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From Molecular Insights to Novel Therapies: Neurological Diseases

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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 March 2025 | Viewed by 11994

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Dr. Margarita Neganova

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Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severnii pr-d 1, Chernogolovka 142432, Russia
Interests: brain cancer; glycolysis; abnormal tumor metabolism; tumor biomarkers; apoptosis; chemotherapy; multitarget anticancer agents
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Dear Colleagues,

Neurological diseases are a diverse group of central and peripheral nervous system pathologies, which together are one of the leading causes of morbidity and mortality worldwide. To date, the range of treatment options for neuropathologies is extremely limited, with rates reflecting the number of FDA-approved drugs remaining low compared to other pharmaceutical industries. The complexity of creating effective therapeutic strategies is due to the polyetiological nature of neurological diseases, which is manifested in the heterogeneity of pathogenetic mechanisms. The combination of these factors leads to an urgent need to identify new biomarkers and create innovative methods of treatment to solve this problem, which places a huge socio-economic burden on the healthcare system and society as a whole.

In this Special Issue, we do not want to limit the authors to only work in the field of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, etc.). Topics of interest also include mental illness, cerebrovascular, psychiatric, autoimmune-related, and traumatic diseases.

We will be sincerely glad to consider reviews of the latest achievements of highly qualified specialists in the neuroscience field, as well as experimental articles containing up-to-date information on the problems and prospects in the development of effective drugs for the various neurological disorder’s treatment.

Dr. Margarita Neganova
Guest Editor

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Keywords

neurological diseases
neurodegenerative diseases
epilepsy
mental illness
transgenic animal models
molecular pathways
metabolism disabilities
mitochondrial dysfunction
oxidative stress
disturbances in epigenetic regulation

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Published Papers (10 papers)

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Research

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19 pages, 4220 KiB

Open AccessArticle

The Neuroprotective Effects of Peripheral Nerve Microcurrent Stimulation Therapy in a Rat Model of Middle Cerebral Artery Occlusion

by Yoon-Jin Lee, Eun Sang Kwon, Yong Suk Moon, Jeong-Rang Jo and Dong Rak Kwon

Int. J. Mol. Sci. 2024, 25(18), 10034; https://doi.org/10.3390/ijms251810034 - 18 Sep 2024

Viewed by 743

Abstract

This study investigated the neuroprotective effects of peripheral nerve microcurrent stimulation therapy in a rat model of middle cerebral artery occlusion (MCAO). Twenty 8-week-old male Sprague Dawley rats weighing 300–330 g were categorised into group A, serving as the healthy control; group B, including rats subjected to MCAO; group C, including rats receiving microcurrent therapy immediately after MCAO, which was continued for one week; and group D, including rats receiving microcurrent therapy one week before and one week after MCAO. A gross morphological analysis, behavioural motion analysis, histological examination, immunohistochemistry, and Western blotting were conducted. Microcurrent therapy significantly reduced ischaemic damage and pyramidal cells of the hippocampus CA1 region. Haematoxylin and eosin staining revealed infarction areas/viable pyramidal cell numbers of 0%/94.33, 28.53%/40.05, 17.32%/80.13, and 5.38%/91.34 in groups A, B, C, and D, respectively (p < 0.001). A behavioural analysis revealed that the total distances moved were 1945.24 cm, 767.85 cm, 1781.77 cm, and 2122.22 cm in groups A, B, C, and D, respectively (p < 0.05), and the mean speeds were 6.48 cm/s, 2.50 cm/s, 5.43 cm/s, and 6.82 cm/s, respectively (p < 0.05). Inflammatory markers (cluster of differentiation 68, interleukin-6, and tumour necrosis factor-α) significantly decreased in the treated groups (p < 0.001). Western blotting revealed reduced proinflammatory, oxidative stress, and apoptosis-related protein levels, along with increased angiogenic factors and mitogen-activated protein kinase (MAPK) pathway modulation in the treated groups. Peripheral nerve microcurrent stimulation therapy effectively mitigates ischaemic damage, promotes recovery, reduces inflammation, and modulates protein expression, emphasising its potential as a therapeutic strategy for ischaemic stroke. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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9 pages, 1771 KiB

Open AccessArticle

ShSPI Inhibits Thrombosis Formation and Ischemic Stroke In Vivo

by Ning Luan, Han Cao, Yunfei Wang, Haihao Zhang, Kangyang Lin, Jingping Hu, Mingqiang Rong and Cunbao Liu

Int. J. Mol. Sci. 2024, 25(16), 9003; https://doi.org/10.3390/ijms25169003 - 19 Aug 2024

Viewed by 654

Abstract

Thrombotic diseases, emerging as a global public health hazard with high mortality and disability rates, pose a significant threat to human health and longevity. Although current antithrombotic therapies are effective in treating these conditions, they often carry a substantial risk of bleeding, highlighting the urgent need for safer therapeutic alternatives. Recent evidence has increasingly pointed to a connection between elastase activity and thrombosis. In the current study, we investigated the antithrombotic effects of ShSPI, an elastase inhibitor peptide derived from the venom of Scolopendra hainanum. Results showed that ShSPI significantly attenuated carrageenan-induced thrombosis in vivo. Furthermore, ShSPI effectively inhibited the carrageenan-induced decrease in serum superoxide dismutase (SOD) activity and increase in prothrombin time, fibrinogen level, and endothelial nitric oxide synthase (eNOS) activity. In addition, ShSPI reduced intracerebral thrombosis and improved functional outcomes following ischemic stroke in a transient middle cerebral artery occlusion (tMCAO) mouse model. Collectively, these findings suggest that ShSPI is a promising candidate for the development of novel thrombotic therapies. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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14 pages, 1214 KiB

Open AccessArticle

Potential Effects of Low-Level Toluene Exposure on the Nervous System of Mothers and Infants

by So Yeon Yu, Seung Hwan Kim, Jeong Hyeop Choo, Sehun Jang, Jihyun Kim, Kangmo Ahn and Seung Yong Hwang

Int. J. Mol. Sci. 2024, 25(11), 6215; https://doi.org/10.3390/ijms25116215 - 5 Jun 2024

Viewed by 1149

Abstract

In day-to-day living, individuals are exposed to various environmentally hazardous substances that have been associated with diverse diseases. Exposure to air pollutants can occur during breathing, posing a considerable risk to those with environmental health vulnerabilities. Among vulnerable individuals, maternal exposure can negatively impact the mother and child in utero. The developing fetus is particularly vulnerable to environmentally hazardous substances, with potentially greater implications. Among air pollutants, toluene is neurotoxic, and its effects have been widely explored. However, the impact of low-level toluene exposure in daily life remains unclear. Herein, we evaluated 194 mothers and infants from the Growing children’s health and Evaluation of Environment (GREEN) cohort to determine the possible effects of early-life toluene exposure on the nervous system. Using Omics experiments, the effects of toluene were confirmed based on epigenetic changes and altered mRNA expression. Various epigenetic changes were identified, with upregulated expression potentially contributing to diseases such as glioblastoma and Alzheimer’s, and downregulated expression being associated with structural neuronal abnormalities. These findings were detected in both maternal and infant groups, suggesting that maternal exposure to environmental hazardous substances can negatively impact the fetus. Our findings will facilitate the establishment of environmental health policies, including the management of environmentally hazardous substances for vulnerable groups. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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22 pages, 4662 KiB

Open AccessArticle

D^Re^Amocracy: A Method to Capitalise on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing

by Kyriaki Savva, Margarita Zachariou, Marilena M. Bourdakou, Nikolas Dietis and George M. Spyrou

Int. J. Mol. Sci. 2024, 25(10), 5319; https://doi.org/10.3390/ijms25105319 - 13 May 2024

Cited by 1 | Viewed by 1186

Abstract

In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, D^Re^Amocracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer’s Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson’s Disease, they include apomorphine, pramipexole and lisuride; for Huntington’s, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, D^Re^Amocracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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Review

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18 pages, 711 KiB

Open AccessReview

Proposed Mechanisms of Cell Therapy for Alzheimer’s Disease

by Ekaterina Belousova, Diana Salikhova, Yaroslav Maksimov, Vladimir Nebogatikov, Anastasiya Sudina, Dmitry Goldshtein and Aleksey Ustyugov

Int. J. Mol. Sci. 2024, 25(22), 12378; https://doi.org/10.3390/ijms252212378 - 18 Nov 2024

Viewed by 278

Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by mitochondria dysfunction, accumulation of beta-amyloid plaques, and hyperphosphorylated tau tangles in the brain leading to memory loss and cognitive deficits. There is currently no cure for this condition, but the potential of stem cells for the therapy of neurodegenerative pathologies is actively being researched. This review discusses preclinical and clinical studies that have used mouse models and human patients to investigate the use of novel types of stem cell treatment approaches. The findings provide valuable insights into the applications of stem cell-based therapies and include the use of neural, glial, mesenchymal, embryonic, and induced pluripotent stem cells. We cover current studies on stem cell replacement therapy where cells can functionally integrate into neural networks, replace damaged neurons, and strengthen impaired synaptic circuits in the brain. We address the paracrine action of stem cells acting via secreted factors to induce neuroregeneration and modify inflammatory responses. We focus on the neuroprotective functions of exosomes as well as their neurogenic and synaptogenic effects. We look into the shuttling of mitochondria through tunneling nanotubes that enables the transfer of healthy mitochondria by restoring the normal functioning of damaged cells, improving their metabolism, and reducing the level of apoptosis. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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25 pages, 7059 KiB

Open AccessReview

SPROUTY2, a Negative Feedback Regulator of Receptor Tyrosine Kinase Signaling, Associated with Neurodevelopmental Disorders: Current Knowledge and Future Perspectives

by Nidhi Puranik, HoJeong Jung and Minseok Song

Int. J. Mol. Sci. 2024, 25(20), 11043; https://doi.org/10.3390/ijms252011043 - 14 Oct 2024

Viewed by 700

Abstract

Growth-factor-induced cell signaling plays a crucial role in development; however, negative regulation of this signaling pathway is important for sustaining homeostasis and preventing diseases. SPROUTY2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase (RTK) signaling that binds to GRB2 during RTK activation and inhibits the GRB2-SOS complex, which inhibits RAS activation and attenuates the downstream RAS/ERK signaling cascade. SPRY was formerly discovered in Drosophila but was later discovered in higher eukaryotes and was found to be connected to many developmental abnormalities. In several experimental scenarios, increased SPRY2 protein levels have been observed to be involved in both peripheral and central nervous system neuronal regeneration and degeneration. SPRY2 is a desirable pharmaceutical target for improving intracellular signaling activity, particularly in the RAS/ERK pathway, in targeted cells because of its increased expression under pathological conditions. However, the role of SPRY2 in brain-derived neurotrophic factor (BDNF) signaling, a major signaling pathway involved in nervous system development, has not been well studied yet. Recent research using a variety of small-animal models suggests that SPRY2 has substantial therapeutic promise for treating a range of neurological conditions. This is explained by its function as an intracellular ERK signaling pathway inhibitor, which is connected to a variety of neuronal activities. By modifying this route, SPRY2 may open the door to novel therapeutic approaches for these difficult-to-treat illnesses. This review integrates an in-depth analysis of the structure of SPRY2, the role of its major interactive partners in RTK signaling cascades, and their possible mechanisms of action. Furthermore, this review highlights the possible role of SPRY2 in neurodevelopmental disorders, as well as its future therapeutic implications. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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34 pages, 1880 KiB

Open AccessReview

A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach

by Rawiah S. Alshehri, Ahmad R. Abuzinadah, Moafaq S. Alrawaili, Muteb K. Alotaibi, Hadeel A. Alsufyani, Rajaa M. Alshanketi and Aysha A. AlShareef

Int. J. Mol. Sci. 2024, 25(20), 10900; https://doi.org/10.3390/ijms252010900 - 10 Oct 2024

Viewed by 1098

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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12 pages, 1479 KiB

Open AccessReview

Pregnant Women with Multiple Sclerosis: An Overview of Gene Expression and Molecular Interaction Using Bioinformatics Analysis

by Jazmin Marquez-Pedroza, Martha Rocio Hernández-Preciado, Edgar Ricardo Valdivia-Tangarife, Francisco J. Alvarez-Padilla, Mario Alberto Mireles-Ramírez and Blanca Miriam Torres-Mendoza

Int. J. Mol. Sci. 2024, 25(12), 6741; https://doi.org/10.3390/ijms25126741 - 19 Jun 2024

Viewed by 1134

Abstract

Multiple sclerosis (MS) is a common disease in young women of reproductive age, characterized by demyelination of the central nervous system (CNS). Understanding how genes related to MS are expressed during pregnancy can provide insights into the potential mechanisms by which pregnancy affects the course of this disease. This review article presents evidence-based studies on these patients’ gene expression patterns. In addition, it constructs interaction networks using bioinformatics tools, such as STRING and KEGG pathways, to understand the molecular role of each of these genes. Bioinformatics research identified 25 genes and 21 signaling pathways, which allows us to understand pregnancy patients’ genetic and biological phenomena and formulate new questions about MS during pregnancy. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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55 pages, 3428 KiB

Open AccessReview

Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases

by Yulia Aleksandrova and Margarita Neganova

Int. J. Mol. Sci. 2023, 24(19), 14766; https://doi.org/10.3390/ijms241914766 - 29 Sep 2023

Cited by 2 | Viewed by 2461

Abstract

The relationship between oncological pathologies and neurodegenerative disorders is extremely complex and is a topic of concern among a growing number of researchers around the world. In recent years, convincing scientific evidence has accumulated that indicates the contribution of a number of etiological factors and pathophysiological processes to the pathogenesis of these two fundamentally different diseases, thus demonstrating an intriguing relationship between oncology and neurodegeneration. In this review, we establish the general links between three intersecting aspects of oncological pathologies and neurodegenerative disorders, i.e., oxidative stress, epigenetic dysregulation, and metabolic dysfunction, examining each process in detail to establish an unusual epidemiological relationship. We also focus on reviewing the current trends in the research and the clinical application of the most promising chemical structures and therapeutic platforms that have a modulating effect on the above processes. Thus, our comprehensive analysis of the set of molecular determinants that have obvious cross-functional pathways in the pathogenesis of oncological and neurodegenerative diseases can help in the creation of advanced diagnostic tools and in the development of innovative pharmacological strategies. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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Other

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9 pages, 466 KiB

Open AccessCase Report

Case Report: A Case of a Patient with Smith–Magenis Syndrome and Early-Onset Parkinson’s Disease

by Tchelet Stern, Yara Hussein, Diogo Cordeiro, Hagit Sadis, Tali Garin-Shkolnik, Ronen Spiegel, Sagit Cohen, Ruth Harari, Ilana Schlesinger and Shani Stern

Int. J. Mol. Sci. 2024, 25(15), 8447; https://doi.org/10.3390/ijms25158447 - 2 Aug 2024

Viewed by 953

Abstract

Smith–Magenis Syndrome (SMS) is a rare genetic disorder, characterized by intellectual disability (ID), behavioral impairments, and sleep disturbances, as well as multiple organ anomalies in some affected individuals. The syndrome is caused by a deletion in the chromosome band around 17p11.2, including the Retinoic Acid Induced 1 (RAI1) gene, a multifaceted transcriptional regulator that modulates the expression of genes involved in cellular proliferation and neurodevelopment. This gene has a positive role in regulating BDNF and, importantly, affects several cell mechanisms and pathways such as the nigro-striatal pathway, which is crucial for motor function. Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in older populations. It is characterized by various physical symptoms including tremors, loss of balance, bradykinesia, and a stooping posture. We present a case study of a patient diagnosed with both SMS and early-onset PD (at the age of 49). The association between both conditions is as yet ambiguous. Genome-wide association studies (GWAS) implicate an association between the RAI1 gene and PD. Similarly, the co-existence of both SMS and PD in the patient suggests a possible association between RAI1 copy number variations (CNVs) and PD, further indicating that RAI1 has strong implications for PD pathogenesis. Our results suggest that RAI1 CNVs and the pathophysiology of PD may be related, underscoring the need for further research in this field. Therefore, caregivers of SMS patients should pay careful attention to the possibility of their patients developing EOPD and should consider starting treatment for PD as soon as the first symptoms appear. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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