Multiple sclerosis (MS) is defined as an inflammatory disorder that chronically affects the central nervous system of young people mostly and is distributed globally. It is associated with degeneration and demyelination of the myelin sheath around the nerves, resulting in multiple neurological disability symptoms ranging from mild to severe cases that end with paralysis sometimes. MS is one of the rising diseases globally that is unfortunately associated with reduced quality of life and adding national economic burdens. The definite MS mechanism is not clearly defined; however, all the previous researches confirm the role of the immune system as the master contributor in the pathogenesis. Innate and adaptive immune cells are activated peripherally then attracted toward the central nervous system (CNS) due to the breakdown of the blood-brain barrier. Recently, the gut-brain axis was shown to depend on gut metabolites that are produced by different microorganisms in the colon. The difference in microbiota composition between individuals is responsible for diversity in secreted metabolites that affect immune responses locally in the gut or systemically when reach blood circulation to the brain. It may enhance or suppress immune responses in the central nervous system (CNS) (repeated short forms); consequently, it may exacerbate or ameliorate MS symptoms. Recent data showed that some metabolites can be used as adjuvant therapy in MS and other inflammatory diseases. This review sheds light on the nature of MS and the possible interaction between gut microbiota and immune system regulation through the gut-brain axis, hence contributing to MS pathogenesis.

Inflammation-induced oligodendrocyte death and CNS demyelination are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions of Grp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels of Grp78 as well as Ho-1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.

The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for various pathogenic and non-pathogenic damage signals and plays a critical role in host defense against pathogens and physiological damage. However, inflammasome activation and its subsequent effects also lead to a variety of inflammatory diseases. In this study, we identified broxyquinoline, an FDA-approved antimicrobial drug, as a effective NLRP3 inflammasome inhibitor. Broxyquinoline suppressed NLRP3 inflammasome-dependent interleukin-1β (IL-1β) release, but did not affect NLRC4 or AIM2 inflammasome activation. Mechanistically, broxyquinoline directly targets Arg165 of NLRP3 protein, thus preventing NEK7-NLRP3 interaction, NLRP3 oligomerization, and ASC speck formation, without affecting the NF-κB pathway. Consequently, broxyquinoline significantly attenuated the progression of monosodium urate (MSU)-induced peritonitis and myelin oligodendrocyte glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE) in murine models. In conclusion, we demonstrated that broxyquinoline directly targets the NLRP3 protein to suppress the activation of NLRP3 inflammasome and provide a promising therapeutic agent for NLRP3 inflammasome-associated diseases.

Multiple sclerosis (MS) is a complex disorder driven by both inflammatory and neurodegenerative processes. While disease-modifying therapies (DMTs) have significantly improved prognosis, robust treatment switching criteria remain essential to balance efficacy and safety over the disease course.

This review examines historical and current criteria for escalating DMTs from moderate- to high-efficacy therapies (HET). The authors summarize emerging clinical, imaging, and biological markers that inform decision-making and explore strategies for de-escalation, including DMT discontinuation and innovative approaches such as exit and bridge therapies.

Recent advances in MS management emphasize earlier initiation of HET and more stringent switching criteria. Although innovative monitoring tools - including clinical evaluations, imaging, biological markers, and patient-reported outcomes (PROs) - enhance disease assessment, they require further validation, standardization, and broader accessibility. Similarly, de-escalation criteria need additional research to optimize patient selection.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder with approximately 80 % of patients suffering from pain and 50 % from paralysis. Using a rodent model for MS, experimental autoimmune encephalomyelitis (EAE), researchers have predominately investigated paralysis/motor disease as the clinical symptom of EAE with fewer studying MS/EAE pain. However, in EAE, all mice exhibit a pain like phenotype and only a subset progresses to paralysis. Despite extensive research characterizing the disease pathology, the etiology that contributes to the range of pain and motor symptom occurrence in MS remains understudied. This is the first study to dissect MS symptom pathophysiology, using the non-PTX EAE model, in mice that experience mechanical hypersensitivity (pain-like phenotype) with and without paralysis. We found that mechanical hypersensitivity experienced by mice with or without paralysis is comparable between the two groups, irrespective of sex. In addition, there is a significant increase in the activation and infiltration of immune cells, demyelination, and heightened protein expression of B cell chemoattractant CXCL13 within the spinal cord of mice exhibiting mechanical hypersensitivity and paralysis, compared to mice only experiencing mechanical hypersensitivity.

Blood-brain barrier dysfunction (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We have previously shown that blocking microglial proliferation using GW2580, a selective inhibitor of CSF1R (Colony stimulating factor 1 receptor), reduced disease progression and severity and prevented the relapse phase. However, whether this was due to effects of GW2580 on the functional integrity of the BBB was not determined. Therefore, here, we examine BBB properties in rats during EAE under GW2580 treatment. Our data suggest that blocking early microglial proliferation through selective targeting of CSF1R signaling has a therapeutic effect in EAE by protecting BBB integrity and reducing peripheral immune cell infiltration. Taken together, our results identify a novel mechanism underlying the effects of GW2580, which could offer a novel therapy for MS.

The main function of oligodendrocytes is to assemble and maintain myelin that wraps and insulates axons in the central nervous system (CNS). Traditionally, myelin structure, particularly its thickness, was believed to remain remarkably stable in adulthood (including early and middle adulthood, but not late adulthood or aging). However, emerging evidence reveals that the thickness of originally-existing, mature myelin (OEM) can undergo dynamic changes in the adult CNS. This overview highlights recent findings on the alteration of OEM thickness in the adult CNS, explores the underlying mechanisms, and proposes that progressive thinning of OEM represents a novel, nondestructive form of myelin loss in myelin disorders of the CNS.

Multiple sclerosis (MS) is an disease of the central nervous system, which is reflected in impaired transmission of impulses due to damage to the myelin layer. In addition to the visual evoked potentials, the vestibular evoked myogenic potentials (VEMPs) are increasingly considered for diagnosis. Due to a low signal-to-noise ratio, several hundred stimulus responses are usually averaged in order to determine the amplitude and latencies from these curves. However, this averaging procedure also filters out information that, if taken into account, could provide further insights into the course of the disease.16 young patients with MS and an EDSS score of 1.4 ± 0.6 were compared with 92 healthy subjects of the same age. Amplitude, latency, AR and five new parameters from the analysis were used as parameters from the tactile evoked oVEMPs.The total n10 amplitude and the n10 amplitude on the left side showed relevant differences tough not reaching statistical significance. In contrast, the n10 amplitude on the right side and the LSD parameter were not significantly different. All n10 latencies and the AR as well as all parameters from the novelty analysis were significantly different.On the one hand, the present study confirms already known changes in the registration of oVEMPs in patients with MS compared to healthy subjects and, on the other hand, the new parameters have the potential to better describe the current state of the disease and to provide detailed information about the current state of myelination or the site of pathophysiological processes within the CNS.

Multiple sclerosis (MS) is a chronic autoimmune illness characterized by demyelination, neurodegeneration, and inflammation in the central nervous system. The AXL gene, which codes for a receptor tyrosine kinase, has emerged as a promising therapeutic target due to its involvement in neuroinflammation and oligodendrocyte dysfunction. In the current study, we employed in silico techniques to design Antisense Oligonucleotides (ASOs) that selectively target AXL gene transcripts to modulate AXL expression and mitigate MS pathology. Three ASOs, A1, A2, and A3, were designed to specifically target the 5' untranslated region (5'UTR) and coding region of the AXL gene transcripts. The ASOs were optimized with a focus on stability, binding affinity, and specificity towards AXL mRNA while minimizing off-target effects. To investigate ASO-mRNA interactions and gauge their ability to alter AXL expression, Molecular Docking was performed. Our analyses showed that A1, A2, and A3 had substantial interactions with AXL mRNA, with binding affinities of -9.5 kcal/mol, -10.8 kcal/mol, and -10.6 kcal/mol, respectively. The targeting of AXL gene transcripts through ASOs shows promise in reducing MS symptoms. Precision ASO-based therapies could effectively manage MS by targeting the essential pathways involved in the disease. ASOs provide a highly targeted approach for treating MS and offer a precise therapeutic strategy for this debilitating condition. The study lays the groundwork for future in vitro and in vivo studies to confirm the therapeutic potential of these ASOs for the treatment of MS.

Multiple Sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS). In this study, the concentration of heavy metals was measured in stool samples of MS patients by Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS) method and compared with healthy people. Also, another goal of this study is to investigate the alteration of the gut microbiome of MS patients by metagenomics technique based on the 16S rRNA gene sequencing. The IL-10 ELISA assay showed no significant differences between the serum level of the IL-10 in the patients and the control group (p = 0.510). Heavy metal measurement by ICP-MS showed significantly higher levels of arsenic (As, Mean = 32.77 μg/kg), nickel (Ni, Mean = 7.154 μg/kg), manganese (Mn, Mean = 3723 μg/kg), and zinc (Zn, Mean = 5508 μg/kg) in the stool samples of the MS group compared to the control group, while concentrations of iron (Fe, Mean = 9585 μg/kg), lead (Pb, Mean = 18.54 μg/kg), titanium (Ti, Mean = 69.69 μg/kg), and tin (Sn, Mean = 13.92 μg/kg) were significantly lower. The result of gut microbiome analysis showed an increase in the abundance of the Verrumicrobiaceae, Lachnospiraceae and Ruminococcaceae families was considerably increased in MS patients compared to the control group (p < 0.05). This study reports that high levels of heavy metals such as Ars, Ni, Mn, and Zn, deficiency of Fe, Pb, Ti, and Sn, and alteration of the gut microbiome are involved in the pathogenesis of MS. The novelty of this study lies in its multi-faceted approach to understanding MS by integrating the measurement of heavy metals in stool samples with the analysis of gut microbiome alterations, thereby providing comprehensive insights into heavy metals, the gut microbiome, and potential therapeutic avenues. This study suggests several potential applications and practical implications based on its findings regarding heavy metals, gut microbiome alterations, and IL-10 levels in MS. First, the identification of elevated levels of specific heavy metals and deficiencies in others may lead to targeted screening and monitoring, informing preventive strategies for MS patients. Additionally, the observed gut microbiome changes could facilitate the development of microbiome-based therapies, such as probiotics or dietary interventions, aimed at restoring microbial balance. Finally, exploring the interplay between heavy metals, gut microbiome, and immune response may guide the creation of novel therapeutic interventions, ultimately enhancing treatment efficacy and providing new avenues for managing MS, thereby alleviating the burden of this chronic condition.

Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.

Acute upper respiratory tract infections are a major public health issue, with uncontrolled inflammation triggered by upper respiratory viruses being a significant cause of patient deterioration or death. This study focuses on the Janus kinase-signal transducer and activator of transcription Rho-associated coiled-coil containing protein kinase (JAK-STAT-ROCK) signaling pathway, providing an in-depth analysis of the interplay between uncontrolled inflammation after upper respiratory tract infections and the development of neurodegenerative diseases. It offers a conceptual framework for understanding the lung-brain-related immune responses and potential interactions. The relationship between the ROCK-JAK-STAT signaling pathway and inflammatory immunity is a complex and multi-layered research area and exploring potential common targets could open new avenues for the prevention and treatment of related inflammation.

Forecasting the progression of the disease in the early inflammatory stage of the most prevalent type of multiple sclerosis (MS), referred to as relapsing-remitting multiple sclerosis (RRMS), is essential for making prompt treatment modifications, aimed to reduce clinical relapses and disability. In total, 58 patients with RRMS, having an Expanded Disability Status Scale (EDSS) score less than 4, were included in this study. Baseline magnetic resonance imaging (MRI) was performed, and brain and spinal cord lesions were evaluated. The disability of the patients was evaluated using EDSS at baseline and follow-up; enzyme-linked immunosorbent assays (ELISAs) were also used to determine the level of blood-based inflammation markers in plasma at baseline. The main results demonstrated that the baseline level of LBP was correlated with an increase in EDSS in a short (8-10 months) follow-up period. Furthermore, the prognostic significance of LBP was only observed in patients who received disease-modifying treatment (DMT) before the study. Our results suggest that the baseline level of LBP may be among the predictors of disability progression in RRMS over short follow-up periods, particularly in those receiving treatment. It highlights the effect of endotoxins in the pathogenesis of RRMS.

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The 32 CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary-EAE (AR-EAE), accompanied by distinct immunopathology. Sex differences in EAE severity were observed in 6 strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity (Abcc4 and Gpc6) and AR-EAE (Yap1 and Dync2h1). This work expands the EAE phenotypic repertoire and identifies potentially novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.

To investigate the acute effect of myofascial stretching exercises on spasticity, balance, ambulation status and mobility of posterior chain muscles in multiple sclerosis.

The study was conducted as a randomised controlled experimental study. The study included a total of 80 individuals diagnosed with multiple sclerosis (MS) with a mean age of 43.5 ± 9.62 years (experimental group) and 41.4 ± 10.4 years (control group). All individuals were treated once and evaluated before and after the session. After recording the sociodemographic characteristics, spasticity assessment was performed with the Modified Ashword Scale (MAS), balance assessment with the Berg Balance Scale (BBS), ambulation status with the Timed Up and Go Test (TUG), and posterior chain muscle mobility (PCMM) with finger-to-ground distance measurement.

The TUG (time to complete the distance) measurements of the experimental group after treatment were lower than those of the control group (p < 0.05). The value of PCMM measurements of the experimental group before the treatment was lower than that of the control group (p < 0.001). The difference in positive increase in PCMM measurements in the experimental group was higher than that in the control group (p < 0.05). After the treatment, the MAS value in the left knee of the experimental group was lower than that of the control group (p < 0.05).

Myofascial stretching exercises applied to individuals with MS made an acute contribution to ambulation status and mobility of posterior chain muscles. There was no difference in the evaluation of spasticity and balance.

Falls are a common and consequential concern for persons with multiple sclerosis (PwMS), with trunk impairment frequently observed even in the early stages of the disease. However, the relationship between falls and trunk impairment using the trunk impairment scale in this population remains unclear. This study aims to explore this association and identify potential factors contributing to falls in PwMS.

Sixty-four patients were assessed for falls or near falls in the past 6 months, trunk impairment using the Trunk Impairment Scale (TIS), balance and gait using the Performance-Oriented Mobility Assessment (POMA), depression and anxiety using the Hospital Anxiety and Depression Scale (HADS), fatigue using the Modified Fatigue Impact Scale (MFIS), and fear of falling using the Modified Falls Efficacy Scale (MFES).

Simple binary logistic regression revealed significant associations for TIS (OR = 0.75, p = 0.001, 95 % CI: 0.63 to 0.88), POMA (OR = 0.75, p ≤ 0.001, 95 % CI: 0.65 to 0.87), MFES (OR = 0.96, p ≤ 0.001, 95 % CI: 0.93 to 0.98), MFIS (OR = 1.05, p = 0.002, 95 % CI: 1.02 to 1.08), and HADS (OR = 1.09, p = 0.01, 95 % CI: 1.02 to 1.17). The multiple logistic regression model identified TIS (OR = 0.78, p = 0.007, 95 % CI: 0.66 to 0.94) and MFES (OR = 0.96, p = 0.005, 95 % CI: 0.93 to 0.98) as significant factors of falls.

This study confirms the significant impact of trunk impairment, tested by the trunk impairment scale and fear of falling as factors of falls among PwMS. Additionally, it highlights the roles of balance, gait, fatigue, and depression as factors that contribute to fall risk. These findings suggest that a comprehensive assessment incorporating these elements may be crucial for developing effective fall prevention strategies in this population. This research underscores the need for targeted interventions that address both physical and psychological aspects to mitigate the risk of falls in PwMS.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA. SIGNIFICANCE STATEMENT: Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body's limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.

Slow-burning inflammation at the edge, and chronic demyelination at the core, of established multiple sclerosis (MS) lesions are potential mediators of disease progression. However, their relative contribution to progressive axonal damage has not been explored. Therefore, in this study, we investigated the comparative contribution of slow-burning inflammation and chronic demyelination to axonal attrition within MS lesions by measuring progressive tissue rarefaction. In addition, we use the visual system as a model to investigate the effect of chronic demyelination on the acceleration of axonal death in a sub-group of patients with unilateral optic neuritis.

Pre- and post-gadolinium 3D-T1, 3D FLAIR, diffusion tensor images, Optical Coherence tomography and multifocal visual evoked potentials were acquired from 52 relapsing-remitting MS patients who completed at least 5 years follow-up. Lesion expansion was measured using custom software, and the rate of tissue rarefication inside lesion core was assessed by measuring increase of normalized mean diffusivity (nMD). Axonal loss was also examined in eyes with severe optic nerve demyelination.

Among the 361 lesions analyzed, 104 were expanding (a minimum of 4 % expansion per year) and 257 were stable. Expanding lesions showed a significantly higher rate of progressive tissue rarefication inside lesion (1.12 % per year) core compared to stable lesions (0.21 % per year, p = 0.01). The magnitude of nMD change was significantly correlated with the rate of lesion expansion (r = 0.4, p < 0.001). Analysis of retinal ganglion cells in eyes with severe optic nerve demyelination (Inter-eye latency delay of >10 ms) revealed a similar rate of axonal loss (0.19 %) to the degree of tissue rarefaction observed in stable lesions (0.21 %).

The results of the study suggest that the slow-burning inflammation at the lesion's edge (as measured by lesion expansion), is likely to have a greater impact on tissue damage (as measured by nMD change), when compared to stable chronically demyelinated lesions. The similar modest degree of tissue damage was also observed in chronically demyelinated fibers of the optic nerve.

In recent years, the incidence of neurodegenerative diseases (NDs) has gradually increased over the past decades due to the rapid aging of the global population. Traditional research has had difficulty explaining the relationship between its etiology and unhealthy lifestyle and diets. Emerging evidence had proved that the pathogenesis of neurodegenerative diseases may be related to changes of the gut microbiota's composition. Metabolism of gut microbiota has insidious and far-reaching effects on neurodegenerative diseases and provides new directions for disease intervention. Here, we delineated the basic relationship between gut microbiota and neurodegenerative diseases, highlighting the metabolism of gut microbiota in neurodegenerative diseases and also focusing on treatments for NDs based on gut microbiota. Our review may provide novel insights for neurodegeneration and approach a broadly applicable basis for the clinical therapies for neurodegenerative diseases.

Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota-gut-brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut-brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer's disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer's neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson-Konovalov disease (WD), multisystem atrophy (MSA), Huntington's chorea (HC), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut-brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases.

Even though several highly effective treatments have been developed for multiple sclerosis (MS), the underlying pathological mechanisms and drivers of the disease have not been fully elucidated. In recent years, there has been a growing interest in studying neuroinflammation in the context of glial cell involvement as there is increasing evidence of their central role in disease progression. Although glial cell communication and proper function underlies brain homeostasis and maintenance, their multiple effects in an MS brain remain complex and controversial. In this review, we aim to provide an overview of the contribution of glial cells, oligodendrocytes, astrocytes, and microglia in the pathology of MS during both the activation and orchestration of inflammatory mechanisms, as well as of their synergistic effects during the repair and restoration of function. Additionally, we discuss how the understanding of glial cell involvement in MS may provide new therapeutic targets either to limit disease progression or to facilitate repair.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of unknown etiology characterized by infiltration of encephalitogenic cells in the central nervous system (CNS) resulting in the presence of multifocal areas of demyelination leading to neurodegeneration. The infiltrated immune cells population is composed mainly of effector CD4+ and CD8+ T lymphocytes, B cells, macrophages, and dendritic cells that secrete pro-inflammatory factors that eventually damage myelin leading to axonal damage. The most common clinical form of MS is relapsing-remitting (RR), characterized by neuroinflammatory episodes followed by partial or total recovery of neurological deficits. The first-line treatment for RRMS relapses is a high dose of glucocorticoids, especially methylprednisolone, for three to five consecutive days. Several studies have reported the beneficial effects of melatonin in the context of neuroinflammation associated with MS or experimental autoimmune encephalomyelitis (EAE), the preclinical model for MS. Therefore, the objective of this study was to evaluate the effect of the combined treatment of melatonin and methylprednisolone on the neuroinflammatory response associated with the EAE development. This study shows for the first time the protective synergistic effect of co-treatment with melatonin and methylprednisolone on reducing the severity of EAE by decreasing CD4 lymphocytes, B cells, macrophages and dendritic cells in the CNS, as well as modulating the population of infiltrated T and B cells toward regulatory phenotypes to the detriment of pro-inflammatory effector functions. In addition to the potentiation of the protective role of methylprednisolone, treatment with melatonin from the clinical onset of EAE improves the natural course of the EAE and the response to a subsequent treatment with methylprednisolone in a later relapse of the disease, pointing melatonin as potential therapeutic tool in combination with methylprednisolone for the treatment of relapses in MS.

A robust adaptive immune response is essential for combatting pathogens. In the wrong context such as due to genetic and environmental factors, however, the same mechanisms crucial for self-preservation can lead to a loss of self-tolerance. Resulting autoimmunity manifests in the development of a host of organ-specific or systemic autoimmune diseases, hallmarked by aberrant immune responses and tissue damage. The prevalence of autoimmune diseases is on the rise, medical management of which focuses primarily on pharmacological immunosuppression that places patients at a risk of side effects, including opportunistic infections and tumorigenesis. Biomaterial-based drug delivery systems confer many opportunities to address challenges associated with conventional disease management. Hydrogels, in particular, can protect encapsulated cargo (drug or cell therapeutics) from the host environment, afford their presentation in a controlled manner, and can be tailored to respond to disease conditions or support treatment via multiplexed functionality. Moreover, localized delivery to affected sites by these approaches has the potential to concentrate drug action at the site, reduce off-target exposure, and enhance patient compliance by reducing the need for frequent administration. Despite their many benefits for the management of autoimmune disease, such biomaterial-based approaches focus largely on the downstream effects of hypersensitivity mechanisms and have a limited capacity to eradicate the disease. In contrast, direct targeting of mechanisms of hypersensitivity reactions uniquely enables prophylaxis or the arrest of disease progression by mitigating the basis of autoimmunity. One promising approach is to induce self-antigen-specific tolerance, which specifically subdues damaging autoreactivity while otherwise retaining the normal immune responses. In this review, we will discuss hydrogel-based systems for the treatment of autoimmune disease, with a focus on those that target hypersensitivity mechanisms head-on. As the field continues to advance, it will expand the range of therapeutic choices for people coping with autoimmune diseases, providing fresh prospects for better clinical outcomes and improved quality of life.

Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut-brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut-brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.

The early identification of individuals with radiologically isolated syndrome (RIS) who are at an elevated risk of progressing to multiple sclerosis (MS) is essential for making informed treatment decisions. This study aimed to evaluate the predictive potential of multifocal Visual Evoked Potentials (mfVEP) measures in individuals with RIS with respect to their conversion to MS. A prospective observational cohort study was conducted, involving 21 individuals with RIS recruited from a MS center. Baseline assessments, including mfVEP, magnetic resonance imaging (MRI), and clinical examinations, were performed, and participants were longitudinally followed for up to 24 months. The primary outcome measures were the conversion to MS. Over a clinical follow-up period of 24 months, five individuals (5/21) with RIS progressed to MS. MfVEP amplitude responses (interocular and monocular probability analysis) demonstrated abnormal cluster visual field defects in 47.6% of RIS eyes at baseline, whereas multifocal VEP latency analysis showed significant delays in 38.4%. A reduction in interocular amplitude [OR = 0.036, (95% CI 0.003-0.503); P = 0.014], monocular amplitude [OR = 0.083, (95% CI 0.007-0.982); P = 0.048], and a prolonged interocular latency [OR = 0.095, (95% CI 0.009-0.972); P = 0.047] were associated with a higher relative risk of clinical conversion at the 2-year follow-up. Multifocal VEP may serve as a novel and independent risk factor for predicting the conversion to MS in individuals with Radiologically Isolated Syndrome.

Damage or microstructural alterations of the white matter can cause dysfunction of the intrinsic neural networks in a condition termed as white matter disease (WMD). Frequently detected on brain computed tomography and magnetic resonance imaging scans, WMD is commonly presented in inflammatory demyelinating diseases like multiple sclerosis (MS) and vascular diseases such as cerebral small vessel disease (CSVD). Prevention of MS and CSVD progression requires early treatments with drastically different medications and approaches, as such, early and accurate diagnosis of WMD, derived from vascular or demyelinating etiologies, is of paramount importance. However, the clinical and imaging similarities between MS, especially during the early stage, and CSVD, pose a significant dilemma in differentiating these two conditions. In this review, we attempt to summarize and contrast the distinguishing features of MS and CSVD for aiding accurate diagnosis to ensure timely corresponding management in the early stages of MS and CSVD.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, affecting nearly 2 million people worldwide. The etiology of MS is multifactorial: Approximately 30% of the MS risk is genetic, which implies that the remaining ~70% is environmental, with a number of factors proposed. One recently implicated risk factor for MS is the composition of the gut microbiome. Numerous case-control studies have identified changes in gut microbiota composition of people with MS (pwMS) compared with healthy control individuals, and more recent studies in animal models have begun to identify the causative microbes and underlying mechanisms. Here, we review some of these mechanisms, with a specific focus on the role of host genetic variation, dietary inputs, and gut microbial metabolism, with a particular emphasis on short-chain fatty acid and tryptophan metabolism. We put forward a model where, in an individual genetically susceptible to MS, the gut microbiota and diet can synergize as potent environmental modifiers of disease risk and possibly progression, with diet-dependent gut microbial metabolites serving as a key mechanism. We also propose that specific microbial taxa may have divergent effects in individuals carrying distinct variants of MS risk alleles or other polymorphisms, as a consequence of host gene-by-gut microbiota interactions. Finally, we also propose that the effects of specific microbial taxa, especially those that exert their effects through metabolites, are highly dependent on the host dietary intake. What emerges is a complex multifaceted interaction that has been challenging to disentangle in human studies, contributing to the divergence of findings across heterogeneous cohorts with differing geography, dietary preferences, and genetics. Nonetheless, this provides a complex and individualized, yet tractable, model of how the gut microbiota regulate susceptibility to MS, and potentially progression of this disease. Thus, we conclude that prophylactic or therapeutic modulation of the gut microbiome to prevent or treat MS will require a careful and personalized consideration of host genetics, baseline gut microbiota composition, and dietary inputs.

Dietary administration of a copper chelator, cuprizone (CPZ), has long been reported to induce intense and reproducible demyelination of several brain structures such as the corpus callosum. Despite the widespread use of CPZ as an animal model for demyelinating diseases such as multiple sclerosis (MS), the mechanism by which it induces demyelination and then allows robust remyelination is still unclear. An intensive mapping of the cell dynamics of oligodendrocyte (OL) lineage during the de- and remyelination course would be particularly important for a deeper understanding of this model. Here, using a panel of OL lineage cell markers as in situ hybridization (ISH) probes, including Pdgfra, Plp, Mbp, Mog, Enpp6, combined with immunofluorescence staining of CC1, SOX10, we provide a detailed dynamic profile of OL lineage cells during the entire course of the model from 1, 2, 3.5 days, 1, 2, 3, 4,5 weeks of CPZ treatment, as well as after 1, 2, 3, 4 weeks of recovery from CPZ treatment. The result showed an unexpected early death of mature OLs and response of OL progenitor cells (OPCs) in vivo upon CPZ challenge, and a prolonged upregulation of myelin-forming OLs compared to the intact control even 4 weeks after CPZ withdrawal. These data may serve as a basic reference system for future studies of the effects of any intervention on de- and remyelination using the CPZ model, and imply the need to optimize the timing windows for the introduction of pro-remyelination therapies in demyelinating diseases such as MS.

A subtype of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is suggested to be responsible for the outbreak in Northern China since the quarantine was lifted in December 2022. The coronavirus disease 2019 virus is primarily responsible for the development of respiratory illnesses, however, it can present a plethora of symptoms affecting a myriad of body organs. This virus has been theorized to be linked to demyelinating lesions of the peripheral and central nervous system including transverse myelitis and acute retrobulbar optic neuritis (ARON). For example, magnetic resonance imaging (MRI) of the orbit and brain showed enlargement of the retrobulbar intraorbital segments of the optic nerve with high T2 signal, and no abnormalities were seen in the brain tissue. In this case series, we analyzed the connection between SARS-CoV-2 infection and the onset of ARON.

Fifteen patients, and a teenage boy who did not have any pre-existing ocular or demyelinating diseases suddenly experienced a loss of vision after SARS-CoV-2 infection. The patients expressed a central scotoma and a fever as the primary concern. The results of the fundus photography were found to be normal. However, the automated perimetry and MRI scans showed evidence of some typical signs. Out of the 15 patients diagnosed with ARON after SARS-CoV-2 infection, only one individual tested positive for the aquaporin-4 antibody.

Direct viral invasion of the central nervous system and an immune-related process are the two primary causes of SARS-CoV-2-related ARON.

Multiple sclerosis (MS) is a chronic and debilitating disease that not only leads to disability and associated condition but also impacts one's ability to maintain a professional life. People's acceptance and utilization of medicinal plants (MPs) play an important role in managing their treatment process. As a result, this study aims to investigate the use of medicinal herbs among patients with MS.

A descriptive cross-sectional study was conducted on 150 MS patients who visited a private clinic and the MS Association in Kerman, Iran in 2021. A questionnaire comprising questions about sociodemographic information, disease variables, and aspects of MPs usage was utilized for data collection. Statistical analysis was performed using SPSS version 20 (SPSS Inc., Chicago, IL). The Chi-square test was employed to identify any association between demographic characteristics and MPs usage. To determine the prevalence of plant use in a specific area and the consensus among informants, the use value (UV) and Informant consensus factor (Fic) were calculated.

The study revealed a high prevalence of MPs usage among MS patients. Chamomile (66.6%) and golegavzaban (62.0%) were the most commonly used plants with the highest UV indices (0.88 and 0.82 respectively), while St. John's wort and licorice were rarely used (0.67% and 4% respectively). Participants cited pursuing a healthier lifestyle as the primary reason for using MPs (24%). St. John's wort, lavender, and chamomile were the most satisfying plants (100%, 100%, and 53.0% respectively). Chamomile had the highest Fic too. Most patients were motivated to get MPs from their relatives.

Given the widespread use of MPs among MS patients, neurologists should enhance their knowledge in this area to guide patients away from seeking advice from non-professionals. Providing standardized formulations can help prevent potential interactions between MPs and mainstream drugs, thereby improving patients safety and outcomes.

Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the molecular basis of antigen presentation and the clinical course of patients with both Adult-Onset MS (AOMS) and Pediatric-Onset MS (POMS). Among the numerous polymorphisms of the Human Leucocyte Antigens (HLA), within MHC II complex, HLA-DRB1*15:01 has been labeled, in Caucasian ethnic groups, as a high-risk allele for MS due to the ability of its structure to increase affinity to Myelin Basic Protein (MBP) epitopes. This characteristic, among others, in the context of the trimolecular complex or immunological synapsis, provides the foundation for autoimmunity triggered by environmental or endogenous factors. As with all professional antigen presenting cells, macrophages are characterized by the expression of MHC II and are often implicated in the formation of MS lesions. Increased presence of M1 macrophages in MS patients has been associated both with progression and onset of the disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic alterations can promote dysregulation of this population's homeostasis in the periphery and the Central Nervous System (CNS). We also explore the potential interconnection in observed pathological macrophage mechanisms and the function of the diverse structure of HLA alleles in neurodegenerative CNS, seen in MS, by comparing available clinical with molecular data through the prism of HLA-immunogenetics. Finally, we discuss available and experimental pharmacological approaches for MS targeting the trimolecular complex that are based on cell phenotype modulation and HLA genotype involvement and try to reveal fertile ground for the potential development of novel drugs.

Multiple sclerosis (MS) is a chronic inflammatory condition that impacts the central nervous system. It is distinguished by processes like demyelination, gliosis, neuro-axonal harm, and inflammation. The prevailing theory suggests that MS originates from an immune response directed against the body's own antigens within the central nervous system.

The main aim of this research paper "Neuroinflammation-on-a-Chip" for studying multiple sclerosis is to enhance our comprehension of MS development, demonstrate the application of cutting-edge technology, and potentially provide valuable insights for therapeutic approaches.

The available literature for this Narrative Review was searched on various bibliographic databases, PubMed, NCBI, and many other medical references using an individually verified, prespecified approach. Studies regarding the significance of MS and its neuroinflammatory pathogenesis in addition to the development and optimization of neuroinflammatory-on-a-chip and the advancement in innovations in this field have been reviewed in this research for a better understanding of "Neuroinflammation-on-a-chip for multiple sclerosis". The level of evidence of the included studies was considered as per the Centre for Evidence-Based Medicine recommendations.

Several studies have indicated that the brain-chip model closely mimics cortical brain tissue compared to commonly used conventional cell culture methods like the Transwell culture system. Additionally, these studies have clearly demonstrated that further research using brain chips has the potential to enhance our understanding of the molecular mechanisms and roles of blood-brain barrier (BBB) transporters in both normal and disease conditions.

Understanding neuroinflammation processes remains essential to establish new MS treatments approaches. The utilization of brain chips promises to advance our understanding of the molecular processes involving BBB transporters, both in normal and diseased states. Further research needs to be addressed in order to enhance the performance and understanding of neuroinflammation on a chip, hence aiming to provide more effective treatments for all CNS diseases.

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic condition characterized by venous thromboembolism, arterial thrombosis, and pregnancy morbidity. Among neurological manifestations, arterial thrombosis is only one of the possible associated clinical and neuroradiological features. The aim of this review is to address from a neurovascular point of view the multifaceted range of the arterial side of APS. A modern neurovascular approach was proposed, dividing the CNS involvement on the basis of the size of affected arteries, from large to small arteries, and corresponding clinical and neuroradiological issues. Both large-vessel and small-vessel involvement in APS were detailed, highlighting the limitations of the available literature in the attempt to derive some pathomechanisms. APS is a complex disease, and its neurological involvement appears multifaceted and not yet fully characterized, within and outside the diagnostic criteria. The involvement of intracranial large and small vessels appears poorly characterized, and the overlapping with the previously proposed inflammatory manifestations is consistent.

Cannabis sativa is a plant of the Cannabaceae family, whose molecular composition is known for its vast pharmacological properties. Cannabinoids are the molecules responsible for Cannabis sativa potential effects, especially tetrahydrocannabinol and cannabidiol. Scientific development has shown interest in the potential of cannabidiol in various health conditions, as it has demonstrated lower adverse events and great pharmacological potential, especially when administered topically. The present study aims to carry out a scoping review, focusing on the use of cannabidiol, in vivo models, for topical administration. Thus, the methodological approach used by the Joanna Briggs Institute was applied, and the studies were selected based on previously established inclusion criteria. Even though more information regarding the dose to achieve pharmacological potential is still needed, cannabidiol demonstrated potential in treating and preventing different conditions, such as glaucoma, atopic dermatitis, epidermolysis bullosa, and pyoderma gangrenosum.

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The thirty-two CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary (AR)-EAE, accompanied by distinct immunopathology. Sex differences in EAE severity were observed in six strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity ( Abcc4 and Gpc6 ) and AR-EAE ( Yap1 and Dync2h1 ). This work expands the EAE phenotypic repertoire and identifies novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.

The genetic basis of disease heterogeneity in multiple sclerosis (MS) remains elusive. We leveraged the Collaborative Cross to expand the phenotypic repertoire of the experimental autoimmune encephalomyelitis (EAE) model of MS and identify loci controlling EAE severity, trajectory, and presentation.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) belong to a complex family of RNA-binding proteins that are essential to control alternative splicing, mRNA trafficking, synaptic plasticity, stress granule formation, cell cycle regulation, and axonal transport. Over the past decade, hnRNPs have been associated with different brain disorders such as Alzheimer's disease, multiple sclerosis, and schizophrenia. Given their essential role in maintaining cell function and integrity, it is not surprising that dysregulated hnRNP levels lead to neurological implications. This review aims to explore the primary functions of hnRNPs in neurons, oligodendrocytes, microglia, and astrocytes, and their roles in brain disorders. We also discuss proteomics and other technologies and their potential for studying and evaluating hnRNPs in brain disorders, including the discovery of new therapeutic targets and possible pharmacological interventions.

Demyelination is a proper syndrome in plenty of central nervous system (CNS) diseases, which is the main obstacle to recovery and still lacks an effective treatment. To overcome the limitations of the brain-blood barrier on drug permeability, we modified an exosome secreted by neural stem cells (NSCs), which had transfected with lentivirus armed with platelet-derived growth factors A (PDGFA)-ligand. Through the in vivo and in vitro exosomes targeting test, the migration ability to the lesion areas and OPCs significantly improved after ligand modification. Furthermore, the targeted exosomes loaded with 3,5, 30-L-triiodothyronine (T3) have a critical myelination ability in CNS development, administrated to the cuprizone animal model treatment. The data shows that the novel drug vector loaded with T3 significantly promotes remyelination compared with T3 alone. At the same time, it improved the CNS microenvironment by reducing astrogliosis, inhibiting pro-inflammatory microglia, and alleviating axon damage. This investigation provides a straightforward strategy to produce a targeting exosome and indicates a possible therapeutic manner for demyelinating disease.

Observational studies have found a potential bidirectional positive association between multiple sclerosis and psoriasis, but these studies are susceptible to confounding factors. We examined the directionality of causation using Mendelian randomization and estimated the genetic correlation using the linkage disequilibrium score. We performed Mendelian randomization analysis using large-scale genome-wide association studies datasets from the International Multiple Sclerosis Genetics Consortium (IMSGC, 115,803 individuals of European ancestry) and FinnGen (252,323 individuals of European ancestry). We selected several Mendelian randomization methods including causal analysis using summary effect (CAUSE), inverse variance-weighted (IVW), and pleiotropy-robust methods. According to CAUSE and IVW the genetic liability to MS reduces the risk of psoriasis (CAUSE odds ratio [OR] 0.93, p = 0.045; IVW OR 0.93, p = 2.51 × 10-20), and vice versa (CAUSE OR 0.72, p = 0.001; IVW OR 0.71, p = 4.80 × 10-26). Pleiotropy-robust methods show the same results, with all p-values < 0.05. The linkage disequilibrium score showed no genetic correlation between psoriasis and MS (rg =  - 0.071, p = 0.2852). In summary, there is genetic evidence that MS reduces the risk of psoriasis, and vice versa.