UNASSIGNED: Neuroplasticity as a mechanism to overcome central nervous system injury resulting from different neurological diseases has gained increasing attention in recent years. However, deficiency of these repair mechanisms leads to the accumulation of neuronal damage and therefore long-term disability. To date, the mechanisms by which remyelination occurs and why the extent of remyelination differs interindividually between multiple sclerosis patients regardless of the disease course are unclear. A member of the neurotrophins family, the brain-derived neurotrophic factor (BDNF) has received particular attention in this context as it is thought to play a central role in remyelination and thus neuroplasticity, neuroprotection, and memory.
UNASSIGNED: To analyse the current literature regarding BDNF in different areas of multiple sclerosis and to provide an overview of the current state of knowledge in this field.
UNASSIGNED: To date, studies assessing the role of BDNF in patients with multiple sclerosis remain inconclusive. However, there is emerging evidence for a beneficial effect of BDNF in multiple sclerosis, as studies reporting positive effects on clinical as well as MRI characteristics outweighed studies assuming detrimental effects of BDNF. Furthermore, studies regarding the Val66Met polymorphism have not conclusively determined whether this is a protective or harmful factor in multiple sclerosis, but again most studies hypothesized a protective effect through modulation of BDNF secretion and anti-inflammatory effects with different effects in healthy controls and patients with multiple sclerosis, possibly due to the pro-inflammatory milieu in patients with multiple sclerosis. Further studies with larger cohorts and longitudinal follow-ups are needed to improve our understanding of the effects of BDNF in the central nervous system, especially in the context of multiple sclerosis.

BACKGROUND: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated.
METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination.
RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway.
CONCLUSIONS: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.

Niacin was found in the lysolecithin model of multiple sclerosis (MS) to promote the phagocytic clearance of debris and enhance remyelination. Lysolecithin lesions have prominent microglia/macrophages but lack lymphocytes that populate plaques of MS or its experimental autoimmune encephalomyelitis (EAE) model. Thus, the current study assessed the efficacy of niacin in EAE. We found that niacin inconsistently affects EAE clinical score, and largely does not ameliorate neuropathology. In culture, niacin enhances phagocytosis by macrophages, but does not reduce T cell proliferation. We suggest that studies of niacin for potential remyelination in MS should include a therapeutic that targets adaptive immunity.

Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.

Multiple sclerosis is a chronic inflammatory demyelinating disorder of the CNS characterized by continuous myelin damage accompanied by deterioration in functions. Clobetasol propionate (CP) is the most potent topical corticosteroid with serious side effects related to systemic absorption. Previous studies introduced CP for remyelination without considering systemic toxicity. This work aimed at fabrication and optimization of double coated nano-oleosomes loaded with CP to achieve brain targeting through intranasal administration. The optimized formulation was coated with lactoferrin and chitosan for the first time. The obtained double-coated oleosomes had particle size (220.07 ± 0.77 nm), zeta potential (+30.23 ± 0.41 mV) along with antioxidant capacity 9.8 μM ascorbic acid equivalents. Double coating was well visualized by TEM and significantly decreased drug release. Three different doses of CP were assessed in-vivo using cuprizone-induced demyelination in C57Bl/6 mice. Neurobehavioral tests revealed improvement in motor and cognitive functions of mice in a dose-dependent manner. Histopathological examination of the brain showed about 2.3 folds increase in corpus callosum thickness in 0.3 mg/kg CP dose. Moreover, the measured biomarkers highlighted the significant antioxidant and anti-inflammatory capacity of the formulation. In conclusion, the elaborated biopolymer-integrating nanocarrier succeeded in remyelination with 6.6 folds reduction in CP dose compared to previous studies.

The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.

The research aims to study the therapeutic impact of HEK293-XPack-Olig2 cell-derived exosomes on remyelination of the corpus callosum in a cuprizone-induced demyelinating disease model. A lentiviral vector expressing Olig2 was constructed using XPack technology. The highly abundant Olig2 exosomes (ExoOs) were isolated by centrifugation for subsequent experiments. Western blot, nanoparticle tracking analysis (NTA), and electron microscopy showed no significant difference in particle size and morphology between Exos and ExoOs, and a high level of Olig2 expression could be detected in ExoOs, indicating that exosome modification by XPack technology was successful. The Black Gold/Fluromyelin staining analysis showed that the ExoOs group significantly reduced the demyelination area in the corpus callosum compared to the PBS and Exos groups. Additionally, the PDGFRα/APC staining of the demyelinating region revealed an increase in APC+ oligodendrocytes and a decrease in PDGFRα+ oligodendrocyte progenitor cells (OPCs) in the ExoOs group. Furthermore, there was evident myelin regeneration in the demyelinated areas after ExoOs treatment, with better g-ratio and a higher number of intact myelin compared to the other treatment groups. The level of Sox10 expression in the brain tissue of the ExoOs group were higher compared to those of the PBS and Exos groups. The demyelination process can be significantly slowed down by the XPack-modified exosomes, the differentiation of OPCs promoted, and myelin regeneration accelerated under pathological conditions. This process is presumed to be achieved by changing the expression level of intracellular differentiation-related genes after exosomes transport Olig2 enriched into oligodendrocyte progenitors.

White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the regulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression, and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI.

OBJECTIVE: Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T-MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months.
METHODS: Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0-2)] underwent 3 Tesla-MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3-dimensional (3D)-segmented echo-planar-imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow-up were computed using high-resolution 3D T1-weighted images.
RESULTS: Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty-four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM-iso-/hypo-intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM-hyperintense WMLs showed a positive correlation with total brain volume reduction at follow-up (r = 0.705; p =  .02). No lesion was classified as different between baseline and follow-up.
CONCLUSIONS: Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso-/hypo-intense lesions was found, which could account for the higher remyelination potential in pediatric MS.