Recurrent simultaneous central nervous system demyelination with possible peripheral demyelination / nodopathy in a seronegative patient.

Combined central and peripheral demyelination (CCPD) is a rare disease entity. Onset with the simultaneous central nervous system (CNS) and peripheral nervous system (PNS) involvement and its recurrence are exceptional. Anti-neurofascin antibodies have been shown to be present in up to 70% of cases, yet seronegative patients also exist. We present a case of seronegative recurrent CCPD. The PNS involvement was compatible with two episodes of recurrent Guillain-Barre syndrome (GBS), whereas the CNS involvement pattern was not typical for either multiple sclerosis (MS) or acute disseminated encephalomyelitis. The prognosis was excellent with pulse methylprednisolone, intravenous immunoglobulin, and plasmapheresis. This case highlights the varied clinical presentations of CCPD, extending beyond the realms of MS and chronic inflammatory demyelinating polyneuropathy, and underscores the potential for relapse. Importantly, to the best of our knowledge, this represents the inaugural instance of CCPD featuring PNS involvement in the form of recurrent GBS.

Compensatory changes after spinal cord injury in a remyelination deficient mouse model.

The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury-induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3-month-old mice. The present analysis investigated two potential mechanisms by which animals can re-establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage-gated sodium channel, a sub-type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI.

Sox2-mediated transdifferentiation of hAT-MSCs into induced neural progenitor-like cells for remyelination therapies.

Mesenchymal stem cells (MSCs) are converted to neural cells using growth factors and chemicals. Although these neural cells are effective at modulating disease symptoms, they are less effective at replacing lost neural cells. Direct transdifferentiation seems to be a promising method for generating the required cells for regenerative medicine applications. Sox2 is a key transcription factor in neural progenitor (NP) fate determination and has been frequently used for transdifferentiating different cell types to NPs. Here, we demonstrated that the overexpression of a single transcription factor, Sox2, in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) led to the generation of induced NPs-like cells that were clonogenic, proliferative and passageable, and showed the potential to differentiate into three neural lineages. NPs are known as progenitors with the potential to differentiate into oligodendrocytes. In vivo, following transplantation into demyelinated adult mouse brains, they survived, differentiated and integrated into the adult brain while participating in the remyelination process and behavioral improvement. This report introduces a beneficial, low-cost and effective approach for generating NPs from an accessible adult source for autologous applications in treating neurodegenerative diseases, including remyelination therapies for multiple sclerosis and other demyelinating diseases.

Risk Factors for Overly Rapid Correction in Patients with Profound Hyponatremia: A Retrospective Cohort Study.

Objective Overly rapid correction of profound hyponatremia can lead to osmotic demyelination syndrome; however, the incidence of and risk factors for overly rapid correction in patients with profound hyponatremia have not been thoroughly examined. Therefore, this study examined the incidence of and risk factors for overly rapid correction in patients with profound hyponatremia. Methods This single-center, retrospective cohort study conducted at an 865-bed teaching hospital analyzed data from 144 new inpatients with profound hyponatremia (initial serum sodium [Na+] level of <125 mEq/L) treated in our department between January 2014 and December 2022. Overly rapid correction was defined as serum Na+ correction of >10 mEq/L at 24 h. We examined the incidence of and risk factors for overly rapid correction.Results Thirty (20.8%) patients met the overly rapid correction criteria; however, none developed osmotic demyelination syndrome. A low initial serum Na+ level, female sex, primary polydipsia, and low frequency of follow-up in 24 h were significant independent risk factors for overly rapid correction in the multivariable analysis (p=0.020, p=0.011, p=0.014, and p=0.025, respectively). Conclusion Our study shows that a low initial serum Na+ level, female sex, primary polydipsia, and low frequency of follow-up within 24 h are associated with an increased risk for overly rapid correction of profound hyponatremia. Therefore, we suggest that physicians perform careful management when managing patients with profound hyponatremia with the risk factors for overly rapid correction identified in this study.

Acute Hemorrhagic Leukoencephalitis in a Patient With Hepatitis B.

Acute hemorrhagic leukoencephalitis (AHLE), also known as Weston-Hurst syndrome or Hurst disease, is a rare and rapidly progressive form of acute disseminated encephalomyelitis. It is characterized by severe inflammation, hemorrhage, and necrosis within the white matter of the brain. AHLE often follows an upper respiratory infection or other systemic illnesses, suggesting a potential post-infectious autoimmune mechanism. The disease is associated with a high mortality rate and significant disability among survivors. We present the case of a 46-year-old Indian woman with a history of chronic hepatitis B (HBV) who presented with an insidious onset of right-sided limb weakness and bi-frontal headaches. Initial brain MRIs showed features of tumefactive demyelination. Despite aggressive treatment with intravenous (IV) methylprednisolone, IV immunoglobulin, and anti-edema measures, the patient's condition rapidly deteriorated, leading to a diagnosis of AHLE following the emergence of hemorrhagic white matter lesions on repeat MRI. Remarkably, with continued treatment, the patient survived and showed gradual neurological improvement, although she remained significantly debilitated at the time of discharge. AHLE represents one of the most severe forms of demyelinating diseases, often resulting in rapid neurological decline and high mortality. This case highlights the potential link between chronic HBV infection with a high viral load and the onset of AHLE. The patient's recovery underscores the importance of early recognition and aggressive treatment in improving outcomes, even in conditions with traditionally poor prognosis. Clinicians should maintain a high index of suspicion for AHLE in patients with chronic viral infections presenting with neurological symptoms. Prompt and aggressive management can be life-saving, and ongoing research is needed to better understand the pathogenesis and optimal treatment strategies for this rare but devastating condition.

Characteristics of anti-contactin1 antibody positive autoimmune nodopathies combined with membranous nephropathy.

BACKGROUND: Autoimmune nodopathy (AN) is a very rare new disease entity, especially when combined with membranous nephropathy (MN). METHODS: Antibodies against nodal-paranodal cell adhesion molecules in the serum were detected using cell-based assays. Antibody subtypes against contactin-1 (CNTN1) were confirmed. Cases of anti-CNTN1 antibody-positive AN with and without MN were retrieved through a literature search to compare clinical and electrophysiological characteristics. RESULTS: A 65-year-old male patient with MN developed limb numbness and weakness, along with walking instability. Serum CNTN1 antibodies were positive, primarily those of the IgG4 subtype. Electromyography showed prominent demyelination patterns in both the proximal and distal segments of the nerves compared to the middle nerve trunk. Magnetic resonance imaging revealed enlargement of the bilateral brachial and lumbosacral plexuses and local hyperintensity of the right C5-C6 nerve roots. Thirty-five cases with anti-CNTN1 antibody-positive AN with MN and 51 cases with anti-CNTN1 antibody-positive AN without MN were compared. Furthermore, the proportion of patients with MN combined with AN presenting with acute or subacute onset was higher than that observed in the MN without AN group. Nevertheless, no substantial differences were noted between the two groups concerning the clinical and electrophysiological characteristics, which were mainly elderly men, manifested as sensory ataxia, IgG4 antibody subtype, electrophysiological demyelination, and a certain effect on immunotherapy. CONCLUSION: In cases of electrophysiological manifestation of demyelinating peripheral neuropathy, especially in distal and poximal segments of nerves, AN should be considered, and further screening for renal function should be performed. Concomitant MN does not aggravate or alleviate peripheral nerve symptoms.

Clinical Problem-Solving: A 19-Year-Old Woman With Progressive Neurological Decline and Multiple Intracranial Lesions.

The differential diagnosis for multiple intracranial lesions in a young adult is broad and includes demyelinating, neoplastic, and infectious etiologies. In this report, we describe the case of a 19-year-old immunocompetent woman presenting with progressive headaches and aphasia. MRI of the brain revealed multiple, large supratentorial lesions with concentric bands of alternating T2 signal intensities and peripheral contrast enhancement. Cerebrospinal fluid (CSF) analysis was overall bland with negative oligoclonal bands. Serum antibody testing for neuromyelitis optica (NMO) and myelin-oligodendrocyte associated disease (MOGAD) were negative. A broad infectious work-up was also unrevealing. A definitive diagnosis was ultimately obtained after brain biopsy and the patient was started on appropriate therapy. This case highlights a diagnostic framework in evaluating immunocompetent patients presenting with multiple intracranial lesions and progressive neurological decline. The main differential diagnoses for this constellation of radiological and clinical findings are discussed and a literature review is performed on the revealed diagnosis. Lastly, both acute and long-term therapeutic approaches are reviewed.

The Initial Clinical and Electrophysiological Characteristics of Different Subtypes of Guillain-Barré Syndrome Diagnosed Based on Serial Electrophysiological Examinations.

BACKGROUND: We aimed to identify different Guillain-Barré syndrome (GBS) subtypes, demyelination, axonal degeneration, and reversible conduction failure (RCF) as early as possible by analyzing the initial clinical and electrophysiological examinations. METHODS: This study retrospectively collected GBS patients between October 2018 and December 2022 at Beijing Tiantan Hospital. The diagnostic criteria for the initial electrophysiological study were based on Rajabally's criteria, and the criteria for the serial electrophysiological study were based on Uncini's criteria. All subjects underwent clinical and electrophysiological evaluations at least twice within 8 weeks. RESULTS: A total of 47 eligible patients with GBS were included, comprising 19 acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 18 axonal degenerations, and 10 RCFs. In the RCF group, 40%, 30%, and 30% patients were diagnosed as AIDP, axonal, and equivocal at the initial study, respectively. The AIDP group had significantly higher cerebrospinal fluid (CSF) protein than the RCF (123.8 [106.4, 215.1] mg/dL vs. 67.1 [36.8, 85.6] mg/dL, p = 0.002) and axonal degeneration (123.8 [106.4, 215.1] mg/dL vs. 60.8 [34.8, 113.0] mg/dL, p < 0.001) groups. The RCF group had significantly lower Hughes functional grades at admission (3 [2, 4] vs. 4 [4, 4], p = 0.012) and discharge (1.0 [1.0, 2.0] vs. 3.0 [2.0, 3.0], p < 0.001) than the axonal degeneration group and showed significantly shorter distal motor latency (DML), Fmin, Fmean, Fmax, and lower F% than the AIDP group (p < 0.05). DISCUSSION: The early identification of RCF from AIDP had relatively obvious features, including slightly elevated CSF protein levels and normal or slightly prolonged DML and F-wave latencies, contrasting with the apparent elevation and prolongation seen in AIDP. Differentiating RCF from axonal degeneration remains challenging. One potential distinguishing factor is that the motor function in RCF tends to be better than in the latter.

Tumefactive Multiple Sclerosis: The Lethal Chameleon.

Tumefactive multiple sclerosis (TMS) is a rare variant of multiple sclerosis that presents with a large demyelinating lesion in the central nervous system, accompanied by peripheral ring-like enhancement, perilesional oedema and mass effect. We report a case of a 59-year-old woman who was admitted to the hospital with a four-day history of somnolence, muscle weakness in her left extremities and ultimately, loss of consciousness. Over the following 48 hours, the patient's condition worsened with progressive consciousness impairment. Although the results of the initial head computed tomography (CT) scan supported the diagnosis of a multifocal ischaemic stroke, toxoplasmosis was proposed as the most credible diagnostic hypothesis by brain magnetic resonance imaging (MRI). Due to the adverse clinical progression following the initiation of targeted therapy and inconclusive investigation, a brain biopsy was performed, which was indicative of active TMS in a subacute phase. The patient was started on plasmapheresis and natalizumab along with corticosteroids, with a very good response. In conclusion, we report a biopsy-proven TMS diagnosis in a patient that clinically mimicked an acute stroke and was radiographically confounded with intracranial toxoplasmosis. It highlights that TMS is an uncommon neurological demyelinating disease that is often misdiagnosed. It also emphasises the importance of establishing an accurate differential diagnosis to promptly initiate aggressive immunosuppressive treatment, which may result in a more favourable prognosis. LEARNING POINTS: Tumefactive multiple sclerosis is an uncommon variant of multiple sclerosis that presents a substantial diagnostic challenge due to its potential to resemble the clinical and radiological characteristics of other central nervous system (CNS) pathologies, including neoplasms, granulomatous diseases, abscesses and vasculitis.Despite the fact that multimodal imaging studies may help narrow the differential diagnosis, a biopsy is often required to reach a definitive diagnosis and should not be delayed.Awareness of this condition among non-neurologists is critical since a timely and accurate diagnosis prompts aggressive immunomodulatory treatments that may delay a second demyelinating event or progression to clinically definite multiple sclerosis.

Neurotropic Murine ß-Coronavirus Infection Causes Differential Expression of Connexin 47 in Oligodendrocyte Subpopulations Associated with Demyelination.

Gap junctions (GJs) play a crucial role in the survival of oligodendrocytes and myelination of the central nervous system (CNS). In this study, we investigated the spatiotemporal changes in the expression of oligodendroglial GJ protein connexin 47 (Cx47), its primary astroglial coupling partner, Cx43, and their association with demyelination following intracerebral infection with mouse hepatitis virus (MHV). Neurotropic strains of MHV, a ß-coronavirus, induce an acute encephalomyelitis followed by a chronic demyelinating disease that shares similarities with the human disease multiple sclerosis (MS). Our results reveal that Cx47 GJs are persistently lost in mature oligodendrocytes, not only in demyelinating lesions but also in surrounding normal appearing white and gray matter areas, following an initial loss of astroglial Cx43 GJs during acute infection. At later stages after viral clearance, astroglial Cx43 GJs re-emerge but mature oligodendrocytes fail to fully re-establish GJs with astrocytes due to lack of Cx47 GJ expression. In contrast, at this later demyelinating stage, the increased oligodendrocyte precursor cells appear to exhibit Cx47 GJs. Our findings further highlight varying degrees of demyelination in distinct spinal cord regions, with the thoracic cord showing the most pronounced demyelination. The regional difference in demyelination correlates well with dynamic changes in the proportion of different oligodendrocyte lineage cells exhibiting differential Cx47 GJ expression, suggesting an important mechanism of progressive demyelination even after viral clearance.

Glutamate chemical exchange saturation transfer (GluCEST) MRI to evaluate the relationship between demyelination and glutamate content in depressed mice.

Glutamatergic alteration is one of the potential mechanisms of depression. However, there is no consensus on whether glutamate metabolism changes affect the myelin structure of depression in mouse models. Glutamate chemical exchange saturation transfer (GluCEST) is a novel and powerful molecular imaging technique that can visualize glutamate distribution. In this study, we used the GluCEST imaging technique to look at glutamate levels in mice under chronic unpredictable mild stress (CUMS) and how they relate to demyelination. The CUMS mice were exposed to different stress factors for 6 weeks. Evaluated of depression in CUMS mice by behavioral tests. MRI scans were then performed, including T2-mapping, GluCEST, and diffusion tensor imaging (DTI) sequences. Brain tissues were collected for Luxol Fast Blue staining and immunofluorescence staining to analyze the changes in the myelin sheath. Artificially sketched regions of interest (ROI) (corpus callosum, hippocampus, and thalamus) were used to calculate the GluCEST value, fractional anisotropy (FA), and T2 value. Compared with the control group, the GluCEST value in the ROIs of CUMS mice significantly decreased. Similarly, the FA value in ROIs was lower in the CUMS group than in the CTRL group, but the T2 value did not differ significantly between the two groups. The histological results showed that ROIs in the CUMS group had demyelination compared with the CTRL group, indicating that DTI was more sensitive than T2 mapping in detecting myelin abnormalities. Furthermore, the GluCEST value in the ROIs correlates positively with the FA value. These findings suggest that altered glutamate metabolism may be one of the important factors leading to demyelination in depression, and GluCEST is expected to serve as an imaging biological marker for the diagnosis of demyelination in depression.

Effects of long-term magnesium L-threonate supplementation on neuroinflammation, demyelination and blood-brain barrier integrity in mice with neuromyelitis optica spectrum disorder.

In clinical practice, we found cerebrospinal fluid magnesium concentration significantly lower in neuromyelitis optica spectrum disorder (NMOSD) patients compared to controls with non-autoimmune encephalitis neurological diseases. To investigate the effects and potential mechanisms of long-term magnesium supplementation on neuroinflammation, demyelination, and blood-brain barrier (BBB) integrity in NMOSD, we used two models: (1) NMOSD mouse model, which was induced by intraperitoneal injection of purified NMO-IgG to experimental autoimmune encephalomyelitis (EAE) mice, and (2) cultured human cerebral microvascular endothelial cells/D3 (hCMEC/D3). In the NMOSD mouse model, Magnesium L-threonate (MgT) pretreatment alleviated NMO-IgG-induced effects, including AQP4 loss, leukocyte infiltration, astrocyte and microglia activation, demyelination, decreased tight junction (TJ) protein expression, and neurological deficits. In vitro, MgT pretreatment ameliorated NMO-IgG induced damage to TJ protein expression in a (transient receptor potential melastatin 7) TRPM7-dependent manner. Magnesium supplementation shows potential protective effects against NMOSD, suggesting it may be a novel therapeutic approach for this condition. The beneficial effects appear to be mediated through preservation of blood-brain barrier integrity and reduction of neuroinflammation and demyelination.

Transcranial direct current stimulation as a potential remyelinating therapy: Visual evoked potentials recovery in cuprizone demyelination.

AIMS: Non-invasive neuromodulation by transcranial direct current stimulation (tDCS), owing to its reported beneficial effects on neuronal plasticity, has been proposed as a treatment to promote functional recovery in several neurological conditions, including demyelinating diseases like multiple sclerosis. Less information is available on the effects of tDCS in major pathological mechanisms of multiple sclerosis, such as demyelination and inflammation. To learn more about the latter effects, we applied multi-session anodal tDCS in mice exposed to long-term cuprizone (CPZ) diet, known to induce chronic demyelination. METHODS: Visual evoked potentials (VEP) and motor performance (beam test) were employed for longitudinal monitoring of visual and motor pathways in 28 mice undergoing CPZ diet, compared with 12 control (H) mice. After randomization, anodal tDCS was applied for 5 days in awake, freely-moving surviving animals: 12 CPZ-anodal, 10 CPZ-sham, 5H-anodal, 5 h-sham. At the end of the experiment, histological analysis was performed on the optic nerves and corpus callosum for myelin, axons and microglia/macrophages. KEY FINDINGS: CPZ diet was associated with significantly delayed VEPs starting at 4 weeks compared with their baseline, significant compared with controls at 8 weeks. After 5-day tDCS, VEPs latency significantly recovered in the active group compared with the sham group. Similar findings were observed in the time to cross on the beam test Optic nerve histology revealed higher myelin content and lower microglia/macrophage counts in the CPZ-Anodal group compared with CPZ-Sham. SIGNIFICANCE: Multiple sessions of anodal transcranial direct current stimulation (tDCS) in freely moving mice induced recovery of visual nervous conduction and significant beneficial effects in myelin content and inflammatory cells in the cuprizone model of demyelination. Altogether, these promising findings prompt further exploration of tDCS as a potential therapeutic approach for remyelination.

Neuropathology of white matter disorders.

The hallmark neuropathologic feature of all leukodystrophies is depletion or alteration of the white matter of the central nervous system; however increasing genetic discoveries highlight the genetic heterogeneity of white matter disorders. These discoveries have significantly helped to advance the understanding of the complexity of molecular mechanisms involved in the biogenesis and maintenance of healthy white matter. Accordingly, genetic discoveries and functional studies have enabled us to firmly establish that multiple distinct structural defects can lead to white matter pathology. Leukodystrophies can develop not only due to defects in proteins essential for myelin biogenesis and maintenance or oligodendrocyte function, but also due to mutations encoding myriad of proteins involved in the function of neurons, astrocytes, microglial cells as well as blood vessels. To a variable extent, some leukodystrophies also show gray matter, peripheral nervous system, or multisystem involvement. Depending on the genetic defect and its role in the formation or maintenance of the white matter, leukodystrophies can present either in early childhood or adulthood. In this chapter, the classification of leukodystrophies will be discussed from the cellular defect point of view, followed by a description of known neuropathologic alterations for all leukodystrophies.

Intensive Care Management of Severe Hyponatraemia-An Observational Study.

Background and Subject: Hyponatraemia is a common electrolyte disorder. For patients with severe hyponatraemia, intensive care unit (ICU) admission may be required. This will enable close monitoring and allow safe management of sodium levels effectively. While severe hyponatraemia may be associated with significant symptoms, rapid overcorrection of hyponatraemia can lead to complications. We aimed to describe the management and outcomes of severe hyponatraemia in our ICU and identify risk factors for overcorrection. Materials and Methods: This was a retrospective single-centre cohort that included consecutive adults admitted to the ICU with serum sodium < 120 mmol/L between 1 January 2017 and 8 March 2023. Anonymised data were collected from electronic records. We included 181 patients (median age 67 years, 51% male). Results: Median admission serum sodium was 113 mmol/L (IQR: 108-117), with an average rate of improvement over the first 48 h of 10 mmol/L/day (IQR: 5-15 mmol/L). A total of 62 patients (34%) met the criteria for overcorrection at 48 h, and they were younger, presented with severe symptoms (seizures/arrythmias), and had lower admission sodium concentration. They were more likely to be treated with hypertonic saline infusions. Lower admission sodium was an independent risk factor for overcorrection within 48 h, whereas the presence of liver cirrhosis and fluid restriction was associated with normal correction. No difference was identified between the normal and overcorrected cohorts for ICU/hospital length of stay or mortality. Conclusions: In some patients with severe hyponatraemia, overcorrection is inevitable to avoid symptoms such as seizures and arrhythmias, and consequently, we highlight the key factors associated with overcorrection. Overall, we identified that overcorrection was common and concordant with the current literature.

Systematic review of photobiomodulation for multiple sclerosis.

Background: Multiple sclerosis (MS) is an inflammatory chronic autoimmune and neurodegenerative disorder of the brain and spinal cord, resulting in loss of motor, sensorial, and cognitive function. Among the non-pharmacological interventions for several brain conditions, photobiomodulation (PBM) has gained attention in medical society for its neuroprotective effects. We systematically reviewed the effects of PBM on MS. Methods: We conducted a systematic search on the bibliographic databases (PubMed and ScienceDirect) with the keywords based on MeSH terms: PBM, low-level laser therapy, multiple sclerosis, autoimmune encephalomyelitis, demyelination, and progressive multiple sclerosis. Data search was limited from 2012 to July 2024. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The initial systematic search identified 126 articles. Of these, 68 articles were removed by duplicity and 50 by screening. Thus, 8 studies satisfied the inclusion criteria. Results: The reviewed studies showed that PBM modulates brain markers linked to inflammation, oxidative stress, and apoptosis. Improvements in motor, sensorial, and cognitive functions in MS patients were also observed after PBM therapy. No study reported adverse effects of PBM. Conclusion: These findings suggest the potential of PBM as a promising non-pharmacological intervention for the management of MS, although further research is needed to standardize PBM protocols and assess its long-term effects.

Meningeal lymphatic function promotes oligodendrocyte survival and brain myelination.

The precise neurophysiological changes prompted by meningeal lymphatic dysfunction remain unclear. Here, we showed that inducing meningeal lymphatic vessel ablation in adult mice led to gene expression changes in glial cells, followed by reductions in mature oligodendrocyte numbers and specific lipid species in the brain. These phenomena were accompanied by altered meningeal adaptive immunity and brain myeloid cell activation. During brain remyelination, meningeal lymphatic dysfunction provoked a state of immunosuppression that contributed to delayed spontaneous oligodendrocyte replenishment and axonal loss. The deficiencies in mature oligodendrocytes and neuroinflammation due to impaired meningeal lymphatic function were solely recapitulated in immunocompetent mice. Patients diagnosed with multiple sclerosis presented reduced vascular endothelial growth factor C in the cerebrospinal fluid, particularly shortly after clinical relapses, possibly indicative of poor meningeal lymphatic function. These data demonstrate that meningeal lymphatics regulate oligodendrocyte function and brain myelination, which might have implications for human demyelinating diseases.

Effects of aerobic exercise on demyelination and brain morphology in the cuprizone rat model of multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that led to brain atrophy. The purpose of this study was to investigate the effects of pre-and post-conditioning with exercise on demyelination and brain morphology. Thirty male rats were randomly divided into five groups (n = 6 per group), consisting of a healthy control group (Control), an MS group, and three exercise groups: the group that performed the exercise protocol (running on a treadmill 5 days/week for 6 weeks) before the MS induction (EX + MS), the group that performed the exercise protocol during the MS induction (MS + EX), and the group that performed the exercise protocol before and during the MS induction (EX + MS + EX). The expression of Myelin basic protein (MBP), and demyelination in the corpus callosum and the volume, weight, length, width, and height of the brain were measured. The EX + MS + EX showed a significant increase in the expression of MBP compared to other MS groups (**p < 0.01) as well as a significant decrease in the area of demyelination of the corpus callosum compared to MS and MS + EX groups (**p < 0.01). However, there were no significant differences between the MS group and exercised groups for brain morphology. The exercise showed neuroprotective effects, as evidenced by decreased areas of demyelination and improved MBP expression.

Inhibition of GZMB activity ameliorates cognitive dysfunction by reducing demyelination in diabetic mice.

BACKGROUND: Diabetic cognitive dysfunction (DCD) has attracted increased attention, but its precise mechanism remains to be explored. Oligodendrocytes form myelin sheaths that wrap around axons. Granzyme B (GZMB) can cause axonal degeneration of the central nervous system. However, the role of GZMB in diabetic cognitive dysfunction (DCD) has not been reported. This study aimed to investigate whether GZMB promotes demyelination and participates in DCD by regulating the endoplasmic reticulum stress function of oligodendrocytes. METHODS: Streptozotocin was injected intraperitoneally to establish a diabetic model in C57BL/6 mice. The mice were randomly divided into four groups: control group, diabetic group, diabetic + SerpinA3N group, and diabetic + saline treatment group. We performed the Morris water maze test to assess the learning and memory abilities of the mice. An immunofluorescence assay was performed to detect the expression sites of GZMB and OLIG2 in the hippocampal CA1 region. Luxol Fast Blue staining and electron microscopy were performed to detect the myelin number and myelin plate densities. Immunohistochemistry was used to detect the expression levels of MBP and CNPase. Protein blotting was used to assess the expression levels of GZMB, PERK, p-PERK, eIF2α, p-eIF2α, NLRP3, Caspase-1, GSDMD-N, IL-1ß, and IL-18 as well as MBP and CNPase. RESULTS: The GZMB inhibitor SerpinA3N reduces escape latency and increases the traversing platforms and residence time in the target area, improving DCD in mice. It also reduces endoplasmic reticulum stress in hippocampal oligodendrocytes and focal prolapse, further promoting MBP and CNPase expression and reducing demyelination. CONCLUSIONS: Our findings suggest that inhibition of GZMB activity modulates oligodendrocyte endoplasmic reticulum stress and pyroptosis, reduces demyelination, and ameliorates diabetes-related cognitive impairment.

Modulation of αv integrins by lebecetin, a viper venom-derived molecule, in experimental neuroinflammation and demyelination models.

Several neurodegenerative diseases, such as multiple sclerosis and Parkinson's disease, are linked to alterations in myelin content or structure. Transmembrane receptors such as integrins could be involved in these alterations. In the present study, we investigated the role of αv-integrins in experimental models of neuroinflammation and demyelination with the use of lebecetin (LCT), a C-lectin protein purified from Macrovipera lebetina viper venom, as an αv-integrin modulator. In a model of neuroinflammation, LCT inhibited the upregulation of αv, ß3, ß5, α5, and ß1 integrins, as well as the associated release of pro-inflammatory factor IL-6 and chemokine CXCL-10, and decreased the expression of phosphorylated NfκB. The subsequent "indirect culture" between reactive astrocytes and oligodendrocytes showed a down-regulation of αv and ß3 integrins versus upregulation of ß1 one, accompanied by a reduced expression of myelin basic protein (MBP). Treatment of oligodendrocytes with LCT rectified the changes in integrin and MBP expression. Through Western blot quantification, LCT was shown to upregulate the expression levels of PI3K and p-mTOR while downregulating expression levels of p-AKT in oligodendrocytes, suggesting the neuroprotective and pro-myelinating effects of LCT may be related to the PI3K/mTor/AKT pathway. Concomitantly, we found that LCT promoted remyelination by tracking the increased expression of MBP in the brains of cuprizone-intoxicated mice. These results point to an involvement of integrins in not only neuroinflammation but demyelination as well. Thus, targeting αv integrins could offer potential therapeutic avenues for the treatment of demyelinating diseases.