457; https://doi.org/10.3390/ijms27083457 - 12 Apr 2026

Viewed by 234

Abstract

Oligodendroglial cells are the myelinating glial cells of the central nervous system (CNS), and their morphological differentiation is a prerequisite for efficient myelin formation, which is essential for proper neuronal function. While oligodendroglial morphological changes normally proceed through tightly regulated developmental transitions, disruption of the underlying molecular mechanisms can lead to aberrant cellular phenotypes characterized by either premature, insufficient, or excessive differentiation. Although the phosphatidylinositol 3-kinase (PI3K) and its downstream Akt kinase signaling are well established as major drivers of oligodendrocyte morphological differentiation, myelination, and CNS white matter formation, how its negative regulator, phosphatase and tensin homolog (PTEN), is involved in the regulation of oligodendroglial morphogenesis remains incompletely understood. Recent genetic studies have highlighted a spectrum of disorders caused by PTEN dysfunction, conceptually established but currently evolving as PTENopathy, which has been partially associated with white matter abnormalities. Here, we report that, in an experimental model using the FBD-102b cell line, a well-established model of oligodendroglial cell differentiation, chemical inhibition of PTEN enhances pronounced morphological changes characterized by widespread membranes, accompanied by increased expression of differentiation and/or myelin marker proteins. We then focused on Rho family small GTPases, central regulators of cell morphogenesis, and examined their potential involvement downstream of this signaling. Expression of the RhoG-binding domain (RBD) of engulfment and cell motility 1 (ELMO1) attenuated the increased morphological changes. Similarly, inhibition of downstream Akt signaling also reversed these changes. Taken together, these results provide insight into how balanced regulation between PTEN and downstream signaling molecules governs oligodendroglial cell differentiation and suggest that dysregulation of this signaling equilibrium may contribute to cellular phenotypes relevant to disease-associated cellular alterations. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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10 pages, 2252 KB

Open AccessArticle

Dose-Dependent Neuroprotective Effects of Valproate on Motor Function and Striatal D2 Receptor Stability in a 6-OHDA Rat Model of Parkinson’s Disease

by Alfonso Alfaro-Rodríguez, Angélica González-Maciel, Samuel Reyes Long, Beatriz Pérez-Guille, Rosa Eugenia Soriano-Rosales, José Francisco Gonzalez-Zamora, Herlinda Bonilla-Jaime and José Luis Cortes-Altamirano

Int. J. Mol. Sci. 2026, 27(5), 2320; https://doi.org/10.3390/ijms27052320 - 1 Mar 2026

Viewed by 453

Abstract

Parkinson’s disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons, leading to motor dysfunction and compensatory postsynaptic dopamine receptor alterations. Valproic acid (VPA), a histone deacetylase inhibitor, has shown neuroprotective properties; however, its dose-dependent effects on dopaminergic integrity and dopamine D2 receptor (D2R) regulation remain unclear. Adult male Wistar rats received VPA (200 or 400 mg/kg, p.o.) or vehicle for 20 days prior to unilateral 6-hydroxydopamine (6-OHDA) lesioning. Motor performance was evaluated using the beam balance test, exploratory behavior in the open field, striatal dopamine levels by PLC-electrochemical detection, and D2R protein expression by Western blot. The 6-OHDA lesion induced marked motor deficits, reduced striatal dopamine content, and significantly increased D2R expression. VPA at 200 mg/kg produced only minor, non-significant effects. In contrast, VPA at 400 mg/kg preserved motor performance, attenuated dopamine depletion, and normalized striatal D2R expression. These findings demonstrate a clear dose-dependent neuroprotective effect of VPA and indicate that stabilization of postsynaptic D2R expression accompanies preservation of dopaminergic terminals in the 6-OHDA rat model. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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17 pages, 825 KB

Open AccessArticle

Gallic Acid, 3-Hydroxytyrosol, and Quercetin Modulate Cholinesterase Activity in Drosophila melanogaster

by Tugba Ucar Akyurek, Fatma Sezer Senol Deniz, Ilkay Erdogan Orhan, Memet Gozuboyuk, Gulnur Ipek Erdemli and Guzin Emecen

Int. J. Mol. Sci. 2026, 27(2), 859; https://doi.org/10.3390/ijms27020859 - 15 Jan 2026

Cited by 1 | Viewed by 504 | Correction

Abstract

The current study investigates the modulatory effects of gallic acid (GA), 3-hydroxytyrosol (3-HT), and quercetin (QUE) on key cholinesterase enzymes using Drosophila melanogaster (fruit fly) head homogenates as a source of central cholinesterases following in vivo larval exposure. The choice of these plant phenolics was predicated on their cholinesterase (ChE) inhibitory effect reported recently by our group. The study utilized D. melanogaster larvae subjected to varying doses of GA, 3-HT, and QUE, subsequently evaluating enzymatic activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Galanthamine HBr was used as a positive control. All three phenolic compounds exhibited elevated ΔOD/min values for BChE inhibition compared to the negative control (ethanol). GA and QUE inhibited AChE, though with lower potency than galanthamine; at 1 mM, GA and QUE achieved 79.23% and 80.98% inhibition, respectively, compared to 98.34% for galanthamine. Interestingly, the effect of 3-HT on AChE was inversely related to the dose. The results indicate that GA and QUE modulate cholinesterase activity in vivo, consistent with our prior in vitro reports. This study also provides the first in vivo evidence of 3-HT’s ChE-modulating activity in Drosophila within a whole-organism model. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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15 pages, 4353 KB

Open AccessArticle

The ErbB2–Dock7 Signaling Axis Mediates Excessive Cell Morphogenesis Induced by Autism Spectrum Disorder- and Intellectual Disability-Associated Sema5A p.Arg676Cys

by Mikito Takahashi, Hideji Yako, Ayaka Suzuki, Ryuma Isa, Yuki Miyamoto and Junji Yamauchi

Int. J. Mol. Sci. 2025, 26(21), 10656; https://doi.org/10.3390/ijms262110656 - 1 Nov 2025

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Abstract

Characterized by social communication deficits and the presence of restricted and repetitive behaviors, autism spectrum disorder (ASD) is a significant neurodevelopmental condition. Genetic studies have revealed a strong association between ASD and numerous mutations that alter the function of key proteins, either through activation or inactivation. These alterations are widely hypothesized to affect neuronal morphogenesis; however, a comprehensive understanding of the specific molecular cascades driving these cellular and symptomatic changes remains lacking. In this study, we report for the first time that signaling through the atypical Rho family guanine-nucleotide exchange factor (GEF) Dock7 and ErbB2, an activator acting upstream of Dock7, drives the excessive elongation of neuronal processes observed in association with the ASD- and intellectual disability (ID)-linked semaphorin-5A (Sema5A) Arg676Cys variant (p.Arg676Cys). Knockdown of Dock7 using short hairpin RNA or inhibition of ErbB2 kinase signaling with a specific chemical inhibitor reduced this excessive process elongation in primary cortical neurons. Similar results were obtained in the N1E-115 cell line, a neuronal cell model that undergoes neuronal morphological differentiation. Moreover, inhibition of ErbB2-Dock7 signaling specifically decreased the overactivation of the downstream molecules Rac1 and Cdc42. These findings indicate that the ErbB2–Dock7 signaling axis plays a role in mediating the aberrant neuronal morphology associated with the ASD- and ID-linked Sema5A p.Arg676Cys. Targeting this pathway may therefore offer a potential approach to addressing the molecular and cellular developmental challenges observed in ASD. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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24 pages, 1146 KB

Open AccessReview

Serum Biomarkers in Restless Legs Syndrome: Beyond the Classical Iron Paradigm—A Scoping Review

by Krasimir Avramov, Todor Georgiev, Aneliya Draganova and Kiril Terziyski

Int. J. Mol. Sci. 2026, 27(8), 3385; https://doi.org/10.3390/ijms27083385 - 9 Apr 2026

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Abstract

Restless legs syndrome (RLS) is one of the most prevalent sleep disorders, yet its diagnosis continues to rely almost entirely on subjective symptom descriptions. This persistent dependence on phenomenology reflects the absence of reliable biological markers to aid in the process of diagnosis or monitoring. However, there is accumulating molecular evidence that suggests that RLS is associated with systemic biological alterations. These extend beyond the traditional paradigm of iron deficiency. The present scoping review synthesizes the current research on circulating serum biomarkers investigated in RLS outside classical iron indices. A comprehensive search of PubMed, Scopus, and Web of Science databases identified 1050 records, of which 50 studies met eligibility criteria and were included. In the processing of data, clusters emerged into several recurring biological domains, including dysregulated iron regulatory signaling (hepcidin), low-grade immune activation, oxidative stress, and neuroaxonal injury markers. High-throughput omics studies reveal molecular network perturbations involving inflammatory pathways, complement activation, metabolic signaling, and cellular stress responses. Biomarker associations appear stronger when linked to objective motor burden. These findings suggest that RLS may involve multifarious molecular changes detectable in the serum. Consequently, this can support the transition from symptom-based diagnosis toward biomarker-informed stratification, which may enable more precise disease characterization and improved diagnostic accuracy. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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16 pages, 1777 KB

Open AccessReview

Molecular and Mechanistic Divergence of Seizures in Pediatric Acute Lymphoblastic Leukemia: CNS Infiltration Versus Chemotherapy-Induced Neurotoxicity

by Jin Joo, Woo Sub Yang and Hyun Jung Koh

Int. J. Mol. Sci. 2026, 27(7), 3307; https://doi.org/10.3390/ijms27073307 - 6 Apr 2026

Viewed by 338

Abstract

Neurological complications, particularly seizures, represent a significant and often under-recognized clinical challenge in pediatric hematologic malignancies. Distinguishing CNS leukemia-associated epilepsy from chemotherapy-induced neurotoxicity is critical for optimizing therapy but remains difficult due to overlapping clinical presentations. This review highlights the distinct molecular mechanisms underlying these two entities. CNS leukemia-associated seizures are primarily driven by blood–brain barrier (BBB) disruption following leukemic infiltration, which triggers a neuroinflammatory cascade involving pro-inflammatory cytokines such as IL-6 and TNF-α, and impairs glutamate homeostasis. In contrast, chemotherapy-induced seizures, particularly those associated with high-dose methotrexate, arise from disrupted folate metabolism, intracellular oxidative stress, and subsequent N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. We provide a comparative analysis of these pathways, integrating current evidence on pharmacogenomic susceptibility—including polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and drug transporter genes—as well as epigenetic factors. By synthesizing these molecular insights, we propose a mechanistic framework for precise clinical differentiation, which may inform biomarker-driven diagnostic approaches and targeted neuroprotective strategies in this vulnerable population. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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35 pages, 2757 KB

Open AccessReview

Modern Analytical Techniques in Epilepsy Research

by Katarzyna Idzikowska, Paulina Gątarek and Joanna Kałużna-Czaplińska

Int. J. Mol. Sci. 2026, 27(5), 2395; https://doi.org/10.3390/ijms27052395 - 4 Mar 2026

Cited by 1 | Viewed by 623

Abstract

Epilepsy remains one of the most prevalent neurological disorders, characterised by complex aetiology encompassing genetic, structural, metabolic, and inflammatory factors. Despite advances in neuroimaging and neurophysiological diagnostics, there is a persistent lack of sensitive and specific biomarkers to enable early diagnosis, risk stratification, and monitoring of therapeutic efficacy. Key epilepsy biomarkers include neurotransmitters, energy–related compounds, tryptophan pathway metabolites, and choline derivatives. Their determination employs liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS), high–performance liquid chromatography (HPLC) with electrochemical or fluorescence detection, gas chromatography with tandem mass spectrometry (GC–MS/MS), high–resolution mass spectrometry (HRMS), and proton nuclear magnetic resonance (¹H–NMR) spectroscopy, revealing metabolic disturbances in neurotransmission, energy metabolism, and oxidative stress associated with epileptogenesis. Among these techniques, LC–MS/MS currently provides the highest analytical sensitivity and specificity for quantifying low–abundance epilepsy–related metabolites, while HPLC with conventional detection remains a simpler and more cost–effective alternative for routine clinical laboratories. This review presents the current state of knowledge regarding chromatographic techniques applied to the analysis of mentioned metabolites, as well as therapeutic drug monitoring of antiepileptic drugs. Key sample preparation stages are also discussed. Various biological matrices–plasma, serum, urine, cerebrospinal fluid (CSF), dried blood spots (DBSs), and brain tissue—are evaluated. Novel approaches are also presented, including hair samples, microsampling techniques, and headspace analysis of volatile metabolites. Chromatographic techniques constitute the foundation of contemporary metabolomic research in epileptology, enabling biomarker identification and supporting personalised medicine. Further standardisation and translational validation remain necessary, as current evidence is insufficient for routine clinical implementation. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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33 pages, 2564 KB

Open AccessReview

Unraveling Lennox–Gastaut Syndrome: From Molecular Pathogenesis to Precision Diagnosis and Targeted Therapy Evolving Therapeutic Strategies

by Ji-Hoon Na and Young-Mock Lee

Int. J. Mol. Sci. 2026, 27(3), 1382; https://doi.org/10.3390/ijms27031382 - 30 Jan 2026

Viewed by 794

Abstract

Lennox–Gastaut syndrome (LGS) is a rare and severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, mandatory tonic seizures, cognitive and behavioral impairment, and distinctive electroencephalographic features, including slow spike–wave discharges and generalized paroxysmal fast activity. Despite decades of therapeutic advances, LGS remains associated with profound lifelong disability and the absence of a single disease-defining molecular mechanism. Recent advances in genetics, neurophysiology, and network neuroscience have reframed LGS as a convergent network encephalopathy, in which diverse genetic, structural, metabolic, immune, and acquired insults funnel into shared molecular hubs, leading to thalamocortical network dysfunction. This framework helps explain the limited efficacy of purely syndrome-based treatments. This review synthesizes current evidence on electroclinical phenotyping, molecular and network pathogenesis, and contemporary diagnostic workflows and proposes a molecule-to-precision-therapy framework for LGS. We critically appraise pharmacologic, dietary, surgical, and neuromodulatory therapies, emphasizing drop seizures as a major driver of morbidity. Among available treatments, cannabidiol shows the most consistent and clinically meaningful efficacy for drop seizures, with benefits extending beyond seizure counts to seizure-free days and caregiver-relevant outcomes. Finally, we highlight key gaps and future directions, including etiology-stratified trials, network-guided interventions, and outcome measures that capture long-term developmental and quality-of-life impacts. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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22 pages, 4168 KB

Open AccessReview

Methamphetamine-Associated Cardiomyopathy and Cardioembolic Stroke: Brain–Heart–Gut Axis Crosstalk, Diagnostic Strategies, and Anticoagulation Challenges

by Pei-Jung Lin, Chia-Hui Wu, Jen-Hung Huang, Jakir Hossain Bhuiyan Masud, Chien-Tai Hong, Lung Chan and Chen-Chih Chung

Int. J. Mol. Sci. 2025, 26(24), 11908; https://doi.org/10.3390/ijms262411908 - 10 Dec 2025

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Abstract

Methamphetamine (MA) abuse has emerged as a multisystem insult driving cardiovascular and neurovascular consequences. Methamphetamine-associated cardiomyopathy (MACM) remains an underrecognized cause of cardioembolic stroke through left ventricular thrombus (LVT) formation. MA-induced gut dysbiosis and enteric neural disruption exacerbate systemic inflammation and autonomic imbalance, resulting in broader dysregulation of the brain–heart–gut axis. This study aimed to synthesize contemporary evidence on chronic MA exposure and its role in LVT formation, stroke pathogenesis, diagnostic approaches, and anticoagulation management. We conducted a focused narrative review of PubMed- and Scopus-indexed literature (1990–2025) addressing cardiovascular, neurovascular, and gut-mediated consequences of chronic MA exposure. Observational cohorts and case reports were integrated to characterize pathophysiology, imaging approaches, and therapeutic considerations, supplemented by a representative clinical case. Chronic MA exposure mediates persistent catecholamine excess, myocardial fibrosis, ventricular dysfunction, and a prothrombotic milieu. Gut dysbiosis-related inflammation and autonomic dysregulation further promote intracardiac stasis. Affected individuals are typically young men with severe systolic dysfunction (left ventricular ejection fraction 20–30%), with a substantial proportion demonstrating apical or mural LVT on systematic imaging. Case-level evidence highlights a broader systemic embolic burden, involving the limbs, kidneys, and aorta. Echocardiography remains the first-line screening method, while cardiac CT and MRI offer greater sensitivity for thrombus detection. Anticoagulation is challenged by bleeding risk, inconsistent adherence, and the absence of standardized protocols. MACM represents a critical and underrecognized etiology of cardioembolic stroke in young adults. Early recognition of brain–heart–gut axis disruption, systematic cardiac imaging, and individualized anticoagulation are crucial for preventing emboli. Prospective registries and standardized imaging-guided treatment strategies are needed to improve outcomes in this high-risk population. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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