Myelin oligodendrocyte glycoprotein-associated transverse myelitis after SARS-CoV-2 infection: A case report.

BACKGROUND: Cases of myelin oligodendrocyte glycoprotein (MOG) antibody-related disease have a history of coronavirus disease 2019 infection or its vaccination before disease onset. Severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection has been considered to be a trigger of central nervous system autoimmune diseases. CASE SUMMARY: Here we report a 20-year male with MOG-associated transverse myelitis after a SARS-CoV-2 infection. The patient received a near-complete recovery after standard immunological treatments. CONCLUSION: Attention should be paid to the evaluation of typical or atypical neurological symptoms that may be triggered by SARS-CoV-2 infection.

Diverse functions of DEAD-box proteins in oligodendrocyte development, differentiation, and homeostasis.

Oligodendrocytes, a type of glial cell in the central nervous system, have a critical role in the formation of myelin around axons, facilitating saltatory conduction, and maintaining the integrity of nerve axons. The dysregulation of oligodendrocyte differentiation and homeostasis have been implicated in a wide range of neurological diseases, including dysmyelinating disorders (e.g., Pelizaeus-Merzbacher disease), demyelinating diseases (e.g., multiple sclerosis), Alzheimer's disease, and psychiatric disorders. Therefore, unraveling the mechanisms of oligodendrocyte development, differentiation, and homeostasis is essential for understanding the pathogenesis of these diseases and the development of therapeutic interventions. Numerous studies have identified and analyzed the functions of transcription factors, RNA metabolic factors, translation control factors, and intracellular and extracellular signals involved in the series of processes from oligodendrocyte fate determination to terminal differentiation. DEAD-box proteins, multifunctional RNA helicases that regulate various intracellular processes, including transcription, RNA processing, and translation, are increasingly recognized for their diverse roles in various aspects of oligodendrocyte development, differentiation, and maintenance of homeostasis. This review introduces the latest insights into the regulatory networks of oligodendrocyte biology mediated by DEAD-box proteins.

Quality of life in patients with myelin oligodendrocyte glycoprotein antibody associated disease compared to patients with AQP4-IgG positive neuromyelitis optica spectrum disorders: A Korean multicenter study.

BACKGROUND: Little is known about the quality of life (QOL) of patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We compared QOL and associated factors in patients with MOGAD and aquaporin4 IgG (AQP4-IgG) positive neuromyelitis optica spectrum disorder (NMOSD). METHODS: This multicenter questionnaire study compared the QOL of 41 patients with MOGAD and 78 with AQP4-IgG positive NMOSD. Patients who were positive for AQP4-IgG or MOG antibodies were included. WHO Quality of Life Scale Brief Version was used to assess QOL in physical, psychological, social, and environmental domains. QOL, sleep quality, pain, fatigue, and depression were compared between the two groups. The factors associated with QOL in each group and the entire cohort were analyzed. RESULTS: The proportion of patients with poor QOL was not significantly different between MOGAD (51.22 %) and AQP4-IgG positive NMOSD (58.97 %, p = 0.054). In the MOGAD group, the pain score (ß=-1.032, p = 0.001) and depression score (ß=-0.694, p = 0.007) were negatively associated with physical and psychological QOL, respectively. Sleep quality was negatively associated with physical (ß=-1.506, p = 0.034) and psychological (ß =-2.064, p = 0.033) QOL. When the entire cohort was analyzed, a positive MOG antibody was independently associated with worse psychological QOL (ß=-8.998, p = 0.013) compared to positive AQP4-Ab after adjustment for sleep quality, depression, fatigue, and pain. CONCLUSIONS: The overall QOL of the patients of MOGAD was comparable to that of AQP4-IgG positive NMOSD. Patients with MOGAD were experiencing sleep disorder, fatigue, and depression at similar degrees to those of patients with AQP4-IgG positive NMOSD. Further consideration of sleep quality and psychological QOL is required to improve QOL in patients with MOGAD.

Myelin water imaging of in vivo and ex vivo human brains using multi-echo gradient echo at 3 T and 7 T.

PURPOSE: To compare the myelin water fraction (MWF) measurements between 3 T and 7 T and between in vivo and ex vivo human brains, and to investigate the relationship between multi-echo gradient-echo (mGRE)-based 3D MWF and myelin content using histological staining, which has not been validated in the human brain. METHODS: In this study, we performed 3D mGRE-based MWF measurements on five ex vivo human brain hemispheres and five healthy volunteers at 3 T and 7 T with 1 mm isotropic resolution. The data were fitted with the T 2 * $$ {\mathrm{T}}_2^{\ast } $$ based on a three compartment complex-valued model to estimate MWF. We obtained myelin basic protein (MBP) staining from two tissue blocks and co-registered the MWF map and histology image for voxel-wise correlation between the two. RESULTS: The MWF values measured from 7 T were overall higher than 7 T, but data between the two field strength demonstrated high correlations both in vivo (r = 0.88) and ex vivo (r = 0.83) across 19 white matter regions. Moreover, the MWF measurements showed a good agreement between in vivo and ex vivo assessments at 3 T (r = 0.61) and 7 T (r = 0.54). Based on MBP staining, the MWF values exhibited strong positive correlations with myelin content on both 3 T (r = 0.68 and r = 0.78 for the two tissue blocks) and 7 T (r = 0.64 and r = 0.82 for the two tissue blocks). CONCLUSION: The findings demonstrated that the mGRE-based MWF mapping can be used to quantify myelin content in the human brain, despite the field-strength dependency of the measurements.

Nerve injury converts Schwann cells in a long-term repair-like state in human neuroma tissue.

Peripheral nerve injury (PNI) induces neuroma formation at the severed nerve stump resulting in impaired nerve regeneration and functional recovery in patients. So far, molecular mechanisms and cell types present in the neuroma impeding on regeneration have only sparsely been analyzed. Herein we compare resected human neuroma tissue with intact donor nerves from the same patient. Neuroma from several post-injury timepoints (1-13 months) were included, thereby allowing for temporal correlation with molecular and cellular processes. We observed reduced axonal area and percentage of myelin producing Schwann cells (SCs) compared to intact nerves. However, total SOX10 positive SC numbers were comparable. Notably, markers for SCs in a repair mode including c-JUN, the low-affinity neurotrophin receptor (NTR) p75, SHH (sonic hedgehog) and SC proliferation (phospho-histone H3) were upregulated in neuroma, suggesting presence of SCs in repair status. In agreement, in neuroma, pro-regenerative markers such as phosphorylated i.e. activated CREB (pCREB), ATF3, GAP43 and SCG10 were upregulated. In addition, neuroma tissue was infiltrated by several types of macrophages. Finally, when taken in culture, neuroma SCs were indistinguishable from controls SCs with regard to proliferation and morphology. However, cultured neuroma SCs retained a different molecular signature from control SCs including increased inflammation and reduced gene expression for differentiation markers such as myelin genes. In summary, human neuroma tissue consists of SCs with a repair status and is infiltrated strongly by several types of macrophages.

Aggressive Course of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): An Illustration of Two Cases and Review of Literature.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a central nervous system demyelinating disease that has become a major source of morbidity among children and adults. In the first case, we present an 18-year-old Hispanic female with a recently resolved upper respiratory infection who presented with fever, headache, progressive quadriparesis, urinary retention, and encephalopathy. The hospital course involved autonomic dysfunction and prolonged intubation requiring tracheostomy and gastrostomy. Cerebrospinal fluid (CSF) showed pleocytosis and a positive MOG titer (1:40). Magnetic resonance imaging (MRI) showed longitudinally extensive cervicothoracic T2 hyperintensity and brain multifocal T2 hyperintensities. After high-dose intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG), she had full neurological recovery by the last follow-up. The second case is of a 22-year-old Hispanic male who presented with progressive lower extremity paresthesia and weakness over six weeks. CSF demonstrated pleocytosis, elevated protein, oligoclonal bands, and MOG antibody. MRI revealed multiple subcortical T2-hyperintense lesions and enhancing midcervical and lower thoracic lesions. Treatment with IVMP led to minor improvement with discharge on steroid taper and azathioprine. The patient's disease progressed with a fluctuating course requiring two readmissions with upper extremity weakness, right optic neuritis, and urinary sphincteric dysfunction with neuroradiologic worsening. Treatment throughout multiple admissions included intravenous steroids, IVIG, plasmapheresis, mycophenolate mofetil, and rituximab with minimal improvement, symptom recurrence, and progression of multifocal lesions. The patient died four months after the symptom onset. These cases had markedly different treatment responses despite similar baseline characteristics. The difference in morbidity and disability burden highlights the importance of further investigation of this condition through clinical trials.

Charting Cortical-Layer Specific Area Boundaries Using Gibbs' Ringing Attenuated T1w/T2w-FLAIR Myelin MRI.

Cortical areas have traditionally been defined by their distinctive layer cyto- and/or myelo- architecture using postmortem histology. Recent studies have delineated many areas by measuring overall cortical myelin content and its spatial gradients using the T1w/T2w ratio MRI in living primates, including humans. While T1w/T2w studies of areal transitions might benefit from using the layer profile of this myelin-related contrast, a significant confound is Gibbs' ringing artefact, which produces signal fluctuations resembling cortical layers. Here, we address these issues with a novel approach using cortical layer thickness-adjusted T1w/T2w-FLAIR imaging, which effectively cancels out Gibbs' ringing artefacts while enhancing intracortical myelin contrast. Whole-brain MRI measures were mapped onto twelve equivolumetric layers, and layer-specific sharp myeloarchitectonic transitions were identified using spatial gradients resulting in a putative 182 area/subarea partition of the macaque cerebral cortex. The myelin maps exhibit unexpectedly high homology with humans suggesting cortical myelin shares the same developmental program across the species. Comparison with histological Gallyas myelin stains explains over 80% of the variance in the laminar T1w/T2w-FLAIR profiles, substantiating the validity of the method. Altogether, our approach provides a novel, noninvasive means for precision mapping layer myeloarchitecture in the primate cerebral cortex, advancing the pioneering work of classical neuroanatomists.

Quantitative myelin water assessment for multiple sclerosis using multi-inversion magnetic resonance fingerprinting.

BACKGROUND: Multiple sclerosis (MS) is a demyelination disease. Myelin water is a biomarker of myelin and thus myelin water imaging is a vital tool to provide insight into the demyelination process. PURPOSE: This study aimed to characterize the multiple compartments including myelin water fraction (MWF), gray matter (GM) cellular water, white matter (WM) cellular water, and cerebrospinal fluid (CSF) using multiple inversion recovery (mIR) magnetic resonance fingerprinting (MRF) on a clinical MS cohort. METHODS: The Phantom experiment was conducted with tubes containing different WM and GM concentrations extracted from pig brains. For the in-vivo experiment, 23 healthy control (HC) volunteers and 18 MS patients were recruited for this study. The experiments were performed using a clinical 3T MRI. A multi-slice, fast imaging with a steady-state precession (FISP) based mIR MRF protocol was used to obtain the MWF measurements, with 6 min of scan time for each volunteer. The quantification was based on the iterative non-negative least squares (NNLS) with reweighting. The brain compartments quantified were myelin water, WM cellular water, GM cellular water, and CSF. A radiologist with 6 years of experience labeled the MS lesions on FLAIR, MPRAGE, and MWF. Statistical analysis was performed by applying unpaired and paired student's t-tests to compare the MWF results in different groups and in normal-appearing white matter (NAWM) and MS lesions. RESULTS: The phantom result demonstrated the ability to detect MWF with various myelin concentrations. The maps derived from mIR MRF, including MWF, WM cellular water, GM cellular water, and CSF were consistent with the anatomical structures observed in FLAIR and MPRAGE. The MWF values in the NAWM of MS patients were significantly different from those in HC, with values of 0.32 ± 0.025 and 0.25 ± 0.036, respectively. Additionally, the MWF values in WM lesions were significantly smaller than in NAWM at 0.034 ± 0.036. CONCLUSION: The mIR-MRF technique, using multi-compartment analysis, can simultaneously generate maps of MWF, WM cellular water, GM cellular water, and CSF with sufficient brain coverage and in a reasonably short scan time. The MWF map might provide insights into the demyelination associated with MS.

Optimal different adeno-associated virus capsid/promoter combinations to target specific cell types in the common marmoset cerebral cortex.

To achieve cell-type-specific gene expression, using target cell-type-tropic different adeno-associated virus (AAV) capsids is advantageous. However, their tropism across brain cell types in nonhuman primates has not been fully elucidated. We assessed the tropism of nine AAV serotype capsids (AAV1, 2, 5, 6, 7, 8, 9, rh10, and DJ) expressing EGFP by chicken ß-actin hybrid (CBh) promoter in marmoset cerebral cortical cells. All nine AAV capsid vectors, especially AAV9 and AAVrh10, caused highly neuron-selective EGFP expression. Some AAV capsids, including AAV5, induced EGFP expression to a lesser extent in oligodendrocytes. Different ubiquitous cytomegalovirus (CMV) and CMV early enhancer/chicken ß-actin (CAG) promoters exhibited similar neuron-predominant transgene expression. Conversely, all nine AAV capsid vectors with the astrocyte-specific hGFA(ABC1D) promoter selectively expressed EGFP in astrocytes, except AAV5, which modestly expressed EGFP in oligodendrocytes. Oligodendrocyte-specific mouse myelin basic protein (mMBP) promoter in AAV5 vectors expressed EGFP in oligodendrocytes specifically and efficiently. The following are optimal combinations of capsids and promoters for cell-type-specific expression: AAV9 or AAVrh10 and ubiquitous CBh or CMV promoter for neuron-specific transgene expression, AAV2 or AAV7 and hGFA(ABC1D) promoters for astrocyte-specific transgene expression, and AAV5 and mMBP promoters for oligodendrocyte-specific transgene expression.

Employment, work hours, and wages in adults with myelin oligodendrocyte glycoprotein antibody disease: An international cohort study.

OBJECTIVES: The objectives were to understand the employment impacts of myelin oligodendrocyte glycoprotein-associated antibody disease (MOGAD) on adults in an international cohort by determining lost employment, work hours, and wages. BACKGROUND: Clinically, MOGAD can be associated with significant disability; however, its socioeconomic consequences for adults are barely reported. METHODS: Participants of potential working age (18-70 years old) with neurologist-diagnosed MOGAD were recruited from clinical sites in 13 countries, April 2022 to August 2023. Each participant completed a one-time survey. Regression models assessed associations with post-MOGAD (1) unemployment and (2) work hours. RESULTS: A total of 117 participants (66.7% female), mean age 39.7 years, median disease duration 3 years (25th, 75th percentile: 1, 7) were analyzed. Employment post-MOGAD reduced from 74 (63.2%) to 57 (48.7%) participants. Participants employed pre-diagnosis reduced their work hours, on average, from 31.6 hours/week to 19.5 hours/week post-diagnosis. Residence in a high-income country was statistically significantly associated with post-diagnosis employment and higher weekly work hours. Depressed mood was associated with unemployment. MOGAD-related pain and history of myelitis were independently associated with lost work hours. CONCLUSION: MOGAD can have significant impacts on adult employment, particularly in non-high-income countries. Depressed mood and pain are potentially modifiable factors related to socioeconomic status in MOGAD.

CXCR2 mediated trafficking of neutrophils and neutrophil extracellular traps are required for myelin clearance after a peripheral nerve injury.

Neutrophils are a vital part of the innate immune system. Many of their functions eliminate bacteria & viruses, like neutrophil extracellular traps (NETs), which trap bacteria, enhancing macrophage phagocytosis. It was surprising when it was demonstrated that neutrophils are a part of Wallerian degeneration, a process that is essential for nerve regeneration after a nerve injury. It is not known what signals attract neutrophils into the nerve and how they aid Wallerian degeneration. Neutrophils accumulate in the distal nerve within one day after an injury and are found in the nerve from one to three days. We demonstrate that CXCR2 mediates the trafficking of neutrophils into the distal nerve, and without CXCR2 Wallerian degeneration, as indicated by luxol fast blue staining, was reduced seven days after a sciatic nerve crush or transection injury. NETs were detected in the distal nerve after a sciatic nerve transection. NET formation has been shown to require protein arginine deiminase 4 (PAD4), which citrullinates histone 3. Inhibiting PAD4 reduced NET formation significantly in the distal nerve at two days and myelin clearance at seven days indicating that NETs aid myelin clearance. These results demonstrate another function for NETs other than clearing pathogens. Neutrophils have been detected after injuries to the central nervous system and diseases in humans and animal models. Our results demonstrate neutrophils aid myelin clearance, suggesting a role for their presence in central nervous system injuries and diseases.

Case report: Antibodies to myelin basic protein in a podenco-crossbreed dog with seizures.

A 6-year-old female spayed Podenco-crossbreed dog was presented with an unusual type of focal impaired awareness seizures, including sensory ataxia and postictal rest. Magnetic resonance imaging examination revealed pre- and post-contrast agent T1-weighted bilateral symmetric hyperintensities in the lentiform nuclei and globus pallidus. Repeated cerebrospinal fluid sampling showed lymphocytic pleocytosis. Cerebrospinal fluid immunoglobulin G autoantibodies to myelin basic protein (MBP) were detected by immunofluorescence examination with strong binding to myelinated fiber tracts. The absence of binding to MBP-depleted mouse brains confirmed MBP as an antigenic target. Although the patient had minor seizure episodes every 2 months, and the owners avoided seizure triggers, they refused medical treatment before presenting to the veterinarian. To the best of our knowledge, this is the first description of MBP autoantibody-positive encephalitis in a dog.

High-yield production of recombinant human myelin oligodendrocyte glycoprotein in SHuffle bacteria without a refolding step.

Experimental autoimmune encephalomyelitis (EAE) is a model for central nervous system (CNS) autoimmune demyelinating diseases such as multiple sclerosis (MS) and MOG antibody-associated disease (MOGAD). Immunization with the extracellular domain of recombinant human MOG (rhMOG), which contains pathogenic antibody and T cell epitopes, induces B cell-dependent EAE for studies in mice. However, these studies have been hampered by rhMOG availability due to its insolubility when overexpressed in bacterial cells, and the requirement for inefficient denaturation and refolding. Here, we describe a new protocol for the high-yield production of soluble rhMOG in SHuffle cells, a commercially available E. coli strain engineered to facilitate disulfide bond formation in the cytoplasm. SHuffle cells can produce a soluble fraction of rhMOG yielding >100 mg/L. Analytical size exclusion chromatography multi-angle light scattering (SEC-MALS) and differential scanning fluorimetry of purified rhMOG reveals a homogeneous monomer with a high melting temperature, indicative of a well-folded protein. An in vitro proliferation assay establishes that purified rhMOG can be processed and recognized by T cells expressing a T cell receptor (TCR) specific for the immunodominant MOG35-55 peptide epitope. Lastly, immunization of wild-type, but not B cell deficient, mice with rhMOG resulted in robust induction of EAE, indicating a B cell-dependent induction. Our SHuffle cell method greatly simplifies rhMOG production by combining the high yield and speed of bacterial cell expression with enhanced disulfide bond formation and folding, which will enable further investigation of B cell-dependent EAE and expand human research of MOG in CNS demyelinating diseases.

Developmental maturation and regional heterogeneity but no sexual dimorphism of the murine CNS myelin proteome.

The molecules that constitute myelin are critical for the integrity of axon/myelin-units and thus speed and precision of impulse propagation. In the CNS, the protein composition of oligodendrocyte-derived myelin has evolutionarily diverged and differs from that in the PNS. Here, we hypothesized that the CNS myelin proteome also displays variations within the same species. We thus used quantitative mass spectrometry to compare myelin purified from mouse brains at three developmental timepoints, from brains of male and female mice, and from four CNS regions. We find that most structural myelin proteins are of approximately similar abundance across all tested conditions. However, the abundance of multiple other proteins differs markedly over time, implying that the myelin proteome matures between P18 and P75 and then remains relatively constant until at least 6 months of age. Myelin maturation involves a decrease of cytoskeleton-associated proteins involved in sheath growth and wrapping, along with an increase of all subunits of the septin filament that stabilizes mature myelin, and of multiple other proteins which potentially exert protective functions. Among the latter, quinoid dihydropteridine reductase (QDPR) emerges as a highly specific marker for mature oligodendrocytes and myelin. Conversely, female and male mice display essentially similar myelin proteomes. Across the four CNS regions analyzed, we note that spinal cord myelin exhibits a comparatively high abundance of HCN2-channels, required for particularly long sheaths. These findings show that CNS myelination involves developmental maturation of myelin protein composition, and regional differences, but absence of evidence for sexual dimorphism.

Axonal Regeneration after Spinal Cord Injury: Molecular Mechanisms, Regulatory Pathways, and Novel Strategies.

Axonal regeneration in the spinal cord after traumatic injuries presents a challenge for researchers, primarily due to the nature of adult neurons and the inhibitory environment that obstructs neuronal regrowth. Here, we review current knowledge of the intricate network of molecular and cellular mechanisms that hinder axonal regeneration, with a focus on myelin-associated inhibitors (MAIs) and other inhibitory guidance molecules, as well as the pivotal pathways implicated in both inhibiting and facilitating axonal regrowth, such as PKA/AMP, PI3K/Akt/mTOR, and Trk, alongside the regulatory roles of neurotrophins and axonal guidance cues. We also examine current insights into gene therapy, tissue engineering, and pharmacological interventions that show promise in overcoming barriers to axonal regrowth.

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.

Stem and progenitor cell-based therapy of myelin disorders.

Much of clinical neurology is concerned with diseases of-or involving-the brain's subcortical white matter. Common to these disorders is the loss of myelin, reflecting the elimination or dysfunction of oligodendrocytes and fibrous astrocytes. As such, the introduction of glial progenitor cells, which can give rise to new oligodendrocytes and astrocytes alike, may be a feasible strategy for treating a broad variety of conditions in which white matter loss is causally involved. This review first covers the sourcing and production of human glial progenitor cells, and the preclinical evidence for their efficacy in achieving myelin restoration in vivo. It then discusses both pediatric and adult disease targets for which transplanted glial progenitors may prove of therapeutic value, those challenges that remain in the clinical application of a glial cell replacement strategy, and the clinical endpoints by which the efficacy of this approach may be assessed.

Bone marrow mesenchymal stem cells in treatment of peripheral nerve injury.

Peripheral nerve injury (PNI) is a common neurological disorder and complete functional recovery is difficult to achieve. In recent years, bone marrow mesenchymal stem cells (BMSCs) have emerged as ideal seed cells for PNI treatment due to their strong differentiation potential and autologous transplantation ability. This review aims to summarize the molecular mechanisms by which BMSCs mediate nerve repair in PNI. The key mechanisms discussed include the differentiation of BMSCs into multiple types of nerve cells to promote repair of nerve injury. BMSCs also create a microenvironment suitable for neuronal survival and regeneration through the secretion of neurotrophic factors, extracellular matrix molecules, and adhesion molecules. Additionally, BMSCs release pro-angiogenic factors to promote the formation of new blood vessels. They modulate cytokine expression and regulate macrophage polarization, leading to immunomodulation. Furthermore, BMSCs synthesize and release proteins related to myelin sheath formation and axonal regeneration, thereby promoting neuronal repair and regeneration. Moreover, this review explores methods of applying BMSCs in PNI treatment, including direct cell transplantation into the injured neural tissue, implantation of BMSCs into nerve conduits providing support, and the application of genetically modified BMSCs, among others. These findings confirm the potential of BMSCs in treating PNI. However, with the development of this field, it is crucial to address issues related to BMSC therapy, including establishing standards for extracting, identifying, and cultivating BMSCs, as well as selecting application methods for BMSCs in PNI such as direct transplantation, tissue engineering, and genetic engineering. Addressing these issues will help translate current preclinical research results into clinical practice, providing new and effective treatment strategies for patients with PNI.

Changes in short-chain fatty acids affect brain development in mice with early life antibiotic-induced dysbacteriosis.

Background: Early enteral nutrition and the gut microbiota profoundly influence neonatal brain development, with short-chain fatty acids (SCFAs) from the microbiota playing a pivotal role. Understanding the relationship between dysbiosis, SCFAs, and brain development is crucial. In this study, we investigated the impact of antibiotics on the concentration of SCFAs in neonatal feces. Additionally, we developed a model of gut dysbiosis in neonatal mice to examine the potential relationship between this imbalance, SCFAs production, and brain function development. Methods: We measured the SCFAs content in the feces of two groups of neonates, categorized based on whether antibiotics were used, and conducted the Neonatal Behavioral Neurological Assessment (NBNA) test on all neonates. Then we evaluated fecal SCFAs levels in neonates and neonatal mice post-antibiotic treatment using liquid chromatography-mass spectrometry (LC-MS) analysis. Morris water maze (MWM) tests assessed behavioral performance, and western blot analysis examined brain tissue-related proteins-neuron-specific enolase (NSE), ionized calcium binding adaptor molecule-1 (IBA1), and myelin basic proteins (MBP). Results: The use of antibiotics did not affect the NBNA scores of the two groups of neonates, but it did reduce the SCFAs content in their feces. Antibiotic administration induced gut dysbiosis in mice, resulting in decreased IBA1 and MBP expression. Interventions to restore gut microbiota ameliorated these effects. Mice with dysbiosis displayed cognitive deficits in the MWM test. SCFAs levels decreased during dysbiosis, and increased upon microbiota recovery. Conclusions: Neonatal dysbiosis affects the microbiota-gut-brain axis, impairing cognitive function and nervous system development. Reduced SCFAs may contribute significantly to these alterations.

Korean Red Ginseng and Rb1 restore altered social interaction, gene expressions in the medial prefrontal cortex, and gut metabolites under post-weaning social isolation in mice.

Background: Post-weaning social isolation (SI) reduces sociability, gene expressions including myelin genes in the medial prefrontal cortex (mPFC), and alters microbiome compositions in rodent models. Korean Red Ginseng (KRG) and its major ginsenoside Rb1 have been reported to affect myelin formation and gut metabolites. However, their effects under post-weaning SI have not been investigated. This study investigated the effects of KRG and Rb1 on sociability, gene expressions in the mPFC, and gut metabolites under post-weaning SI. Methods: C57BL/6J mice were administered with water or KRG (150, 400 mg/kg) or Rb1 (0.1 mg/kg) under SI or regular environment (RE) for 2 weeks during the post-weaning period (P21-P35). After this period, mice underwent a sociability test, and then brains and ceca were collected for qPCR/immunohistochemistry and non-targeted metabolomics, respectively. Results: SI reduced sociability compared to RE; however, KRG (400 mg/kg) and Rb1 significantly restored sociability under SI. In the mPFC, expressions of genes related to myelin, neurotransmitter, and oxidative stress were significantly reduced in mice under SI compared to RE conditions. Under SI, KRG and Rb1 recovered the altered expressions of several genes in the mPFC. In gut metabolomics, 313 metabolites were identified as significant among 3027 detected metabolites. Among the significantly changed metabolites in SI, some were recovered by KRG or Rb1, including metabolites related to stress axis, inflammation, and DNA damage. Conclusion: Altered sociability, gene expression levels in the mPFC, and gut metabolites induced by two weeks of post-weaning SI were at least partially recovered by KRG and Rb1.