Previous
The relationship between the gut microbiota and the central nervous system has gained attention as a biological axis that may influence the development of several neurological disorders. Recent evidence integrating genomic, neurobiological, and microbiota research shows how bacterial composition, host genetic variability, and the mechanisms of the microbiota-gut-brain axis interact in conditions such as autism spectrum disorder, epilepsy, and schizophrenia. These interactions function through neural, metabolic, and immunological related pathways involving intestinal and blood-brain barrier permeability. Genome-wide association studies (GWAS) and Mendelian randomization analyses highlight shared immunogenetic pathways that may shape both microbial profiles and neurological susceptibility. Consistent patterns of dysbiosis and alterations in neuroactive metabolites have also been reported, linking microbiota changes to neuroinflammation and disrupted neuronal signaling. This review synthesizes the current evidence supporting the integration of the microbiota-gut-brain axis and its underlying communication pathways. It also outlines the present therapeutic strategies for neurological disorders such as autism spectrum disorder, epilepsy, and schizophrenia, highlighting their potential to modulate neurological function. Additionally, it discusses the existing limitations in the field and offers insights into future research directions within this rapidly evolving area.
The relationship between the gut microbiota and the central nervous system has gained attention as a biological axis that may influence the development of several neurological disorders. Recent evidence integrating genomic, neurobiological, and microbiota research shows how bacterial composition, host genetic variability, and the mechanisms of the microbiota-gut-brain axis interact in conditions such as autism spectrum disorder, epilepsy, and schizophrenia. These interactions function through neural, metabolic, and immunological related pathways involving intestinal and blood-brain barrier permeability. Genome-wide association studies (GWAS) and Mendelian randomization analyses highlight shared immunogenetic pathways that may shape both microbial profiles and neurological susceptibility. Consistent patterns of dysbiosis and alterations in neuroactive metabolites have also been reported, linking microbiota changes to neuroinflammation and disrupted neuronal signaling. This review synthesizes the current evidence supporting the integration of the microbiota-gut-brain axis and its underlying communication pathways. It also outlines the present therapeutic strategies for neurological disorders such as autism spectrum disorder, epilepsy, and schizophrenia, highlighting their potential to modulate neurological function. Additionally, it discusses the existing limitations in the field and offers insights into future research directions within this rapidly evolving area.
DOI: https://doi.org/10.37349/ent.2026.1004146
This article belongs to the special issue Role of Microbiota in Neurological Diseases
Background:
Acquired brain injury (ABI) often causes long-lasting impairments in written language and handwriting that limit autonomy and daily functioning. Despite their relevance, these deficits have received limited research attention compared with spoken language disorders. The present work aims to systematically review interventions designed to improve reading, writing, and handwriting abilities in individuals with ABI.
Methods:
Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, American Psychological Association (APA) PsycINFO, Cochrane Library, Web of Science, and Google Scholar were searched from inception to 1 November 2025. Eligible studies were randomized or non-randomized clinical trials (non-RCTs) involving adults or adolescents with ABI and documented written language impairments. Risk of bias was assessed using the Risk of Bias 2 tool (RCTs) and Risk of Bias in Non-randomized Studies—of Interventions tool (non-RCTs).
Results:
Twelve studies met inclusion criteria (2 RCTs, 10 non-RCTs), all conducted in post-stroke populations, highlighting the absence of evidence from other ABI aetiologies. Three main intervention categories emerged: (1) Behavioral treatments, which consistently improved trained spelling and functional writing, with some advantages for errorless learning in maintaining gains. (2) Technology-assisted approaches, including assistive software, digital spelling aids, and handwriting-focused programs, which showed feasibility, high usability, and improvements in accuracy, legibility, and motor fluency. (3) Neuromodulation, with one RCT showing that dual-site transcranial direct current stimulation can modestly enhance behavioral writing therapy. Most non-RCTs showed serious or critical risk of bias, and sample sizes were small, limiting generalizability.
Discussion:
Current evidence—although preliminary and restricted to post-stroke ABI—indicates that behavioral, technological, and neuromodulatory interventions can improve aspects of written language and handwriting after ABI. However, the available literature is characterized by small samples, substantial methodological variability, and a paucity of standardized and ecologically valid outcome measures. High-quality, adequately powered trials with standardized, functional outcomes are urgently needed, particularly in non-stroke ABI populations.
Background:
Acquired brain injury (ABI) often causes long-lasting impairments in written language and handwriting that limit autonomy and daily functioning. Despite their relevance, these deficits have received limited research attention compared with spoken language disorders. The present work aims to systematically review interventions designed to improve reading, writing, and handwriting abilities in individuals with ABI.
Methods:
Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, American Psychological Association (APA) PsycINFO, Cochrane Library, Web of Science, and Google Scholar were searched from inception to 1 November 2025. Eligible studies were randomized or non-randomized clinical trials (non-RCTs) involving adults or adolescents with ABI and documented written language impairments. Risk of bias was assessed using the Risk of Bias 2 tool (RCTs) and Risk of Bias in Non-randomized Studies—of Interventions tool (non-RCTs).
Results:
Twelve studies met inclusion criteria (2 RCTs, 10 non-RCTs), all conducted in post-stroke populations, highlighting the absence of evidence from other ABI aetiologies. Three main intervention categories emerged: (1) Behavioral treatments, which consistently improved trained spelling and functional writing, with some advantages for errorless learning in maintaining gains. (2) Technology-assisted approaches, including assistive software, digital spelling aids, and handwriting-focused programs, which showed feasibility, high usability, and improvements in accuracy, legibility, and motor fluency. (3) Neuromodulation, with one RCT showing that dual-site transcranial direct current stimulation can modestly enhance behavioral writing therapy. Most non-RCTs showed serious or critical risk of bias, and sample sizes were small, limiting generalizability.
Discussion:
Current evidence—although preliminary and restricted to post-stroke ABI—indicates that behavioral, technological, and neuromodulatory interventions can improve aspects of written language and handwriting after ABI. However, the available literature is characterized by small samples, substantial methodological variability, and a paucity of standardized and ecologically valid outcome measures. High-quality, adequately powered trials with standardized, functional outcomes are urgently needed, particularly in non-stroke ABI populations.
DOI: https://doi.org/10.37349/ent.2026.1004145
This article belongs to the special issue Neuropsychology of Handwriting
Background:
Fully immersive virtual reality (IVR) is an emerging technology approach for cognitive training in individuals with mild cognitive impairment (MCI) and dementia. While interest in fully IVR continues to grow, it remains unclear the extent of effectiveness and the key components that contribute to successful implementation. This study aimed to explore the effectiveness of fully IVR cognitive training for individuals with MCI or dementia from previous research literature.
Methods:
A scoping review was conducted using a systematic search strategy based on the population, concept, and context framework.
Results:
Out of the 816 records identified, 123 full texts were screened, and eight studies were included in the review. The included studies all involved participants completing a cognitive training intervention using fully IVR headsets, with cognitive outcomes measured before and after the intervention. The most consistent improvements across the included studies were executive function, memory, and visuospatial abilities. Only two studies explicitly referenced a theoretical model.
Discussion:
Fully IVR cognitive training demonstrates promise for improving specific cognitive domains in individuals living with MCI or dementia. However, inconsistencies in outcomes and limited theoretical grounding highlight the need for further exploration. Broader considerations are discussed in the discussion section.
Background:
Fully immersive virtual reality (IVR) is an emerging technology approach for cognitive training in individuals with mild cognitive impairment (MCI) and dementia. While interest in fully IVR continues to grow, it remains unclear the extent of effectiveness and the key components that contribute to successful implementation. This study aimed to explore the effectiveness of fully IVR cognitive training for individuals with MCI or dementia from previous research literature.
Methods:
A scoping review was conducted using a systematic search strategy based on the population, concept, and context framework.
Results:
Out of the 816 records identified, 123 full texts were screened, and eight studies were included in the review. The included studies all involved participants completing a cognitive training intervention using fully IVR headsets, with cognitive outcomes measured before and after the intervention. The most consistent improvements across the included studies were executive function, memory, and visuospatial abilities. Only two studies explicitly referenced a theoretical model.
Discussion:
Fully IVR cognitive training demonstrates promise for improving specific cognitive domains in individuals living with MCI or dementia. However, inconsistencies in outcomes and limited theoretical grounding highlight the need for further exploration. Broader considerations are discussed in the discussion section.
DOI: https://doi.org/10.37349/ent.2026.1004144
This article belongs to the special issue Innovations in Neurotechnology: Integrating AI, Neuroimaging, and VR for the Assessment and Treatment of Neurological Conditions
Phycocyanobilin (PCB), the covalently bound chromophore of the cyanobacterial protein C-phycocyanin (CPC), is recognized as a bioactive molecule with neuroprotective and anti-inflammatory properties. PCB and CPC, frequently coexisting in Spirulina extracts or experimental formulations, have demonstrated beneficial effects in preclinical models of multiple sclerosis, ischemic stroke, and Alzheimer’s disease. Reported mechanisms include attenuation of oxidative stress, reduction of neuroinflammation, and preservation of mitochondrial function, thereby contributing to a reparative microenvironment within the central nervous system. PCB can be obtained through two complementary approaches: Extraction from cyanobacterial biomass, where it remains covalently bound to CPC, and heterologous biosynthesis in Escherichia coli (E. coli), which enables production of free PCB as a high-purity, scalable linear tetrapyrrole suitable for translational applications. This mini-review summarizes current evidence on the neuroprotective actions of PCB and CPC, highlights their molecular targets, and discusses biotechnological advances that support their potential role in remyelination. By bridging natural pigment pharmacology with recombinant production strategies, PCB is positioned as a multitarget candidate of growing interest for the development of future neuroprotective and neurorepair therapies.
Phycocyanobilin (PCB), the covalently bound chromophore of the cyanobacterial protein C-phycocyanin (CPC), is recognized as a bioactive molecule with neuroprotective and anti-inflammatory properties. PCB and CPC, frequently coexisting in Spirulina extracts or experimental formulations, have demonstrated beneficial effects in preclinical models of multiple sclerosis, ischemic stroke, and Alzheimer’s disease. Reported mechanisms include attenuation of oxidative stress, reduction of neuroinflammation, and preservation of mitochondrial function, thereby contributing to a reparative microenvironment within the central nervous system. PCB can be obtained through two complementary approaches: Extraction from cyanobacterial biomass, where it remains covalently bound to CPC, and heterologous biosynthesis in Escherichia coli (E. coli), which enables production of free PCB as a high-purity, scalable linear tetrapyrrole suitable for translational applications. This mini-review summarizes current evidence on the neuroprotective actions of PCB and CPC, highlights their molecular targets, and discusses biotechnological advances that support their potential role in remyelination. By bridging natural pigment pharmacology with recombinant production strategies, PCB is positioned as a multitarget candidate of growing interest for the development of future neuroprotective and neurorepair therapies.
DOI: https://doi.org/10.37349/ent.2026.1004143
This article belongs to the special issue Natural Products in Neurotherapeutic Applications
Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) is an ultra-rare, progressive neurological disorder, with more than 60 individuals described in the medical literature. It is caused by de novo mutations in the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene, leading to early-onset symptoms including seizures, developmental delays, intellectual disability, and other severe neurological impairments, typically beginning in infancy or early childhood. This review aims to consolidate and refine current knowledge on NEDAMSS, focusing on the molecular functions of IRF2BPL, the spectrum of clinical features, and underlying disease mechanisms. A comprehensive understanding of NEDAMSS is essential for guiding the development of targeted interventions and therapeutic strategies to improve patient outcomes. By integrating current findings, we focus both on the progress made and the gaps that remain in research, providing a foundation for future studies to advance diagnosis, treatment, and overall patient care. We reviewed the published literature through studies available up to 2025 to synthesize current knowledge on clinical features, genetics, and proposed disease mechanisms. Reported phenotypes show substantial heterogeneity, and current genotype-phenotype correlations remain limited by small cohorts and inconsistent reporting. Key next steps include standardized phenotyping, natural history studies, and biomarker development to enable trial-ready outcome measures and accelerate targeted therapy development.
Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) is an ultra-rare, progressive neurological disorder, with more than 60 individuals described in the medical literature. It is caused by de novo mutations in the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene, leading to early-onset symptoms including seizures, developmental delays, intellectual disability, and other severe neurological impairments, typically beginning in infancy or early childhood. This review aims to consolidate and refine current knowledge on NEDAMSS, focusing on the molecular functions of IRF2BPL, the spectrum of clinical features, and underlying disease mechanisms. A comprehensive understanding of NEDAMSS is essential for guiding the development of targeted interventions and therapeutic strategies to improve patient outcomes. By integrating current findings, we focus both on the progress made and the gaps that remain in research, providing a foundation for future studies to advance diagnosis, treatment, and overall patient care. We reviewed the published literature through studies available up to 2025 to synthesize current knowledge on clinical features, genetics, and proposed disease mechanisms. Reported phenotypes show substantial heterogeneity, and current genotype-phenotype correlations remain limited by small cohorts and inconsistent reporting. Key next steps include standardized phenotyping, natural history studies, and biomarker development to enable trial-ready outcome measures and accelerate targeted therapy development.
DOI: https://doi.org/10.37349/ent.2026.1004142
Background:
This systematic review critically evaluates whether machine learning (ML) identifies biologically meaningful sex-related brain architecture or merely exploits methodological artifacts and allometric scaling. While ML models achieve high classification accuracies, it remains unclear if these reflect stable, mechanistically informative dimorphism or are driven by confounds such as total intracranial volume (TIV) and site-specific noise. We examine how imaging modalities, algorithms, and population strata influence both classification outcomes and biological interpretability.
Methods:
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched Web of Science, PubMed, and Scopus through January 2024. Included studies [healthy humans, 3T magnetic resonance imaging (MRI), ML-based sex classification] were assessed for risk of bias, focusing on data leakage, validation strategies, and confound management.
Results:
Thirty-five studies (n > 110,000) were included. While reported accuracies reached 98.06% for T1-weighted MRI, 96.0% for diffusion MRI (dMRI), and 94.72% for functional MRI (fMRI), performance was highly dependent on population characterization and age. Deep learning consistently outperformed traditional ML (TML) but showed high sensitivity to methodological artifacts. Notably, studies failing to correct for TIV reported potentially inflated accuracies, suggesting that many models identify physical scale rather than intrinsic neuroanatomical dimorphism.
Discussion:
High classification accuracies are often bolstered by methodological confounds and a lack of cross-site validation. There is a significant discrepancy between ML-driven predictive power and biological inference validity. Current pipelines do not yet allow for robust, generalizable inference about brain sex. To move beyond statistical separation toward mechanistic understanding, the field must prioritize TIV-corrected benchmarks and diverse non-WEIRD (Western, Educated, Industrialized, Rich, Democratic) datasets. We conclude that while ML is a powerful pattern detector, its results must be interpreted with caution regarding biological dimorphism.
Background:
This systematic review critically evaluates whether machine learning (ML) identifies biologically meaningful sex-related brain architecture or merely exploits methodological artifacts and allometric scaling. While ML models achieve high classification accuracies, it remains unclear if these reflect stable, mechanistically informative dimorphism or are driven by confounds such as total intracranial volume (TIV) and site-specific noise. We examine how imaging modalities, algorithms, and population strata influence both classification outcomes and biological interpretability.
Methods:
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched Web of Science, PubMed, and Scopus through January 2024. Included studies [healthy humans, 3T magnetic resonance imaging (MRI), ML-based sex classification] were assessed for risk of bias, focusing on data leakage, validation strategies, and confound management.
Results:
Thirty-five studies (n > 110,000) were included. While reported accuracies reached 98.06% for T1-weighted MRI, 96.0% for diffusion MRI (dMRI), and 94.72% for functional MRI (fMRI), performance was highly dependent on population characterization and age. Deep learning consistently outperformed traditional ML (TML) but showed high sensitivity to methodological artifacts. Notably, studies failing to correct for TIV reported potentially inflated accuracies, suggesting that many models identify physical scale rather than intrinsic neuroanatomical dimorphism.
Discussion:
High classification accuracies are often bolstered by methodological confounds and a lack of cross-site validation. There is a significant discrepancy between ML-driven predictive power and biological inference validity. Current pipelines do not yet allow for robust, generalizable inference about brain sex. To move beyond statistical separation toward mechanistic understanding, the field must prioritize TIV-corrected benchmarks and diverse non-WEIRD (Western, Educated, Industrialized, Rich, Democratic) datasets. We conclude that while ML is a powerful pattern detector, its results must be interpreted with caution regarding biological dimorphism.
DOI: https://doi.org/10.37349/ent.2026.1004141
Background:
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder in older adults, and growing evidence suggests that alterations in the gut-brain axis may contribute to its pathophysiology. Probiotics have been proposed as a potential adjunctive strategy to modulate gut microbiota and related systemic pathways; however, clinical evidence in AD remains limited and heterogeneous. This systematic review evaluated current evidence on the effects of probiotic supplementation on cognitive outcomes and health-related biomarkers in patients with AD.
Methods:
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, Web of Science, and Scopus were systematically searched for double-blind randomized controlled trials published within the last 10 years (up to November 30, 2025). Studies assessing probiotic supplementation in clinically diagnosed AD patients were included. Methodological quality and risk of bias were evaluated using the Physiotherapy Evidence Database (PEDro) scale, the McMaster assessment tool, and the Cochrane Risk of Bias 2.0 tool.
Results:
Of 253 records identified, five randomized controlled trials met the inclusion criteria, comprising 328 participants. The studies evaluated different probiotic formulations, mainly involving Lactobacillus and Bifidobacterium species, administered over short-term interventions (12 weeks). Some trials reported statistically significant improvements in selected cognitive outcomes, inflammatory and oxidative stress markers, metabolic parameters, brain-derived neurotrophic factor levels, anxiety, and instrumental activities of daily living. However, results were heterogeneous and several outcomes were non-significant. No serious adverse events related to probiotic supplementation were reported.
Discussion:
Probiotic supplementation may be associated with strain-specific and short-term effects on selected cognitive and biological outcomes in patients with AD. Nevertheless, limited trial numbers, small sample sizes, and substantial heterogeneity preclude definitive conclusions. Further well-designed randomized controlled trials with standardized probiotic formulations and longer follow-up periods are required.
Background:
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder in older adults, and growing evidence suggests that alterations in the gut-brain axis may contribute to its pathophysiology. Probiotics have been proposed as a potential adjunctive strategy to modulate gut microbiota and related systemic pathways; however, clinical evidence in AD remains limited and heterogeneous. This systematic review evaluated current evidence on the effects of probiotic supplementation on cognitive outcomes and health-related biomarkers in patients with AD.
Methods:
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, Web of Science, and Scopus were systematically searched for double-blind randomized controlled trials published within the last 10 years (up to November 30, 2025). Studies assessing probiotic supplementation in clinically diagnosed AD patients were included. Methodological quality and risk of bias were evaluated using the Physiotherapy Evidence Database (PEDro) scale, the McMaster assessment tool, and the Cochrane Risk of Bias 2.0 tool.
Results:
Of 253 records identified, five randomized controlled trials met the inclusion criteria, comprising 328 participants. The studies evaluated different probiotic formulations, mainly involving Lactobacillus and Bifidobacterium species, administered over short-term interventions (12 weeks). Some trials reported statistically significant improvements in selected cognitive outcomes, inflammatory and oxidative stress markers, metabolic parameters, brain-derived neurotrophic factor levels, anxiety, and instrumental activities of daily living. However, results were heterogeneous and several outcomes were non-significant. No serious adverse events related to probiotic supplementation were reported.
Discussion:
Probiotic supplementation may be associated with strain-specific and short-term effects on selected cognitive and biological outcomes in patients with AD. Nevertheless, limited trial numbers, small sample sizes, and substantial heterogeneity preclude definitive conclusions. Further well-designed randomized controlled trials with standardized probiotic formulations and longer follow-up periods are required.
DOI: https://doi.org/10.37349/ent.2026.1004140
This article belongs to the special issue Role of Microbiota in Neurological Diseases
Aim:
Attention is a core cognitive function that supports higher-order processes such as reasoning, problem solving, and intelligence. In children with attention deficit hyperactivity disorder (ADHD), particularly the hyperactive subtype, impairments in attentional control may interfere with the development and expression of cognitive abilities. This study examined the relationship between visuospatial attention and both verbal and nonverbal intelligence in children with ADHD-hyperactive type (ADHD-H).
Methods:
A sample of 65 children with ADHD-H and 73 typically developing controls (aged 8–10 years) completed three tasks: the Benton Visual Form Discrimination Test (VFDT), assessing complex visuospatial attention; the Raven’s Colored Progressive Matrices (RCPMs), measuring nonverbal fluid intelligence; and the Verbal Abstraction Test (Comprehension and Verbal Absurdities subtests), assessing verbal reasoning. Independent-samples t-tests and mixed-design ANOVAs were conducted to compare group performance and examine within-task variability.
Results:
Children with ADHD-H performed significantly worse than controls on both the VFDT and the RCPMs total scores. Qualitative analysis revealed a marked decline in performance across VFDT item sets, more frequent peripheral errors in later trials. Group differences in RCPMs emerged in gestalt and analogy subcomponents but not in perceptual similarity items. Conversely, verbal abstraction scores did not differ significantly between groups.
Conclusions:
Findings suggest that attentional deficits, rather than global intellectual impairment, primarily account for lower nonverbal reasoning performance in children with ADHD-H. Verbal reasoning abilities appear relatively preserved. These results underscore the need for differential diagnostic assessment and targeted interventions to strengthen visuospatial attention and cognitive control in ADHD-H.
Aim:
Attention is a core cognitive function that supports higher-order processes such as reasoning, problem solving, and intelligence. In children with attention deficit hyperactivity disorder (ADHD), particularly the hyperactive subtype, impairments in attentional control may interfere with the development and expression of cognitive abilities. This study examined the relationship between visuospatial attention and both verbal and nonverbal intelligence in children with ADHD-hyperactive type (ADHD-H).
Methods:
A sample of 65 children with ADHD-H and 73 typically developing controls (aged 8–10 years) completed three tasks: the Benton Visual Form Discrimination Test (VFDT), assessing complex visuospatial attention; the Raven’s Colored Progressive Matrices (RCPMs), measuring nonverbal fluid intelligence; and the Verbal Abstraction Test (Comprehension and Verbal Absurdities subtests), assessing verbal reasoning. Independent-samples t-tests and mixed-design ANOVAs were conducted to compare group performance and examine within-task variability.
Results:
Children with ADHD-H performed significantly worse than controls on both the VFDT and the RCPMs total scores. Qualitative analysis revealed a marked decline in performance across VFDT item sets, more frequent peripheral errors in later trials. Group differences in RCPMs emerged in gestalt and analogy subcomponents but not in perceptual similarity items. Conversely, verbal abstraction scores did not differ significantly between groups.
Conclusions:
Findings suggest that attentional deficits, rather than global intellectual impairment, primarily account for lower nonverbal reasoning performance in children with ADHD-H. Verbal reasoning abilities appear relatively preserved. These results underscore the need for differential diagnostic assessment and targeted interventions to strengthen visuospatial attention and cognitive control in ADHD-H.
DOI: https://doi.org/10.37349/ent.2026.1004139
This article belongs to the special issue Advances in the Pathogenesis, Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder
Background:
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the central nervous system, the cause of which remains unknown. Environmental, genetic, and immunological factors are considered risk factors. MS has no cure; therefore, therapy focuses on reducing the number of outbreaks, controlling symptoms, and therapies aimed at modifying the course of the disease. Innovative strategies that promote remyelination and repair of damaged brain tissue are under investigation. This review aims to compile and systematize the available knowledge on the multifactorial nature of MS, highlighting the main risk factors. It also discusses the mechanisms underlying the pathogenesis of the disease, current therapies, and prospects, presenting a comprehensive overview of the effect of various drugs on remyelination and repair of central nervous system damage.
Methods:
A comprehensive literature search, guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards, was conducted across PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov to identify relevant clinical trials. Of the studies retrieved, 13 were selected for this review. These trials specifically explored integrated therapeutic approaches, combining pharmacological and non-pharmacological interventions, for managing MS.
Results:
The results reflect the multifactorial nature of MS and the existence of several promising therapies to combat inflammation and demyelination, as well as to promote remyelination. Reducing inflammation remains the main target, but new approaches such as clemastine, liothyronine, interleukin (IL)-2, N-acetylglucosamine, and intracranial transplantation of fetal human neural precursor cells have shown promising results.
Discussion:
Currently, the therapies available for MS target the peripheral immune system. Therefore, more studies are needed on treatment therapies that combine immunomodulation of the peripheral and central nervous systems to reduce the neurological disability of patients. It is also concluded that the therapies were safe and were well tolerated, given the occurrence of a small number of adverse events.
Background:
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the central nervous system, the cause of which remains unknown. Environmental, genetic, and immunological factors are considered risk factors. MS has no cure; therefore, therapy focuses on reducing the number of outbreaks, controlling symptoms, and therapies aimed at modifying the course of the disease. Innovative strategies that promote remyelination and repair of damaged brain tissue are under investigation. This review aims to compile and systematize the available knowledge on the multifactorial nature of MS, highlighting the main risk factors. It also discusses the mechanisms underlying the pathogenesis of the disease, current therapies, and prospects, presenting a comprehensive overview of the effect of various drugs on remyelination and repair of central nervous system damage.
Methods:
A comprehensive literature search, guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards, was conducted across PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov to identify relevant clinical trials. Of the studies retrieved, 13 were selected for this review. These trials specifically explored integrated therapeutic approaches, combining pharmacological and non-pharmacological interventions, for managing MS.
Results:
The results reflect the multifactorial nature of MS and the existence of several promising therapies to combat inflammation and demyelination, as well as to promote remyelination. Reducing inflammation remains the main target, but new approaches such as clemastine, liothyronine, interleukin (IL)-2, N-acetylglucosamine, and intracranial transplantation of fetal human neural precursor cells have shown promising results.
Discussion:
Currently, the therapies available for MS target the peripheral immune system. Therefore, more studies are needed on treatment therapies that combine immunomodulation of the peripheral and central nervous systems to reduce the neurological disability of patients. It is also concluded that the therapies were safe and were well tolerated, given the occurrence of a small number of adverse events.
DOI: https://doi.org/10.37349/ent.2026.1004138
Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke cause progressive and often irreversible neuronal loss, leading to major functional disability. Conventional pharmacological therapies primarily offer symptomatic relief and fail to promote neuro-restoration. Stem cell-derived exosomes have recently gained attention as acellular, regenerative biologics capable of modulating inflammation, enhancing synaptic repair, and facilitating neural recovery. These nanoscale vesicles carry bioactive molecules, including microRNAs (miRNAs) and growth factors, that replicate many of the paracrine benefits of stem cells without the associated risks of tumorigenicity or immune rejection. The objective of this review is to critically evaluate recent evidence on the neuroprotective, immunomodulatory, and translational mechanisms of stem cell-derived exosomes in major neurodegenerative and cerebrovascular disorders, highlighting their clinical relevance and therapeutic potential. Preclinical studies suggest that exosome administration may restore mitochondrial function, reduce oxidative stress, and support neuronal survival, with associated improvements in cognitive and motor outcomes in experimental models of AD, PD, and stroke. Exosomal miRNAs such as miR-21, miR-124, and miR-133b mediate neuroprotective effects through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, while miR-146a promotes immunomodulation by suppressing pro-inflammatory cytokines and facilitating microglial repair phenotypes. Early-phase clinical studies primarily demonstrate feasibility and short-term safety, with exploratory signals of neurological improvement that require confirmation in adequately powered trials. Despite challenges in standardization and regulation, exosome-based therapy represents a scalable, safe, and clinically translatable strategy for neuro-regeneration, with significant promise for future management of brain network disorders.
Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke cause progressive and often irreversible neuronal loss, leading to major functional disability. Conventional pharmacological therapies primarily offer symptomatic relief and fail to promote neuro-restoration. Stem cell-derived exosomes have recently gained attention as acellular, regenerative biologics capable of modulating inflammation, enhancing synaptic repair, and facilitating neural recovery. These nanoscale vesicles carry bioactive molecules, including microRNAs (miRNAs) and growth factors, that replicate many of the paracrine benefits of stem cells without the associated risks of tumorigenicity or immune rejection. The objective of this review is to critically evaluate recent evidence on the neuroprotective, immunomodulatory, and translational mechanisms of stem cell-derived exosomes in major neurodegenerative and cerebrovascular disorders, highlighting their clinical relevance and therapeutic potential. Preclinical studies suggest that exosome administration may restore mitochondrial function, reduce oxidative stress, and support neuronal survival, with associated improvements in cognitive and motor outcomes in experimental models of AD, PD, and stroke. Exosomal miRNAs such as miR-21, miR-124, and miR-133b mediate neuroprotective effects through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, while miR-146a promotes immunomodulation by suppressing pro-inflammatory cytokines and facilitating microglial repair phenotypes. Early-phase clinical studies primarily demonstrate feasibility and short-term safety, with exploratory signals of neurological improvement that require confirmation in adequately powered trials. Despite challenges in standardization and regulation, exosome-based therapy represents a scalable, safe, and clinically translatable strategy for neuro-regeneration, with significant promise for future management of brain network disorders.
DOI: https://doi.org/10.37349/ent.2026.1004137
This article belongs to the special issue Breakthroughs in Mechanisms and Treatments for Neurodegenerative Diseases
Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis, are characterized by multifactorial pathologies that extend beyond neuronal loss to include neuroinflammation, oxidative stress, mitochondrial dysfunction, and glial dysregulation. Despite extensive research, disease-modifying therapies remain elusive, hindered by late diagnosis, limited availability of specific biomarkers, and the persistent dominance of reductionist, single-target strategies. This comprehensive and informative review provides a critical synthesis of integrated neuroprotective strategies, with particular focus on glial mechanisms and biomarker-guided interventions. Therapeutic emphasis is placed on coordinated mechanisms targeting both neurons and non-neuronal cells, such as astrocytes, microglia, and oligodendrocytes. Emerging strategies are reported to include modulation of synaptic plasticity and neurotransmission, delivery of neurotrophic factors, activation of intrinsic cytoprotective pathways (e.g., Nrf2 signaling), restoration of proteostasis, and induction of regeneration via cellular reprogramming. Glial cells are discussed as therapeutic targets involved in inflammation, metabolism, myelination, and neuronal survival. Advances in predictive, preventive, personalized, and participatory (P4) medicine, supported by genomics, multi-omics, imaging, and real-world data, are presented as accelerating biomarker discovery and enabling earlier and more precise stage-specific interventions. Future success in combating neurodegeneration will depend on integrated approaches that combine protective, supportive, and regenerative strategies, appropriate for disease stage and patient profile. By reframing neuroprotection as a systemic, multicellular endeavor, this review highlights the potential to not only extend life expectancy, but also preserve meaningful quality of life in individuals affected by neurodegenerative diseases.
Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis, are characterized by multifactorial pathologies that extend beyond neuronal loss to include neuroinflammation, oxidative stress, mitochondrial dysfunction, and glial dysregulation. Despite extensive research, disease-modifying therapies remain elusive, hindered by late diagnosis, limited availability of specific biomarkers, and the persistent dominance of reductionist, single-target strategies. This comprehensive and informative review provides a critical synthesis of integrated neuroprotective strategies, with particular focus on glial mechanisms and biomarker-guided interventions. Therapeutic emphasis is placed on coordinated mechanisms targeting both neurons and non-neuronal cells, such as astrocytes, microglia, and oligodendrocytes. Emerging strategies are reported to include modulation of synaptic plasticity and neurotransmission, delivery of neurotrophic factors, activation of intrinsic cytoprotective pathways (e.g., Nrf2 signaling), restoration of proteostasis, and induction of regeneration via cellular reprogramming. Glial cells are discussed as therapeutic targets involved in inflammation, metabolism, myelination, and neuronal survival. Advances in predictive, preventive, personalized, and participatory (P4) medicine, supported by genomics, multi-omics, imaging, and real-world data, are presented as accelerating biomarker discovery and enabling earlier and more precise stage-specific interventions. Future success in combating neurodegeneration will depend on integrated approaches that combine protective, supportive, and regenerative strategies, appropriate for disease stage and patient profile. By reframing neuroprotection as a systemic, multicellular endeavor, this review highlights the potential to not only extend life expectancy, but also preserve meaningful quality of life in individuals affected by neurodegenerative diseases.
DOI: https://doi.org/10.37349/ent.2026.1004136
Aim:
This study examined differences in attentional control and awareness of interference among children with attention-deficit/hyperactivity disorder (ADHD), children with subthreshold ADHD (children showing some but not all symptoms required for diagnosis), and children with typical development. Specifically, we investigated how visual and auditory distractions affect behavioral performance and eye movements, to clarify the degree and nature of attentional control impairments associated with subthreshold versus clinically diagnosed ADHD.
Methods:
One hundred and two children (mean age = 7.23 years, SD = 1.23; 34 per group) participated in three eye-tracking tasks involving a bouncing ball under no, visual, and auditory interference. Behavioral accuracy (number of correctly counted bounces), fixation duration on the target, gaze reorientation latency, and distractor awareness were analyzed using mixed-design analyses of variance (ANOVAs) and chi-square tests.
Results:
Significant group differences were found in counting accuracy, F(2, 99) = 16.42, p = 0.00069, η2p = 0.245, with typically developing children performing best, followed by those with subthreshold and full ADHD. Eye-tracking indices showed a similar gradient: fixation duration decreased with symptom severity, F(4, 198) = 7.65, p = 0.00094, η2p = 0.134, while gaze reorientation latency increased, F(2, 99) = 12.18, p = 0.00093, η2p = 0.197 (typical development ≈ 480 ms; subthreshold ≈ 621 ms; ADHD ≈ 721 ms). Awareness of distractors also varied significantly across groups, χ2(2, n = 102) = 38.12, p < 0.001, Cramer’s V = 0.61, with detection rates of approximately 80% (typical development), 50% (subthreshold), and 25% (ADHD).
Conclusions:
Both children with ADHD and children with subthreshold ADHD show measurable deficits in attentional control and awareness of interference, particularly under visual and auditory distraction. Children with subthreshold ADHD exhibited an intermediate profile, supporting a continuum rather than a categorical distinction in cognitive control impairments. These findings highlight the importance of early identification and interventions targeting attentional regulation and metacognitive monitoring across the ADHD spectrum.
Aim:
This study examined differences in attentional control and awareness of interference among children with attention-deficit/hyperactivity disorder (ADHD), children with subthreshold ADHD (children showing some but not all symptoms required for diagnosis), and children with typical development. Specifically, we investigated how visual and auditory distractions affect behavioral performance and eye movements, to clarify the degree and nature of attentional control impairments associated with subthreshold versus clinically diagnosed ADHD.
Methods:
One hundred and two children (mean age = 7.23 years, SD = 1.23; 34 per group) participated in three eye-tracking tasks involving a bouncing ball under no, visual, and auditory interference. Behavioral accuracy (number of correctly counted bounces), fixation duration on the target, gaze reorientation latency, and distractor awareness were analyzed using mixed-design analyses of variance (ANOVAs) and chi-square tests.
Results:
Significant group differences were found in counting accuracy, F(2, 99) = 16.42, p = 0.00069, η2p = 0.245, with typically developing children performing best, followed by those with subthreshold and full ADHD. Eye-tracking indices showed a similar gradient: fixation duration decreased with symptom severity, F(4, 198) = 7.65, p = 0.00094, η2p = 0.134, while gaze reorientation latency increased, F(2, 99) = 12.18, p = 0.00093, η2p = 0.197 (typical development ≈ 480 ms; subthreshold ≈ 621 ms; ADHD ≈ 721 ms). Awareness of distractors also varied significantly across groups, χ2(2, n = 102) = 38.12, p < 0.001, Cramer’s V = 0.61, with detection rates of approximately 80% (typical development), 50% (subthreshold), and 25% (ADHD).
Conclusions:
Both children with ADHD and children with subthreshold ADHD show measurable deficits in attentional control and awareness of interference, particularly under visual and auditory distraction. Children with subthreshold ADHD exhibited an intermediate profile, supporting a continuum rather than a categorical distinction in cognitive control impairments. These findings highlight the importance of early identification and interventions targeting attentional regulation and metacognitive monitoring across the ADHD spectrum.
DOI: https://doi.org/10.37349/ent.2025.1004134
This article belongs to the special issue Advances in the Pathogenesis, Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder
Aim:
Neurodegenerative diseases, such as Alzheimer’s, are strongly associated with amyloid-β aggregation. This study aimed to explore bioactive metabolites from endophytic bacteria as potential anti-aggregation agents with relevance to neuroprotection, focusing on isolate D11 obtained from a geothermal fern at Gedong Songo hot springs.
Methods:
Isolate D11 was characterized by Gram staining and 16S rRNA sequencing. Growth curve analysis was conducted to determine metabolite production phases. Phytochemical screening, bovine serum albumin (BSA) aggregation inhibition assays, liquid chromatography mass spectroscopy (LCMS) profiling, and molecular docking against amyloid-β were employed to evaluate bioactivity and metabolite composition.
Results:
D11 was identified as a Gram-negative rod with 97.94% similarity to Stutzerimonas stutzeri. Metabolite production peaked during the stationary and death phases. Phytochemical tests revealed alkaloids and tannins in aqueous fractions. BSA aggregation inhibition assays demonstrated potent inhibitory activity, with IC50 values (2.40–3.29 µg/mL) significantly lower than quercetin. LCMS profiling identified diverse metabolites, dominated by flavonoid glycosides such as kaempferol-7-O-deoxyhexosyl-3-O-acetylhexoside, along with alkaloids, peptides, and diterpenoids. Molecular docking confirmed strong binding affinities of flavonoid glycosides to amyloid β (–7.6 kcal/mol), outperforming quercetin (–6.0 kcal/mol).
Conclusions:
These findings suggest that isolate D11 Stutzerimonas produces bioactive metabolites with anti-aggregation activity and potential relevance to neuroprotection. However, since Stutzerimonas-derived metabolites remain poorly explored and the docking results are tentative, further in-depth characterization and in vivo validation are required to confirm their therapeutic relevance, and further validation using amyloid-β or α-synuclein models is required to confirm therapeutic implications.
Aim:
Neurodegenerative diseases, such as Alzheimer’s, are strongly associated with amyloid-β aggregation. This study aimed to explore bioactive metabolites from endophytic bacteria as potential anti-aggregation agents with relevance to neuroprotection, focusing on isolate D11 obtained from a geothermal fern at Gedong Songo hot springs.
Methods:
Isolate D11 was characterized by Gram staining and 16S rRNA sequencing. Growth curve analysis was conducted to determine metabolite production phases. Phytochemical screening, bovine serum albumin (BSA) aggregation inhibition assays, liquid chromatography mass spectroscopy (LCMS) profiling, and molecular docking against amyloid-β were employed to evaluate bioactivity and metabolite composition.
Results:
D11 was identified as a Gram-negative rod with 97.94% similarity to Stutzerimonas stutzeri. Metabolite production peaked during the stationary and death phases. Phytochemical tests revealed alkaloids and tannins in aqueous fractions. BSA aggregation inhibition assays demonstrated potent inhibitory activity, with IC50 values (2.40–3.29 µg/mL) significantly lower than quercetin. LCMS profiling identified diverse metabolites, dominated by flavonoid glycosides such as kaempferol-7-O-deoxyhexosyl-3-O-acetylhexoside, along with alkaloids, peptides, and diterpenoids. Molecular docking confirmed strong binding affinities of flavonoid glycosides to amyloid β (–7.6 kcal/mol), outperforming quercetin (–6.0 kcal/mol).
Conclusions:
These findings suggest that isolate D11 Stutzerimonas produces bioactive metabolites with anti-aggregation activity and potential relevance to neuroprotection. However, since Stutzerimonas-derived metabolites remain poorly explored and the docking results are tentative, further in-depth characterization and in vivo validation are required to confirm their therapeutic relevance, and further validation using amyloid-β or α-synuclein models is required to confirm therapeutic implications.
DOI: https://doi.org/10.37349/ent.2025.1004135
This article belongs to the special issue Natural Products in Neurotherapeutic Applications
Age-related neurological disorders such as ALS (Lou Gehrig’s disease), Parkinson’s disease, and Alzheimer’s disease have few truly effective treatment options. At best, these may slow the inexorable disease progression without providing a cure. Part of the problem with therapeutic approaches may arise due to the stage at which these diseases are detected, particularly the sporadic forms. In most cases, early signs and symptoms may be insidious, thus hiding the significant damage done to the areas of the nervous system impacted prior to any firm clinical diagnosis. This situation appears to necessitate the development of earlier detection methods for “biomarkers” that might allow for much earlier phase disease state treatments that might serve to significantly slow or even halt disease progression. Currently, most biomarkers in use serve primarily as aids to disease diagnosis, at which point there are no successful treatment options. In contrast, a search for more effective early treatment options would need to identify characteristic and specific molecular signatures of disease onset and progression using methods that are simple, such as blood-based analytical assays, relatively cheap, and crucially minimally invasive.
Age-related neurological disorders such as ALS (Lou Gehrig’s disease), Parkinson’s disease, and Alzheimer’s disease have few truly effective treatment options. At best, these may slow the inexorable disease progression without providing a cure. Part of the problem with therapeutic approaches may arise due to the stage at which these diseases are detected, particularly the sporadic forms. In most cases, early signs and symptoms may be insidious, thus hiding the significant damage done to the areas of the nervous system impacted prior to any firm clinical diagnosis. This situation appears to necessitate the development of earlier detection methods for “biomarkers” that might allow for much earlier phase disease state treatments that might serve to significantly slow or even halt disease progression. Currently, most biomarkers in use serve primarily as aids to disease diagnosis, at which point there are no successful treatment options. In contrast, a search for more effective early treatment options would need to identify characteristic and specific molecular signatures of disease onset and progression using methods that are simple, such as blood-based analytical assays, relatively cheap, and crucially minimally invasive.
DOI: https://doi.org/10.37349/ent.2025.1004133
Aim:
Parkinson’s disease (PD) and Alzheimer’s disease (AD) represent critical neurological disorders that have emerged as significant health concerns in the 21st century. The pharmacological interventions currently employed to manage these diseases demonstrate limited efficacy and some adverse side effects. Historically, natural products have been used to develop therapeutic agents targeting neurodegenerative disorders. This study aimed to apply in silico techniques to investigate the pharmacological mechanisms of capsaicin as a possible alternative treatment or coadjutant phytotherapy for PD and AD.
Methods:
We obtained target genes for capsaicin, PD, and AD from the HERB database, the Swiss Target Prediction database, the Comparative Toxicogenomics Database, and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and matched them. Subsequently, we constructed a protein-protein interaction network and performed enrichment analysis of the common targets. Then, the interactions of capsaicin with the proteins with the highest degree were tested using molecular docking. The stability of the complexes was verified using molecular dynamics techniques.
Results:
A total of 25 targets were found in common from the databases for capsaicin, AD, and PD. The enrichment analysis revealed that proteins from these targets influenced integrin activity in the IGF1-IGF1R complex, cholinesterase activity, and dopamine neurotransmitter receptor activity, all of which are coupled via protein Gi/Go, among other cellular processes. From the protein-protein interaction network, we identified the hub proteins IL6, GSK3B, CASP, BCL2, ESR1, SIRT1, NGF, IGF1, and HMOX1. Furthermore, molecular docking studies between hub proteins and capsaicin showed strong binding affinity. Finally, molecular dynamics simulations support a stable interaction between capsaicin and SIRT1, ESR1, HMOX1, and NGF.
Conclusions:
This work contributes to understanding the neuroprotective activity of capsaicin in PD and AD. However, these bioinformatic predictions require further experimental validation.
Aim:
Parkinson’s disease (PD) and Alzheimer’s disease (AD) represent critical neurological disorders that have emerged as significant health concerns in the 21st century. The pharmacological interventions currently employed to manage these diseases demonstrate limited efficacy and some adverse side effects. Historically, natural products have been used to develop therapeutic agents targeting neurodegenerative disorders. This study aimed to apply in silico techniques to investigate the pharmacological mechanisms of capsaicin as a possible alternative treatment or coadjutant phytotherapy for PD and AD.
Methods:
We obtained target genes for capsaicin, PD, and AD from the HERB database, the Swiss Target Prediction database, the Comparative Toxicogenomics Database, and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and matched them. Subsequently, we constructed a protein-protein interaction network and performed enrichment analysis of the common targets. Then, the interactions of capsaicin with the proteins with the highest degree were tested using molecular docking. The stability of the complexes was verified using molecular dynamics techniques.
Results:
A total of 25 targets were found in common from the databases for capsaicin, AD, and PD. The enrichment analysis revealed that proteins from these targets influenced integrin activity in the IGF1-IGF1R complex, cholinesterase activity, and dopamine neurotransmitter receptor activity, all of which are coupled via protein Gi/Go, among other cellular processes. From the protein-protein interaction network, we identified the hub proteins IL6, GSK3B, CASP, BCL2, ESR1, SIRT1, NGF, IGF1, and HMOX1. Furthermore, molecular docking studies between hub proteins and capsaicin showed strong binding affinity. Finally, molecular dynamics simulations support a stable interaction between capsaicin and SIRT1, ESR1, HMOX1, and NGF.
Conclusions:
This work contributes to understanding the neuroprotective activity of capsaicin in PD and AD. However, these bioinformatic predictions require further experimental validation.
DOI: https://doi.org/10.37349/ent.2025.1004132
This article belongs to the special issue Natural Products in Neurotherapeutic Applications
The oral microbiome has been increasingly implicated in the development and progression of neurological disorders. This narrative review synthesizes contemporary literature on alterations of oral microbial communities in Alzheimer’s disease, Parkinson’s disease, and migraine and evaluates their potential contribution to neuroinflammation and neurodegeneration. We first outline the core oral taxa that maintain microbial homeostasis and summarize evidence that patients with these neurological conditions exhibit dysbiosis characterized by reduced diversity and enrichment of periodontal pathogens. Proposed mechanisms include hematogenous or neural translocation of oral bacteria and their virulence factors, amplification of systemic inflammation, disruption of the blood-brain barrier, altered production of neuroactive metabolites, and bidirectional signaling along the ‘oral-gut-brain’ axis. On this mechanistic basis, microbiome-targeted strategies, particularly probiotics and fecal microbiota transplantation, have been explored as adjunctive approaches to restore microbial balance and potentially improve neurological outcomes, although available clinical data remain preliminary and heterogeneous. Current evidence is further limited by small samples, methodological variability in microbiome profiling, and a paucity of longitudinal and interventional studies, which hampers causal inference. Future research should adopt standardized sampling and multi-omic approaches and prioritize well-designed clinical trials to determine whether modulation of the oral microbiome can be translated into preventive or therapeutic strategies for neurological diseases.
The oral microbiome has been increasingly implicated in the development and progression of neurological disorders. This narrative review synthesizes contemporary literature on alterations of oral microbial communities in Alzheimer’s disease, Parkinson’s disease, and migraine and evaluates their potential contribution to neuroinflammation and neurodegeneration. We first outline the core oral taxa that maintain microbial homeostasis and summarize evidence that patients with these neurological conditions exhibit dysbiosis characterized by reduced diversity and enrichment of periodontal pathogens. Proposed mechanisms include hematogenous or neural translocation of oral bacteria and their virulence factors, amplification of systemic inflammation, disruption of the blood-brain barrier, altered production of neuroactive metabolites, and bidirectional signaling along the ‘oral-gut-brain’ axis. On this mechanistic basis, microbiome-targeted strategies, particularly probiotics and fecal microbiota transplantation, have been explored as adjunctive approaches to restore microbial balance and potentially improve neurological outcomes, although available clinical data remain preliminary and heterogeneous. Current evidence is further limited by small samples, methodological variability in microbiome profiling, and a paucity of longitudinal and interventional studies, which hampers causal inference. Future research should adopt standardized sampling and multi-omic approaches and prioritize well-designed clinical trials to determine whether modulation of the oral microbiome can be translated into preventive or therapeutic strategies for neurological diseases.
DOI: https://doi.org/10.37349/ent.2025.1004131
This article belongs to the special issue Role of Microbiota in Neurological Diseases
Apparent increases in autism and other forms of neurodivergence are often interpreted as a rise in incidence. Yet demographic expansion, diagnostic broadening, and growing cultural awareness all contribute to higher prevalence estimates. At the same time, contemporary sensory and digital environments have become increasingly overstimulating, characterized by persistent noise, visual saturation, hyperconnectivity, and unpredictable social rhythms. These conditions heighten sensory and cognitive load for many individuals, making neurodivergent traits more visible and increasing the urgency of diagnosis. Drawing on cognitive ecology, sensory neuroscience, and neuroaffirmative scholarship, this perspective proposes that neurodivergence can be understood as an adaptive response to environments that exceed nervous-system thresholds. Autistic regulatory behaviors—including withdrawal, shutdown, sensory avoidance, and monotropism-driven focus—may serve as mechanisms for maintaining coherence in overstimulating contexts. Interpreting neurodivergence as an ecological signal offers new pathways for public health, accessibility design, and social policy. It reframes autistic embodiment not as internal dysfunction but as meaningful information about the livability of contemporary environments.
Apparent increases in autism and other forms of neurodivergence are often interpreted as a rise in incidence. Yet demographic expansion, diagnostic broadening, and growing cultural awareness all contribute to higher prevalence estimates. At the same time, contemporary sensory and digital environments have become increasingly overstimulating, characterized by persistent noise, visual saturation, hyperconnectivity, and unpredictable social rhythms. These conditions heighten sensory and cognitive load for many individuals, making neurodivergent traits more visible and increasing the urgency of diagnosis. Drawing on cognitive ecology, sensory neuroscience, and neuroaffirmative scholarship, this perspective proposes that neurodivergence can be understood as an adaptive response to environments that exceed nervous-system thresholds. Autistic regulatory behaviors—including withdrawal, shutdown, sensory avoidance, and monotropism-driven focus—may serve as mechanisms for maintaining coherence in overstimulating contexts. Interpreting neurodivergence as an ecological signal offers new pathways for public health, accessibility design, and social policy. It reframes autistic embodiment not as internal dysfunction but as meaningful information about the livability of contemporary environments.
DOI: https://doi.org/10.37349/ent.2025.1004130
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, in which gut microbiota alterations have emerged as a potential pathogenic factor, causing disruption of the brain-gut-microbiota (BGM) axis. Recent evidence supports the role of BGM axis disruption in enhancing neuroinflammation, alpha-synuclein (α-syn) aggregation, and dopaminergic neurodegeneration. Emerging therapeutic strategies targeting dysbiosis, such as probiotics and fecal microbiota transplantation (FMT), have become a new focus of investigation for PD treatment. Proposed mechanisms include modulation of immune responses, enhancement of intestinal barrier integrity, production of neuroactive metabolites such as short-chain fatty acids, and reduction of oxidative stress. This narrative review summarizes current evidence on probiotics as a therapeutic strategy in PD. By analyzing data from randomized controlled trials and preclinical studies, we highlight the beneficial effects of probiotics in improving motor and non-motor symptoms of PD, including constipation, depression, and anxiety. Strains such as Lactobacillus plantarum PS128 and Bifidobacterium animalis Probio-M8 show particular promise. Although probiotics have demonstrated a favorable safety profile and potential as an adjunctive therapy for PD, future research should focus on standardized protocols, biomarker identification, and exploration of combined microbiota-targeted strategies.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, in which gut microbiota alterations have emerged as a potential pathogenic factor, causing disruption of the brain-gut-microbiota (BGM) axis. Recent evidence supports the role of BGM axis disruption in enhancing neuroinflammation, alpha-synuclein (α-syn) aggregation, and dopaminergic neurodegeneration. Emerging therapeutic strategies targeting dysbiosis, such as probiotics and fecal microbiota transplantation (FMT), have become a new focus of investigation for PD treatment. Proposed mechanisms include modulation of immune responses, enhancement of intestinal barrier integrity, production of neuroactive metabolites such as short-chain fatty acids, and reduction of oxidative stress. This narrative review summarizes current evidence on probiotics as a therapeutic strategy in PD. By analyzing data from randomized controlled trials and preclinical studies, we highlight the beneficial effects of probiotics in improving motor and non-motor symptoms of PD, including constipation, depression, and anxiety. Strains such as Lactobacillus plantarum PS128 and Bifidobacterium animalis Probio-M8 show particular promise. Although probiotics have demonstrated a favorable safety profile and potential as an adjunctive therapy for PD, future research should focus on standardized protocols, biomarker identification, and exploration of combined microbiota-targeted strategies.
DOI: https://doi.org/10.37349/ent.2025.1004129
This article belongs to the special issue Role of Microbiota in Neurological Diseases
Background:
Ischemic stroke is a leading cause of disability, with calcium (Ca2+) dysregulation contributing to neuronal injury and impaired recovery. While early clinical trials targeting calcium signaling showed limited success, growing preclinical evidence supports the potential of calcium modulation for long-term neuroprotection. This systematic review evaluates the long-term effects of calcium modulation in animal models of ischemic stroke.
Methods:
A comprehensive search across PubMed, Scopus, Web of Science, and the Cochrane Library up to June 2025 identified studies investigating calcium-targeted interventions (e.g., calcium channel blockers, chelators, antioxidants) with ≥ 30 days of follow-up. Risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I).
Results:
Nine studies met the inclusion criteria. Interventions like L-type calcium channel blockers, magnesium sulfate, and ischemic preconditioning consistently reduced infarct volume (e.g., 22.4 ± 0.5% with preconditioning vs. 51.6 ± 2.1% with knockout) and improved neurobehavioral outcomes [e.g., epigallocatechin gallate (EGCG)-treated rats scored 2.17 ± 0.05 vs. 3.63 ± 0.06 in controls]. Molecular pathways involved included phosphoinositide 3-kinase (PI3K)/AKT, stromal interaction molecule 1 (STIM1)/ORAI1, and calcium-sensor proteins such as NCKX2.
Discussion:
Calcium modulation holds strong promise for neuroprotection in ischemic stroke models. Although clinical gaps remain, these findings support the development of calcium-targeted therapies for stroke recovery, especially when combined with multimodal strategies.
Background:
Ischemic stroke is a leading cause of disability, with calcium (Ca2+) dysregulation contributing to neuronal injury and impaired recovery. While early clinical trials targeting calcium signaling showed limited success, growing preclinical evidence supports the potential of calcium modulation for long-term neuroprotection. This systematic review evaluates the long-term effects of calcium modulation in animal models of ischemic stroke.
Methods:
A comprehensive search across PubMed, Scopus, Web of Science, and the Cochrane Library up to June 2025 identified studies investigating calcium-targeted interventions (e.g., calcium channel blockers, chelators, antioxidants) with ≥ 30 days of follow-up. Risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I).
Results:
Nine studies met the inclusion criteria. Interventions like L-type calcium channel blockers, magnesium sulfate, and ischemic preconditioning consistently reduced infarct volume (e.g., 22.4 ± 0.5% with preconditioning vs. 51.6 ± 2.1% with knockout) and improved neurobehavioral outcomes [e.g., epigallocatechin gallate (EGCG)-treated rats scored 2.17 ± 0.05 vs. 3.63 ± 0.06 in controls]. Molecular pathways involved included phosphoinositide 3-kinase (PI3K)/AKT, stromal interaction molecule 1 (STIM1)/ORAI1, and calcium-sensor proteins such as NCKX2.
Discussion:
Calcium modulation holds strong promise for neuroprotection in ischemic stroke models. Although clinical gaps remain, these findings support the development of calcium-targeted therapies for stroke recovery, especially when combined with multimodal strategies.
DOI: https://doi.org/10.37349/ent.2025.1004127
This article belongs to the special issue Therapeutic Targets for Neuroprotection in Ischemic Stroke
Aim:
Alzheimer’s disease (AD) devastates learning and memory, the defining faculties of the human species. Extracellular amyloid beta (Aβ) deposits and intracellular hyperphosphorylated tau are hallmarks of AD pathology. The exact cause of the disease remains unknown, but a lot of data support AD to be a multifactorial disease. Given the central roles of oxidative stress and neuroinflammation in AD pathogenesis, apocynin, a potent antioxidant and anti-inflammatory agent, was selected for investigation. Apocynin is an aromatic ketone, a naturally occurring methoxy-substituted catechol known to possess numerous biological activities, namely anti-oxidant, anti-inflammatory, etc. The present study assessed apocynin’s potential against an Aβ1–42-induced sporadic AD rat model.
Methods:
In the present study, Wistar rats were subjected to intrahippocampal administration of 200 µmol/L of Aβ1–42 peptide in right hemisphere. Further were treated with apocynin 50, 150, and 300 mg/kg per orally for 28 days. The study examined the neurobehavioral aspects using the Barnes Maze test (BMT). Hippocampus was examined for the antioxidant (SOD, GSH, catalase, and LPO), inflammatory (TNF-α) parameters, RAGE, caspase-3, PGC-1α expression, and IHC analysis for Aβ load, adult hippocampal neurogenesis markers (BDNF, Ki67, DCX, NeuN), at the end of 28 days.
Results:
Apocynin administration demonstrated significant improvement in cognitive functions, diminished oxidative stress and inflammatory response triggered by Aβ administration. Apocynin additionally instigated adult hippocampal neurogenesis and triggered mitochondrial biogenesis.
Conclusions:
These primary results strongly advocate apocynin’s nootropic, neurotrophic and neuroprotective potential in an Aβ induced neurotoxicity in rats.
Aim:
Alzheimer’s disease (AD) devastates learning and memory, the defining faculties of the human species. Extracellular amyloid beta (Aβ) deposits and intracellular hyperphosphorylated tau are hallmarks of AD pathology. The exact cause of the disease remains unknown, but a lot of data support AD to be a multifactorial disease. Given the central roles of oxidative stress and neuroinflammation in AD pathogenesis, apocynin, a potent antioxidant and anti-inflammatory agent, was selected for investigation. Apocynin is an aromatic ketone, a naturally occurring methoxy-substituted catechol known to possess numerous biological activities, namely anti-oxidant, anti-inflammatory, etc. The present study assessed apocynin’s potential against an Aβ1–42-induced sporadic AD rat model.
Methods:
In the present study, Wistar rats were subjected to intrahippocampal administration of 200 µmol/L of Aβ1–42 peptide in right hemisphere. Further were treated with apocynin 50, 150, and 300 mg/kg per orally for 28 days. The study examined the neurobehavioral aspects using the Barnes Maze test (BMT). Hippocampus was examined for the antioxidant (SOD, GSH, catalase, and LPO), inflammatory (TNF-α) parameters, RAGE, caspase-3, PGC-1α expression, and IHC analysis for Aβ load, adult hippocampal neurogenesis markers (BDNF, Ki67, DCX, NeuN), at the end of 28 days.
Results:
Apocynin administration demonstrated significant improvement in cognitive functions, diminished oxidative stress and inflammatory response triggered by Aβ administration. Apocynin additionally instigated adult hippocampal neurogenesis and triggered mitochondrial biogenesis.
Conclusions:
These primary results strongly advocate apocynin’s nootropic, neurotrophic and neuroprotective potential in an Aβ induced neurotoxicity in rats.
DOI: https://doi.org/10.37349/ent.2025.1004128
This article belongs to the special issue Natural Products in Neurotherapeutic Applications
