PPMS Studies Update: New Research on PPMS and Multiple Sclerosis

ABSTRACT

Multiple sclerosis (MS) is a central nervous system autoimmune disease primarily driven by Th1 and Th17 cells, whose onset and progression are closely associated with gut microbiota. Kurarinone (KU), an active component from
Radix Sophora Flavescens
, exhibits anti‐inflammatory, immunoregulatory and gut microbiota‐modulating properties. However, whether KU alleviates MS severity via a gut microbiota‐mediated mechanism remains unclear. Here, we demonstrate that KU ameliorates experimental autoimmune encephalomyelitis (EAE)‐an animal model of MS‐by modulating the gut microbiota, particularly via enriching
Akkermansia muciniphila
, and
A. muciniphila
is essential for the protective effects of KU in EAE. Furthermore, KU elevates levels of the tryptophan metabolite indole‐3‐acetaldehyde (IAAld). IAAld levels are positively correlated with the relative abundance of
A. muciniphila
and negatively correlated with EAE severity. In vitro,
A. muciniphila
alone is sufficient to facilitate tryptophan metabolism to produce IAAld. IAAld treatment ameliorates EAE and reduces the frequencies of pathogenic Th1 and Th17 cells in mice. Mechanistically, IAAld activates the aryl hydrocarbon receptor (AhR) and suppresses JAK/STAT signaling, thereby dampening Th1 and Th17 differentiation; these effects are abolished following AhR blockade. Collectively, this study identifies a novel mechanism by which KU mitigates EAE via the gut metabolite IAAld‐AhR‐immune axis and unveils potential therapeutic targets for MS.

Multiple sclerosis (MS) is a persistent immune-mediated condition marked by neuroinflammation, demyelination, and ongoing neurological impairment. Although there have been advancements in therapies aimed at modifying the disease, significant treatment gaps persist, underscoring the need for new strategies focusing on immune regulation and neuroprotection. Trehalose, a natural disaccharide, has attracted interest for its potential in affecting autophagy, managing oxidative stress, and modulating immune pathways via the microbiota. This review summarizes existing evidence on how trehalose might impact the pathological processes associated with MS, with a focus on gut microbiota modulation, immune system regulation, and effects related to the central nervous system. Preclinical research suggests that trehalose could regulate autophagy, decrease inflammatory signaling, and affect immune responses involved in neuroinflammation. Moreover, both in vitro and animal studies indicate that consuming trehalose orally might change the abundance of certain gut microbial groups, such as those linked to short-chain fatty acids. These changes in microbiota may help modulate intestinal barrier functions and immune responses; however, it’s unclear if similar effects occur in MS patients. Experimental models, like experimental autoimmune encephalomyelitis, point to trehalose’s potential role in influencing neuroprotective pathways and processes related to myelin. Current evidence supports the investigation of trehalose as a potential modulator of interactions among microbiota, immunity, and the central nervous system in relation to MS. Nevertheless, most of this evidence stems from preclinical studies. The clinical effectiveness, safety, proper dosing, and therapeutic significance of trehalose for individuals with MS need to be confirmed through well-structured clinical trials.

Oligodendrocyte precursor cells (OPCs) are abundant progenitor cells in the central nervous system. Unlike mature oligodendrocytes, OPCs form functional synapses with neurons and respond to both glutamatergic and GABAergic signals. Glutamate activates calcium-permeable AMPA receptors on OPCs, generating local Ca
2+
signals that regulate myelin sheath formation and stabilization. In parallel, GABAergic signaling modulates OPC proliferation and differentiation through both calcium-dependent and transcriptional mechanisms. Activity-dependent myelination driven by OPCs contributes directly to neural circuit plasticity and behavioral adaptation, including motor learning, spatial memory, fear extinction, and social experience-dependent brain development. Disruption of the OPC–synapse–myelin axis impairs remyelination and circuit function, contributing to neurological and psychiatric disorders such as multiple sclerosis, schizophrenia, and PTSD. In this review, we critically examine neuron–OPC communication across four interconnected levels: synaptic signaling, cellular fate regulation, myelin plasticity, and behavior. We highlight key limitations in the current evidence, including controversies over the functional role of OPC synapses in the adult brain, unclear mechanisms underlying myelin plasticity, and the largely correlative nature of human neuroimaging data. We argue that the field must move beyond descriptive observations toward rigorous mechanistic studies of causality, with particular attention to region- and cell-type-specific heterogeneity.

Abstract

Multiple sclerosis (MS) is a debilitating demyelinating disease of the central nervous system (CNS) in which progressive neurological disability is closely linked to the failure of endogenous remyelination. Reactive astrocytes are hallmarks of MS lesions, yet their functional role in myelin repair remains incompletely understood. Here, we report a pro-regenerative role for reactive astrocytes and demonstrate that their sustained activation during the remyelination phase is essential for oligodendrocyte (OL) precursor cell (OPC) differentiation and myelin repair in a cuprizone (CPZ)-induced demyelination mouse model. Reanalysis of a single-cell transcriptomic atlas combined with in situ immunostaining further revealed the selective upregulation of chemokine C-X-C motif ligand 14 (CXCL14) in reactive astrocytes during remyelination—a finding corroborated in lysolecithin (LPC) mouse model and experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory demyelination model. In vitro, CXCL14 directly drives OPC differentiation into mature OLs by activating the extracellular signal-regulated kinases 1 and 2 (ERK1/2)-mediated mitogen-activated protein kinase (MAPK) signaling pathway, which is independent of its effects on OPC survival or proliferation. Notably, astrocyte‑specific
Cxcl14
knockdown abolished the pro‑differentiation activity of reactive astrocyte‑conditioned medium (ACM) in vitro and concurrently impaired remyelination in both the CPZ mouse model and EAE. Our findings reveal novel astrocyte–OPC crosstalk in pro-remyelination driven by CXCL14-dependent ERK1/2 signaling, highlighting CXCL14 as a promising therapeutic target for demyelinating diseases such as MS.

Thyroid hormones (THs) and transferrin (Tf) are factors capable of favoring myelination due to their positive effects on oligodendroglial cell (OLG) differentiation. The first notion of a combined effect of apotransferrin (aTf) and TH emerged from experiments conducted in young hyperthyroid animals, which showed a seven-fold increase in the expression of Tf mRNA and precocious myelination when compared with control animals. The mechanism underlying this phenomenon in young hyperthyroid rats could consist of an increase in Tf synthesis, which in the CNS is almost exclusively produced by OLG. Overall, our results show that, during the initial stages of OLG differentiation, Tf synthesis triggers thyroid hormone receptor alpha 1 (TRα1) expression in the subventricular zone (SVZ) and promotes proliferating cells to become responsive to this trophic factor. Exposure to TH could then regulate Tf expression through TRα1 and promote the induction of thyroid hormone receptor beta (TRβ) expression, which mediates TH effects on myelination through the activation of final OLG differentiation. This regulation of the combined effects of Tf and THs implies that both factors are fundamental actors during oligodendrogenesis. GLIA 2016;64:1879-1891.

Myelination is a concerted mechanism tightly regulated in the brain. Although several factors are known to participate during this process, the complete sequence of events is far from being fully elucidated. Separate effects of apotransferrin (aTf) and thyroid hormone (TH) are well documented on rat myelin formation. TH promotes the maturation of oligodendrocyte progenitors (OPCs) into myelinating oligodendrocytes (OLGs), while aTf is able to induce the commitment of neural stem cells (NSCs) toward the oligodendroglial linage and favors OLG maturation. We have also demonstrated that Tf mRNA exhibited a seven-fold increase in hyperthyroid animals. These observations have led us to hypothesize that both factors may interplay during oligodendrogenesis. To assess the combined effects of aTf and TH on proper myelination in the rat brain, Tf expression and oligodendroglial maturation were evaluated at postnatal days 10 (P10) and 20 (P20) in several experimental groups. At P10, an up-regulation of both Tf mRNA and protein, as well as myelination, was found in hyperthyroid animals, while a decrease in Tf mRNA levels and myelin formation was detected in the hypothyroid group. At P20, no differences were found either in Tf mRNA or protein levels between hyperthyroid and control (Ctrol) rats, although differences in OLG differentiation remained. Also at P20, hypothyroid animals showed decreased Tf mRNA and protein levels accompanied with a less mature myelinating phenotype. Moreover, TH and aTf differentially regulate the expression of KLF9 transcription factor as well as TRα and TRβ at P10 and P20. Our results suggest that TH is necessary early in OLG development for aTf action, as exogenous aTf administration was unable to counteract the effect of low TH levels in the hypothyroid state in all the time points analyzed. Furthermore, the fact that hyperthyroidism induced an increase in Tf expression and aTf-dependent regulation of TRα strongly suggests that Tf could be involved in some of TH later effects on OLG maturation. Here we describe the possible relationship between TH and aTf and its implication in oligodendrogenesis.

Oligodendrocytes are the cells producing the myelin membrane around the axons in the central nervous system and, although apotransferrin (aTf) is required for oligodendrocyte differentiation, the underlying mechanisms are not fully understood. Fyn tyrosine kinase, a member of the Src family of proteins, has been shown to play an important role in myelination by up-regulating the expression of myelin basic protein; however, a molecular link between aTf and Fyn kinase signaling pathway during oligodendrocytes differentiation has not been established yet. Our aim was to investigate whether Fyn kinase, MEK/ERK and PI3K/Akt signaling pathways are required for aTf-stimulation of oligodendrocyte differentiation and also to determine if the transferrin receptor is involved in these mechanisms. Treatment of primary cultures of oligodendroglial precursor cells with aTf leads to Fyn kinase activation by a mechanism that involves transferrin receptor. In turn, Fyn kinase activation promotes MEK-mediated transient phosphorylation of ERK1/2. On the other hand, transferrin receptor internalization also produces rapid and sustained activation of Akt, which involves phosphatidylinositol 3-kinase (PI3K) activation. Finally, aTf incorporated through clathrin-mediated endocytosis increases myelin basic protein, F3-contactin and β-tubulin through Fyn/MEK/ERK pathways, as well as an activation of the PI3K/Akt pathway. Our results also demonstrate that the activation of the pathways necessary for oligodendroglial precursor cell maturation is dependent on AP2 recruitment onto the plasma membrane for clathrin-mediated endocytosis of transferrin receptor.

The current study presents two different approaches with a view to elucidating the interaction between thyroid hormones (TH) and apo-transferrin (aTf) and their role in myelination and remyelination. First, in vitro assays were conducted to determine the single and combined effects of aTf and triiodothyronine (T3) on oligodendroglial cell lineage proliferation and oligodendrocyte (OLG) maturation in primary cultures. Results revealed higher proliferation rates upon single aTf treatment but Control values upon T3 and aTf + T3 treatments. In addition, both aTf and T3 accelerated OLG maturation, with the greatest effects being exerted by combined aTf + T3 administration in terms of both myelin basic protein (MBP) expression and morphological complexity. Second, in vivo assays were carried out to establish single and combined effects of aTf and T3, as well as TH receptor (THR) inhibitor I-850, on remyelination following a CPZ-induced demyelination protocol. Results showed an increase in myelin deposition and the number of mature remyelinating OLG upon single treatments, but a synergic effect upon combined aTf + T3 treatment which was prevented by THR inhibition. It may be thus concluded that combined treatment yielded the most beneficial effects on OLG maturation parameters in vitro and remyelinating capacity in vivo when compared to single treatments. These findings may help explore the development of new target molecules in the treatment of demyelinating diseases.

Transferrin (Tf) has a major role in T cell activation and proliferation. Here, we investigated whether Tf exerts immunomodulatory effects on T cells and in development of T-cell driven experimental autoimmune encephalomyelitis (EAE). While treatment of concanavalin A-stimulated splenocytes with apotransferrin (ApoTf) did not affect release of IL-1β, TNF, IFN-γ, IL-17, IL-4, and IL-10, it markedly and dose-dependently down-regulated synthesis of IL-2 in these cells. ApoTf also inhibited IL-2 generation in purified CD3+ T cells and the effect was accompanied with down-regulation of MAPK p44/42 and NFκB signaling. Despite impeded IL-2 release, proliferation of splenocytes was not inhibited by ApoTf. Importantly, ApoTf ameliorated EAE in mice and significantly reduced ex vivo IL-2 production in proteolipid protein-specific lymphocytes. Thus ApoTf may be a promising beneficial agent for multiple sclerosis.

Oligodendroglial damage and demyelination are common pathological features characterizing white matter and neurodegenerative disorders. Identifying the signaling pathways involved in myelin repair through oligodendroglial progenitor maturation is essential for the development of new therapies. This article investigated the role of the Notch signaling pathway in CNS demyelination and apotransferrin-induced remyelination in a focal lysolecithin-induced demyelination model in rats. Notch was found activated in Nestin-expressing neural progenitor cells and in NG2-expressing oligodendroglial precursor cells in the subventricular zone and corpus callosum of lysolecithin-demyelinated rats. Notch activation seemed to be driven by Jagged1, which led to a high expression of downstream gene Hes5 in the subventricular zone of demyelinated rats. Apotransferrin injection induced remyelination, while the injection of the γ-secretase inhibitor reversed this effect. In addition, 24 h after apotransferrin injection, evidence showed Notch activation concomitantly with an increase in F3/contactin levels and the up-regulation of the myelin-associated glycoprotein gene in the subventricular zone and corpus callosum of demyelinated rats. Collected evidence supports the participation of both canonical and non-canonical Notch signaling pathways in demyelination/remyelination. Notch activation was found to trigger Hes5 expression as a consequence of focal demyelination, which might promote oligodendroglial precursor cell proliferation. During apotransferrin-induced remyelination, Notch activation seemed to be mediated by the expression of F3/contactin, which might induce apotransferrin-mediated oligodendroglial maturation. Evidence of the participation of Notch signaling in the demyelination/remyelination process will help further understand demyelinating disorders such as Multiple Sclerosis and the use of aTf should be taken into consideration as a possible therapeutic intervention.

Twenty-one-day-old Wistar rats were fed a diet containing 0.6% cuprizone for 2 weeks. Studies carried out after withdrawal of cuprizone showed histological evidences of marked demyelination in the corpus callosum. Biochemical studies of isolated myelin showed a marked decrease in myelin proteins, phospholipids, and galactocerebrosides as well as a marked decrease in myelin yield. Treatment of these animals with a single intracranial injection of 350 ng of apotransferrin at the time of withdrawal of cuprizone induced a marked increase in myelin deposition resulting in a significantly improved remyelination, evaluated by histological, immunocytochemical, and biochemical parameters, in comparison to what was observed in spontaneous recovery. Immunocytochemical studies of cryotome sections to analyze developmental parameters of the oligodendroglial cell population at the time of termination of cuprizone and at different times thereafter showed that in the untreated animals, there was a marked increase in the number of NG2-BrdU-positive precursor cells together with a marked decrease in MBP expression at the peak of cuprizone-induced demyelination. As expected, the amount of precursor cells decreased markedly during spontaneous remyelination and was accompanied by an increase in MBP reactivity. In the apotransferrin-treated animals, these phenomena occurred much faster, and remyelination was much more efficient than in the untreated controls. The results of this study suggest that apotransferrin is a very active promyelinating agent which could be important for the treatment of certain demyelinating conditions.

Tolerogenic dendritic cell (tolDC) vaccines are a promising antigen-specific therapy for multiple sclerosis (MS), yet their efficacy is limited by poor homing to secondary lymphoid organs and rapid loss of the tolerogenic phenotype in native inflamed lymph nodes. Here, we developed a 3D-printed tolerogenic artificial lymph node (tol-aLN) that creates a protected immune niche for durable tolerance induction. tolDCs were loaded onto a porous gelatin methacrylate scaffold engineered for sustained C-C motif chemokine ligand 21 (CCL21) release, recruiting naïve CD4
+
T cells and shielding tolDCs from an inflammatory lymph node. Geometric optimization of an orthogonal lattice scaffold enhanced spatially confined DC–T cell interactions, promoting robust and stable induction of regulatory T cells (T
reg
cells). In experimental autoimmune encephalomyelitis (EAE), tol-aLN implantation attenuated disease even at advanced stages by inducing antigen-specific Foxp3
+
T
reg
cells that trafficked to the spleen, lymph nodes, and central nervous system (CNS). Conditional T
reg
cell depletion abolished therapeutic efficacy, indicating that T
reg
cells are necessary mediators of tol-aLN–induced protection. Long-term studies revealed sustained remission without impairing systemic immunity. In a myelin oligodendrocyte glycoprotein (amino acids 1 to 125) (MOG
1–125
)–induced EAE model, multivalent tol-aLN also efficiently suppressed inflammatory B cells and autoantibody production, reprogramming CNS B cells toward a regulatory state. Single-cell transcriptomics further revealed a global reduction in interferon-stimulated gene activity and restoration of homeostatic microglial phenotypes. Collectively, tol-aLN offers a scalable, antigen-specific platform for immune tolerance and CNS protection, with translational potential for MS and other autoimmune diseases.

Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established. Graphical Abstract

Eur J Pharmacol. 2026 Oct 6:179393. doi: 10.1016/j.ejphar.2026.179393. Online ahead of print.ABSTRACTTetanus toxoid (TT), a widely administered prophylactic immunogen, not only provides protection against tetanus but also exerts neuromodulatory effects, for which experimental evidence remains limited. In this study, we investigated the effect of TT on cognitive function in relation to hippocampal neurogenesis, myelination, key markers for neuroinflammation, oxidative stress and cell death in the brain of twelve-month-old mice. The treatment group exhibited higher levels of immunoglobulin gamma (IgG) and increased lymphocyte count in the blood sample. Results from the novel object recognition (NOR) test, cued radial arm maze (cued RAM), and Morris water maze (MWM) revealed that TT administration enhanced learning and memory in ageing mice. These cognitive improvements were associated with an increased number of doublecortin (DCX)-positive immature neurons and a higher proportion of bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive new neurons in the hippocampus. In addition, TT treatment resulted in enhanced myelination in the corpus callosum, hippocampal hilus and striatum as evidenced by increased intensity of luxol fast blue (LFB) staining and myelin basic protein (MBP) expression. Moreover, TT treatment induced a phenotypic shift in microglial phenotype from the pro-inflammatory M1 state to the neuroprotective M2 state. TT-treated animals showed a significant reduction in the levels of an oxidative stress marker, malondialdehyde (MDA), and a lower number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cells, suggesting that TT alleviates oxidative stress and prevents neuronal apoptosis. Overall, these findings demonstrate TT as a potential modulator of neuroregeneration, remyelination and neuroprotection, emphasizing its therapeutic potential for enhancing cognitive function.PMID:42838211 | DOI:10.1016/j.ejphar.2026.179393

Purpose Multiple sclerosis is a neuroinflammatory and demyelinating condition of brain with limited therapeutic options, many of which are associated with high treatment costs and adverse effects, In this research work, the neuroprotective potential of stigmasterol was investigated in a rat model of cuprizone-induced neuroinflammation and demyelination. Materials and methods A total of 36 Wistar rats (150–200 g) of both sexes were divided into 6 groups (n = 6) in random manner. Neuroinflammation and demyelination were induced by feeding animals a 0.3% cuprizone-containing diet for 5 weeks. Stigmasterol (100, 200, or 400 mg/kg/day) or dimethyl fumarate (15 mg/kg/day) was then administered orally for 3 weeks while cuprizone administration continued. After behavioral analysis, oxidative stress biomarkers, neurotransmitter levels, myelin-basic protein concentration by ELISA, mRNA expression of myelin basic protein and inflammatory cytokines, and histopathological alternations were evaluated. Results Cuprizone administration pointedly increased oxidative stress, impaired behavioral performances, induced marked histopathological alterations, reduced mRNA expression of MBP and the anti-inflammatory cytokines, and elevated expression of inflammatory cytokines. Compared with cuprizone group, stigmasterol treatment prominently improved cognitive and locomotor performance (P < 0.001), restored antioxidant status (P < 0.001), upregulated the mRNA expression of IL-4, IL-10 and MBP, downregulated expression of IL-1β, TNF-α and IL-6, and increased both neurotransmitter concentrations (P < 0.001) and MBP concentrations in a dose-dependent manner. The effects of dimethyl fumarate were comparable to those observed with the highest dose of stigmasterol. Conclusion Stigmasterol alleviated cuprizone-induced neuroinflammation, demyelination, oxidative stress and behavioral deficits while restoring MBP expression and modulating inflammatory cytokines expression. These results suggest that stigmasterol possesses neuroprotective and anti-inflammatory properties and warrants further investigation as an effective therapeutic candidate for demyelinating and neuroinflammatory disorders.

Autoimmune neurological diseases affecting the central nervous system, peripheral nervous system and neuromuscular junction are frequently refractory to conventional B-cell-depleting therapies such as CD20-directed monoclonal antibodies, highlighting a need for more effective treatment approaches. Chimeric antigen receptor T (CAR-T) cell therapy, initially developed for haematological malignancy, has been repurposed to more comprehensively deplete pathogenic B-cell and plasma cell populations in autoimmune disease, raising the possibility of durable, treatment-free remission. This scoping review, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-ScR guidelines, examined published clinical studies from January 2023 to January 2026 in which CAR-T cells targeting CD19, CD20 or B-cell maturation antigen were used to treat autoimmune neurological disease, identifying 19 eligible studies. Efficacy signals were most consistent in refractory acetylcholine receptor antibody-positive generalised myasthenia gravis and Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, with encouraging but more preliminary results reported in multiple sclerosis, Lambert-Eaton myasthenic syndrome, myelin oligodendrocyte glycoprotein antibody-associated disease, chronic inflammatory demyelinating polyneuropathy, stiff-person syndrome and autoimmune encephalitis. Relapse was reported across several conditions, with follow-up generally limited to under two years. The safety profile compared favourably with that seen in oncological CAR-T use, with lower rates of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, although cytopenias, infection and prolonged hypogammaglobulinaemia remain clinically significant, and local immune effector cell-associated toxicity syndrome is an emerging concern not yet formally reported in this population. Current evidence remains limited to small, largely uncontrolled studies with heterogeneous outcome reporting. Adequately powered, longer-term controlled trials are needed before CAR-T therapy can be recommended more broadly in the management of refractory autoimmune neurological disease.

Background
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease characterized by T lymphocyte infiltration and demyelination that can lead to severe disability without treatment. However, effective treatment for MS remains an unmet need. 2′-deoxyinosine (2′-DI), an endogenous nucleoside, has been implicated in tumorigenesis and immune regulation. This study was performed to investigate whether prophylactic 2′-DI intervention could prevent MS progression and elucidate its action mechanism.


Methods
2′-DI was administered to experimental autoimmune encephalomyelitis mice in vivo and cultured peripheral blood samples from MS patients in vitro, followed by pathological analysis, body weight monitoring, and disease severity assessment. Furthermore, RNA sequencing and serum metabolomics were conducted to explore the underlying regulatory mechanism of 2′-DI.


Results
Compared with healthy controls, MS patients exhibited significantly reduced 2′-DI levels in peripheral blood. Prophylactic administration of 2′-DI could prevent the progression of MS and mitigate inflammatory infiltration in the EAE mouse model. Immunomodulatory studies revealed that 2'-DI could decrease Th1 and Th17 cells, whereas increase Treg and Th2 cells. Moreover, 2′-DI could also promote the expression of anti-inflammatory cytokines and transcription factors while inhibiting the expression of pro-inflammatory cytokines and chemokines. Notably, 2′-DI intervention increased AMPK phosphorylation status, suggesting a potential association between elevated AMPK phosphorylation and the 2′-DI-mediated reversal of Th1/Th2 and Th17/Treg cell imbalance.


Conclusion
2′-DI may serve as a promising prophylactic candidate for MS by inhibiting central neuroinflammation and correcting peripheral and central Th1/Th2 and Th17/Treg immune imbalance, with its immunomodulatory effects potentially involving AMPK phosphorylation upregulation, thereby alleviating neuroinflammation and neurodegeneration.

Background
Demyelination and remyelination are critical processes in the pathogenesis of Alzheimer's disease (AD). The selective estrogen receptor modulator bazedoxifene (BZA) has been shown to promote remyelination, suggesting its potential therapeutic efficacy.


Objective
This study aimed to evaluate the therapeutic efficacy of BZA in addressing demyelination and associated cognitive deficits in a mouse model of AD.


Methods
The changes in myelin and oligodendrocyte-related indicators in the brains of APP/PS1 mice were assessed via immunostaining. 5 × FAD transgenic mice received oral administration of BZA or vehicle for 3 months. The therapeutic outcomes were evaluated through behavioral tests, immunostaining and western blotting.


Results
AD mice exhibited pronounced myelin loss and oligodendrocytes depletion. BZA treatment attenuated cognitive decline, restored myelin changes and mitigated neurodegeneration in the brain. These effects were observed independently of alterations in amyloid-β deposition.


Conclusions
These findings provide compelling evidence supporting the involvement of demyelination in AD and suggest that BZA may represent a promising therapeutic agent for AD by targeting myelin repair mechanisms.

Abstract

Objectives
To investigate the effects of naringenin on pathological, molecular, and behavioural alterations in a cuprizone-induced mouse model of demyelination, with particular emphasis on peroxisome proliferator-activated receptor (PPAR) gamma expression, NOD-like receptor family pyrin domain-containing 3 immunoreactivity, and molecular markers of myelin integrity, inflammation, and apoptosis.


Methods
Mice were allocated to four groups: control, naringenin alone, cuprizone, and cuprizone plus naringenin. Demyelination was induced with cuprizone-containing chow, and naringenin was administered orally for three weeks. Motor performance and biochemical, molecular, and histological changes were evaluated using established behavioural, immunological, molecular, and histological techniques.


Key findings
Naringenin improved motor deficits, increased myelin basic protein expression, reduced tumour necrosis factor-alpha, interleukin-1 beta, cyclooxygenase-2, prostaglandin E2, and nuclear factor kappa B p65 levels, and shifted apoptotic signalling towards cell survival by decreasing Bcl-2-associated X and increasing B-cell lymphoma 2 expression. Naringenin also increased PPAR gamma expression while reducing NOD-like receptor family pyrin domain-containing 3 immunoreactivity and suppressor of cytokine signalling 3 expression.


Conclusions
Naringenin attenuated cuprizone-induced brain inflammatory responses, apoptosis, and myelin injury, with findings consistent with modulation of PPAR gamma expression and NOD-like receptor family pyrin domain-containing 3-associated neuroinflammatory responses. These findings support further preclinical evaluation of naringenin for multiple sclerosis.