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1.
J Neuroinflammation ; 20(1): 105, 2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-37138312

RESUMO

BACKGROUND: Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism. METHODS: Bilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7-10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry. RESULTS: CXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2). CONCLUSION: Our study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia.


Assuntos
Isquemia Encefálica , Estenose das Carótidas , Quimiocina CXCL5 , Substância Branca , Animais , Masculino , Camundongos , Astrócitos/patologia , Isquemia Encefálica/patologia , Estenose das Carótidas/patologia , Quimiocina CXCL5/genética , Microglia , Bainha de Mielina/patologia , Fagocitose , Substância Branca/patologia
2.
Proc Natl Acad Sci U S A ; 120(20): e2217635120, 2023 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-37155847

RESUMO

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.


Assuntos
Esclerose Múltipla , Remielinização , Substância Branca , Humanos , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Encéfalo/patologia , Bainha de Mielina/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Imageamento por Ressonância Magnética/métodos , Água , Biomarcadores
3.
Cells ; 12(9)2023 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-37174731

RESUMO

Spinal cord injury (SCI) is characterized by a cascade of events that lead to sensory and motor disabilities. To date, this condition is irreversible, and no cure exists. To improve myelin repair and limit secondary degeneration, we developed a multitherapy based on nanomedicines (NMeds) loaded with the promyelinating agent triiodothyronine (T3), used in combination with systemic ibuprofen and mouse nerve growth factor (mNGF). Poly-L-lactic-co-glycolic acid (PLGA) NMeds were optimized and loaded with T3 to promote sustained release. In vitro experiments confirmed the efficacy of T3-NMeds to differentiate oligodendrocyte precursor cells. In vivo rat experiments were performed in contusion SCI to explore the NMed biodistribution and efficacy of combo drugs at short- and long-term post-lesion. A strong anti-inflammatory effect was observed in the short term with a reduction of type M1 microglia and glutamate levels, but with a subsequent increase of TREM2. In the long term, an improvement of myelination in NG2-IR, an increase in MBP content, and a reduction of the demyelination area were observed. These data demonstrated that NMeds can successfully be used to obtain more controlled local drug delivery and that this multiple treatment could be effective in improving the outcome of SCIs.


Assuntos
Remielinização , Traumatismos da Medula Espinal , Ratos , Camundongos , Animais , Remielinização/fisiologia , Distribuição Tecidual , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Bainha de Mielina/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Glicoproteínas de Membrana/farmacologia , Receptores Imunológicos
4.
Acta Neuropathol Commun ; 11(1): 84, 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37217978

RESUMO

The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are often differentially affected in human neurodegenerative diseases across CNS region, age and sex. We hypothesize that this selective vulnerability is underpinned by physiological variation in white matter glia. Using single nucleus RNA sequencing of human post-mortem white matter samples from the brain, cerebellum and spinal cord and subsequent tissue-based validation we found substantial glial heterogeneity with tissue region: we identified region-specific oligodendrocyte precursor cells (OPCs) that retain developmental origin markers into adulthood, distinguishing them from mouse OPCs. Region-specific OPCs give rise to similar oligodendrocyte populations, however spinal cord oligodendrocytes exhibit markers such as SKAP2 which are associated with increased myelin production and we found a spinal cord selective population particularly equipped for producing long and thick myelin sheaths based on the expression of genes/proteins such as HCN2. Spinal cord microglia exhibit a more activated phenotype compared to brain microglia, suggesting that the spinal cord is a more pro-inflammatory environment, a difference that intensifies with age. Astrocyte gene expression correlates strongly with CNS region, however, astrocytes do not show a more activated state with region or age. Across all glia, sex differences are subtle but the consistent increased expression of protein-folding genes in male donors hints at pathways that may contribute to sex differences in disease susceptibility. These findings are essential to consider for understanding selective CNS pathologies and developing tailored therapeutic strategies.


Assuntos
Neuroglia , Substância Branca , Humanos , Feminino , Masculino , Camundongos , Animais , Neuroglia/metabolismo , Medula Espinal/patologia , Bainha de Mielina/metabolismo , Oligodendroglia/patologia
5.
J Vis Exp ; (193)2023 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-37036195

RESUMO

The satisfactory visualization of cytoskeletal components in the brain is challenging. The ubiquitous distribution of the networks of microtubules, microfilaments, and intermediate filaments in all the neural tissues, together with the variability in the outcomes of fluorescent protein fusion strategies and their limited applicability to dynamic studies of antibodies and drugs as chromophore vehicles, make classical optical approaches not as effective as for other proteins. When tubulin needs to be studied, the label-free generation of second harmonics is a very suitable option due to the non-centrosymmetric organization of the molecule. This technique, when conjugated to microscopy, can qualitatively describe the volumetric distribution of parallel bundles of microtubules in biological samples, with the additional advantage of working with fresh tissues that are unfixed and unpermeabilized. This work describes how to image tubulin with a commercial second harmonic generation microscopy setup to highlight microtubules in the tubulin-enriched structures of the oligodendrocytes, as in hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) tubulinopathy, a recently described myelin disorder.


Assuntos
Bainha de Mielina , Tubulina (Proteína) , Tubulina (Proteína)/metabolismo , Bainha de Mielina/metabolismo , Microtúbulos/metabolismo , Citoesqueleto/metabolismo , Citoesqueleto de Actina/metabolismo
6.
Transl Psychiatry ; 13(1): 115, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-37024484

RESUMO

Amyloid-beta (Aß) aggregates and myelin breakdown are among the earliest detrimental effects of Alzheimer's disease (AD), likely inducing abnormal patterns of neuronal communication within cortical networks. However, human in vivo evidence linking Aß burden, intracortical myelin, and cortical synchronization is lacking in cognitively normal older individuals. Here, we addressed this question combining 18F-Florbetaben-PET imaging, cortical T1-weigthed/T2-weighted (T1w/T2w) ratio maps, and resting-state functional connectivity (rs-FC) in cognitively unimpaired older adults. Results showed that global Aß burden was both positively and negatively associated with the T1w/T2w ratio in different cortical territories. Affected cortical regions were further associated with abnormal patterns of rs-FC and with subclinical cognitive deficits. Finally, causal mediation analysis revealed that the negative impact of T1w/T2w ratio in left posterior cingulate cortex on processing speed was driven by Aß burden. Collectively, these findings provide novel insights into the relationship between initial Aß plaques and intracortical myelin before the onset of cognitive decline, which may contribute to monitor the efficacy of novel disease-modifying strategies in normal elderly individuals at risk for cognitive impairment.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Bainha de Mielina/metabolismo , Imageamento por Ressonância Magnética/métodos , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Tomografia por Emissão de Pósitrons
7.
Neurosci Lett ; 807: 137278, 2023 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-37116573

RESUMO

The functions of Kir4.1 in oligodendrocyte development have been in controversial. We recently reported that inhibiting Kir4.1 impeded oligodendrocyte precursor cell (OPC) differentiation and oligodendrocyte (OL) maturation, due to Kir4.1 altering intracellular pH of OPCs through Na+/H+ exchangers. However, our conclusion was limited by in vitro observation, thereby it becomes necessary to seek in vivo evidence to determine the roles of Kir4.1 on OPC development and CNS myelination. Here, we used Olig1-Cre to knockout Kir4.1 in OPCs from the early developmental stage. We found that the cell-specific deletion of Kir4.1 significantly impeded OPC differentiation and reduced the number of mature OLs in the cerebral cortex and the corpus callosum. Hence, our in vivo evidence supports that Kir4.1 can regulate OPC differentiation and is essential to CNS myelination.


Assuntos
Células Precursoras de Oligodendrócitos , Camundongos , Animais , Camundongos Knockout , Oligodendroglia/fisiologia , Diferenciação Celular/fisiologia , Neurogênese , Bainha de Mielina/fisiologia
8.
Neuroimage ; 274: 120128, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37116765

RESUMO

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes-and their microstructural underpinnings-remain unclear. Eighteen healthy males received 1 h of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.


Assuntos
Destreza Motora , Substância Branca , Masculino , Humanos , Aprendizagem , Substância Branca/diagnóstico por imagem , Extremidade Superior , Bainha de Mielina , Plasticidade Neuronal
9.
Int J Dev Neurosci ; 83(3): 274-296, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37073624

RESUMO

Ultrastructural features of striatal white matter and cells in an in vivo model of glutaric acidemia type I created by intracerebral injection of glutaric acid (GA) were analyzed by transmission electron microscopy and immunohistochemistry. To test if the white matter damage observed in this model could be prevented, we administered the synthetic chemopreventive molecule CH38 ((E)-3-(4-methylthiophenyl)-1-phenyl-2-propen-1-one) to newborn rats, previous to an intracerebroventricular injection of GA. The study was done when striatal myelination was incipient and when it was already established (at 12 and 45 days post-injection [DPI], respectively). Results obtained indicate that that the ultrastructure of astrocytes and neurons did not appear significantly affected by the GA bolus. Instead, in oligodendrocytes, the most prominent GA-dependent injury defects included endoplasmic reticulum (ER) stress and nuclear envelope swelling at 12 DPI. Altered and reduced immunoreactivities against heavy neurofilament (NF), proteolipid protein (PLP), and myelin-associated glycoprotein (MAG) together with axonal bundle fragmentation and decreased myelin were also found at both ages analyzed. CH38 by itself did not affect striatal cells or axonal packages. However, the group of rats that received CH38 before GA did not show evidence neither of ER stress nor nuclear envelope dilation in oligodendrocytes, and axonal bundles appeared less fragmented. In this group, labeling of NF and PLP was similar to the controls. These results suggest that the CH38 molecule is a candidate drug to prevent or decrease the neural damage elicited by a pathological increase of GA in the brain. Optimization of the treatments and identification of the mechanisms underlying CH38 protective effects will open new therapeutic windows to protect myelin, which is a vulnerable target of numerous nervous system diseases.


Assuntos
Chalconas , Bainha de Mielina , Ratos , Animais , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Chalconas/metabolismo , Chalconas/farmacologia , Neurônios/metabolismo , Axônios/metabolismo , Oligodendroglia/metabolismo
10.
Elife ; 122023 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-37057892

RESUMO

Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury, and disease.


Nerve cells in the brain and spinal cord are surrounded by a layer of insulation called myelin that allows cells to transmit messages to each other more quickly and efficiently. This protective sheath is produced by cells called oligodendrocytes which together with their immature counterparts can also repair damage caused to myelin. In the inflammatory disease multiple sclerosis (MS), this insulation is disrupted and oligodendroglia fail to repair breaks in the myelin sheath, leaving nerves vulnerable to further damage. Recently it was discovered that mature and immature oligodendrocytes (which are collectively known as oligodendroglia) sometimes express proteins normally restricted to the immune system called major histocompatibility complexes (or MHCs for short). Researchers believe that MHC expression may allow oligodendroglia to interact with immune cells, potentially leading to the removal of oligodendroglia by the immune system as well as inflammation that exacerbates damage to nerves and hinders myelin repair. Knowing when oligodendroglia start producing MHCs and where these MHC-expressing cells are located is therefore important for understanding their role in MS. However, it is difficult to identify the location of MHC-expressing oligodendroglia using methods that are currently available. To address this, Harrington, Catenacci et al. created a genetically engineered mouse model in which the MHC-expressing oligodendroglia also generated a red fluorescent protein that could be detected under a microscope. This revealed that only a small number of oligodendroglia in the nervous system had MHCs, but these cells were located in areas of the brain and spinal cord with the highest inflammatory activity. Further microscopy studies in mice that developed MS-like symptoms revealed that MHC production in oligodendroglia increased compared with healthy animals, and that the proportion of oligodendroglia that produced MHC was highest in mice with the most severe symptoms. MHC-expressing oligodendroglia also congregated in the most damaged areas of the brain and spinal cord. These results suggest that MHC expression may contribute to inflammation and impact the function of oligodendroglia that have these molecules. In the future, Harrington et al. hope that their new mouse model will help researchers study the role of MHC expression in different diseases, and in the case of MS, aid the development of new treatments.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Camundongos , Animais , Esclerose Múltipla/metabolismo , Doenças Desmielinizantes/metabolismo , Oligodendroglia/metabolismo , Camundongos Transgênicos , Bainha de Mielina/metabolismo
11.
Exp Neurol ; 365: 114412, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37075967

RESUMO

Normal pressure hydrocephalus (NPH) compromises the morphology of the corpus callosum (CC). This study aims to determine whether 60- or 120-day NPH disrupts the cytoarchitecture and functioning of white matter (WM) and oligodendrocyte precursor cells (OPCs) and establish whether these changes are reversible after hydrocephalus treatment. NPH was induced in CD1 adult mice by inserting an obstructive lamina in the atrium of the aqueduct of Sylvius. Five groups were assembled: sham-operated controls (60 and 120 days), NPH groups (60 and 120 days), and the hydrocephalus-treated group (obstruction removal after 60-d hydrocephalus). We analyzed the cellular integrity of the CC by immunohistochemistry, TUNEL analysis, Western blot assays, and transmission electron microscopy (TEM). We found a reduction in the width of the CC at 60 and 120 days of NPH. TEM analysis demonstrated myelin abnormalities, degenerative changes in the WM, and an increase in the number of hyperdense (dark) axons that were associated with significant astrogliosis, and microglial reactivity. Hydrocephalus also caused a decrease in the expression of myelin-related proteins (MOG and CNPase) and reduced proliferation and population of OPCs, resulting in fewer mature oligodendrocytes. Hydrocephalus resolution only recovers the OPC proliferation and MOG protein density, but the rest of the WM abnormalities persisted. Interestingly, all these cellular and molecular anomalies occur in the absence of behavioral changes. The results suggest that NPH severely disrupts the myelin integrity and affects the OPC turnover in the CC. Remarkably, most of these deleterious events persist after hydrocephalus treatment, which suggests that a late treatment conveys irreversible changes in the WM of CC.


Assuntos
Hidrocefalia de Pressão Normal , Células Precursoras de Oligodendrócitos , Camundongos , Animais , Corpo Caloso , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/genética , Bainha de Mielina , Oligodendroglia , Proteínas da Mielina , Proliferação de Células
12.
Elife ; 122023 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-37078701

RESUMO

Oligodendrocytes in the central nervous system exhibit significant variability in the number of myelin sheaths that are supported by each cell, ranging from 1 to 50 (1-8). Myelin production during development is dynamic and involves both sheath formation and loss (3, 9-13). However, how these parameters are balanced to generate this heterogeneity in sheath number has not been thoroughly investigated. To explore this question, we combined extensive time-lapse and longitudinal imaging of oligodendrocytes in the developing zebrafish spinal cord to quantify sheath initiation and loss. Surprisingly, we found that oligodendrocytes repetitively ensheathed the same axons multiple times before any stable sheaths were formed. Importantly, this repetitive ensheathment was independent of neuronal activity. At the level of individual oligodendrocytes, each cell initiated a highly variable number of total ensheathments. However, ~80-90% of these ensheathments always disappeared, an unexpectedly high, but consistent rate of loss. The dynamics of this process indicated rapid membrane turnover as ensheathments were formed and lost repetitively on each axon. To better understand how these sheath initiation dynamics contribute to sheath accumulation and stabilization, we disrupted membrane recycling by expressing a dominant-negative mutant form of Rab5. Oligodendrocytes over-expressing this mutant did not show a change in early sheath initiation dynamics but did lose a higher percentage of ensheathments in the later stabilization phase. Overall, oligodendrocyte sheath number is heterogeneous because each cell repetitively initiates a variable number of total ensheathments that are resolved through a consistent stabilization rate.


Assuntos
Axônios , Peixe-Zebra , Animais , Axônios/fisiologia , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Sistema Nervoso Central
13.
Nat Rev Neurosci ; 24(6): 334-346, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37085728

RESUMO

Multiple system atrophy (MSA) is a rare oligodendroglial α-synucleinopathy characterized by neurodegeneration in striatonigral and olivopontocerebellar regions and autonomic brain centres. It causes complex cumulative motor and non-motor disability with fast progression and effective therapy is currently lacking. The difficulties in the diagnosis and treatment of MSA are largely related to the incomplete understanding of the pathogenesis of the disease. The MSA pathogenic landscape is complex, and converging findings from genetic and neuropathological studies as well as studies in experimental models of MSA have indicated the involvement of genetic and epigenetic changes; α-synuclein misfolding, aggregation and spreading; and α-synuclein strain specificity. These studies also indicate the involvement of myelin and iron dyshomeostasis, neuroinflammation, mitochondrial dysfunction and other cell-specific aspects that are relevant to the fast progression of MSA. In this Review, we discuss these findings and emphasize the implications of the complexity of the multifactorial pathogenic cascade for future translational research and its impact on biomarker discovery and treatment target definitions.


Assuntos
Atrofia de Múltiplos Sistemas , Humanos , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , alfa-Sinucleína/genética , Encéfalo , Oligodendroglia , Bainha de Mielina
14.
Hum Brain Mapp ; 44(9): 3758-3780, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37067096

RESUMO

Assessing the consistency of quantitative MRI measurements is critical for inclusion in longitudinal studies and clinical trials. Intraclass coefficient correlation and coefficient of variation were used to evaluate the different consistency aspects of diffusion- and myelin-based MRI measures. Multi-shell diffusion and inhomogeneous magnetization transfer data sets were collected from 20 healthy adults at a high-frequency of five MRI sessions. The consistency was evaluated across whole bundles and the track-profile along the bundles. The impact of the fiber populations on the consistency was also evaluated using the number of fiber orientations map. For whole and profile bundles, moderate to high reliability of diffusion and myelin measures were observed. We report higher reliability of measures for multiple fiber populations than single. The overall portrait of the most consistent measurements and bundles drawn from a wide range of MRI techniques presented here will be particularly useful for identifying reliable biomarkers capable of detecting, monitoring and predicting white matter changes in clinical applications and has the potential to inform patient-specific treatment strategies.


Assuntos
Substância Branca , Adulto , Humanos , Substância Branca/diagnóstico por imagem , Bainha de Mielina , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética , Estudos Longitudinais , Encéfalo/diagnóstico por imagem
15.
Exp Neurol ; 364: 114395, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37003487

RESUMO

In mice, dietary cuprizone causes brain demyelination with subsequent spontaneous remyelination upon return to normal chow. Heavy water (2H2O) labeling with mass spectrometric analysis can be used to measure brain de novo synthesis of several myelin components including cholesterol, phospholipids, galactocereboside (GalC) and myelin-associated proteins. 24-hydroxycholesterol (24-OHC), the major metabolite of brain cholesterol, is detected in blood and is believed to be specifically derived from CNS cholesterol metabolism. We assessed changes in syntheses of myelin components in brain and of blood sterols during cuprizone-induced experimental demyelination and remyelination, with and without thyroid hormone (T3) treatment. Mice were fed cuprizone for 4 weeks, then returned to control diet and treated with either placebo or T3 (0.005 mg/day). 2H2O was administered for the last 14 days of cuprizone diet, and for either 6, 12 or 19 days of treatment during recovery from cuprizone, after which blood and corpus callosum (CC) samples were collected (n = 5/time point/treatment). 2H incorporation into cholesterol and 24-OHC in blood and CC, and incorporation into phospholipid (PL)-palmitate, GalC, myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) in CC were measured. Cuprizone significantly (p < 0.05) decreased syntheses of cholesterol, 24-OHC, GalC, MBP, CNPase and PL-palmitate in the CC and these effects were all reversed during recovery. T3 treatment significantly (p < 0.05) increased syntheses of cholesterol, 24-OHC and palmitate compared to placebo. 24-OHC and cholesterol turnover rates in brain and blood were nearly identical and 24-OHC rates in blood paralleled rates in CC, indicating that blood 24-OHC derives primarily from the brain and reflects oligodendrocyte function. In summary, changes in synthesis of several lipid and protein components in brain during cuprizone-induced demyelination and remyelination are measurable through stable isotope labeling. Blood 24-OHC turnover rates closely reflect flux rates of brain cholesterol in response to cuprizone and T3, which alter oligodendrocyte function. Labeling of blood 24-OHC has potential as a non-invasive marker of brain de novo cholesterol synthesis and breakdown rates in demyelinating conditions.


Assuntos
Doenças Desmielinizantes , Remielinização , Camundongos , Animais , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Encéfalo/metabolismo , Bainha de Mielina , Corpo Caloso/metabolismo , Oligodendroglia , Proteínas da Mielina/metabolismo , Colesterol/efeitos adversos , Colesterol/metabolismo , Biomarcadores/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
16.
Eur J Pharm Sci ; 185: 106441, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37004962

RESUMO

Phosphodiesterase 4 (PDE4) inhibitors have been extensively researched for their anti-inflammatory and neuroregenerative properties. Despite the known neuroplastic and myelin regenerative properties of nonselective PDE4 inhibitors on the central nervous system, the direct impact on peripheral remyelination and subsequent neuroregeneration has not yet been investigated. Therefore, to examine the possible therapeutic effect of PDE4 inhibition on peripheral glia, we assessed the differentiation of primary rat Schwann cells exposed in vitro to the PDE4 inhibitor roflumilast. To further investigate the differentiation promoting effects of roflumilast, we developed a 3D model of rat Schwann cell myelination that closely resembles the in vivo situation. Using these in vitro models, we demonstrated that pan-PDE4 inhibition using roflumilast significantly promoted differentiation of Schwann cells towards a myelinating phenotype, as indicated by the upregulation of myelin proteins, including MBP and MAG. Additionally, we created a unique regenerative model comprised of a 3D co-culture of rat Schwann cells and human iPSC-derived neurons. Schwann cells treated with roflumilast enhanced axonal outgrowth of iPSC-derived nociceptive neurons, which was accompanied by an accelerated myelination speed, thereby showing not only phenotypic but also functional changes of roflumilast-treated Schwann cells. Taken together, the PDE4 inhibitor roflumilast possesses a therapeutic benefit to stimulate Schwann cell differentiation and, subsequently myelination, as demonstrated in the biologically relevant in vitro platform used in this study. These results can aid in the development of novel PDE4 inhibition-based therapies in the advancement of peripheral regenerative medicine.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores da Fosfodiesterase 4 , Ratos , Animais , Humanos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/metabolismo , Células de Schwann/metabolismo , Bainha de Mielina/genética
17.
Bioinformatics ; 39(4)2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-37018152

RESUMO

MOTIVATION: Identifying and prioritizing disease-related proteins is an important scientific problem to develop proper treatments. Network science has become an important discipline to prioritize such proteins. Multiple sclerosis, an autoimmune disease for which there is still no cure, is characterized by a damaging process called demyelination. Demyelination is the destruction of myelin, a structure facilitating fast transmission of neuron impulses, and oligodendrocytes, the cells producing myelin, by immune cells. Identifying the proteins that have special features on the network formed by the proteins of oligodendrocyte and immune cells can reveal useful information about the disease. RESULTS: We investigated the most significant protein pairs that we define as bridges among the proteins providing the interaction between the two cells in demyelination, in the networks formed by the oligodendrocyte and each type of two immune cells (i.e. macrophage and T-cell) using network analysis techniques and integer programming. The reason, we investigated these specialized hubs was that a problem related to these proteins might impose a bigger damage in the system. We showed that 61%-100% of the proteins our model detected, depending on parameterization, have already been associated with multiple sclerosis. We further observed the mRNA expression levels of several proteins we prioritized significantly decreased in human peripheral blood mononuclear cells of multiple sclerosis patients. We therefore present a model, BriFin, which can be used for analyzing processes where interactions of two cell types play an important role. AVAILABILITY AND IMPLEMENTATION: BriFin is available at https://github.com/BilkentCompGen/brifin.


Assuntos
Esclerose Múltipla , Humanos , Leucócitos Mononucleares , Oligodendroglia/fisiologia , Neurônios , Bainha de Mielina
18.
Nat Rev Neurol ; 19(5): 305-320, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37059811

RESUMO

Despite the large number of immunomodulatory or immunosuppressive treatments available to treat relapsing-remitting multiple sclerosis (MS), treatment of the progressive phase of the disease has not yet been achieved. This lack of successful treatment approaches is caused by our poor understanding of the mechanisms driving disease progression. Emerging concepts suggest that a combination of persisting focal and diffuse inflammation within the CNS and a gradual failure of compensatory mechanisms, including remyelination, result in disease progression. Therefore, promotion of remyelination presents a promising intervention approach. However, despite our increasing knowledge regarding the cellular and molecular mechanisms regulating remyelination in animal models, therapeutic increases in remyelination remain an unmet need in MS, which suggests that mechanisms of remyelination and remyelination failure differ fundamentally between humans and demyelinating animal models. New and emerging technologies now allow us to investigate the cellular and molecular mechanisms underlying remyelination failure in human tissue samples in an unprecedented way. The aim of this Review is to summarize our current knowledge regarding mechanisms of remyelination and remyelination failure in MS and in animal models of the disease, identify open questions, challenge existing concepts, and discuss strategies to overcome the translational roadblock in the field of remyelination-promoting therapies.


Assuntos
Esclerose Múltipla , Remielinização , Animais , Humanos , Esclerose Múltipla/tratamento farmacológico , Bainha de Mielina , Oligodendroglia , Modelos Animais de Doenças , Inflamação , Progressão da Doença
19.
Elife ; 122023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-37083540

RESUMO

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Remielinização , Animais , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Imageamento por Ressonância Magnética/métodos , Encefalomielite Autoimune Experimental/patologia , Callithrix , Modelos Animais de Doenças , Bainha de Mielina
20.
Schizophr Res ; 255: 195-202, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37004331

RESUMO

OBJECTIVE: We investigated changes in brain intracortical myelin (ICM) volume in the frontal lobe after 9 months of treatment with paliperidone palmitate (PP) compared with 9 months of treatment with oral antipsychotics (OAP) in participants with recent-onset schizophrenia or schizophreniform disorder from the Disease Recovery Evaluation and Modification (DREaM) study, a randomized, open-label, delayed-start trial. METHODS: DREaM included 3 phases: Part I, a 2-month oral run-in; Part II, a 9-month disease progression phase (PP or OAP); and Part III, 9 months of additional treatment (participants receiving PP continued PP [PP/PP] and participants receiving OAP were rerandomized to receive either PP [OAP/PP] or OAP [OAP/OAP]). In Part II, magnetic resonance imaging (MRI) and functional and symptomatic assessment was performed at baseline, day 92, and day 260. ICM volume as a fraction of the entire brain volume was quantified by subtraction of a proton density image from an inversion recovery image. Within-treatment-group changes from baseline were assessed by paired t-tests. Analysis of covariance was used to analyze ICM volume changes between treatment groups, adjusting for country. RESULTS: The MRI analysis sample size included 71 DREaM participants (PP, 23; OAP, 48) and 64 healthy controls. At baseline, mean adjusted ICM fraction values did not differ between groups (PP, 0.057; OAP, 0.058, p = 0.79). By day 92, the adjusted ICM fraction in the OAP group had decreased significantly (change from baseline, -0.002; p = 0.001), whereas the adjusted ICM fraction remained unchanged from baseline in the PP group (0.000; p = 0.80). At day 260, the change from baseline in adjusted ICM fraction was -0.004 (p = 0.004) in the OAP group and -0.001 (p = 0.728) in the PP group. The difference between treatment groups did not reach statistical significance (p = 0.147). CONCLUSIONS: In participants with recent-onset schizophrenia or schizophreniform disorder, frontal ICM volume was preserved at baseline levels in those treated with PP over 9 months. However, a decrease of frontal ICM volume was observed among participants treated with OAPs. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02431702.


Assuntos
Antipsicóticos , Esquizofrenia , Humanos , Administração Oral , Antipsicóticos/farmacologia , Preparações de Ação Retardada/uso terapêutico , Lobo Frontal/patologia , Imageamento por Ressonância Magnética , Bainha de Mielina , Palmitato de Paliperidona , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia
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