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1.
Cardiovasc Toxicol ; 23(1): 46-60, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36650404

RESUMO

Cuprizone (CPZ) is a neurotoxic agent that is used to induce demyelination and neurotoxicity in rats. This study aimed to investigate the protective potential of sulforaphane (SF), nuclear factor E2 related factor (Nrf-2) activator, against CPZ-induced cardiotoxicity and hepatotoxicity. Male adult Wistar rats (n = 18) were fed with a regular diet or a CPZ-contained diet (0.2%) for four weeks. The rats were divided into three groups (n = 6): negative control rats, CPZ-exposed rats, and CPZ + SF treated rats. SF was intraperitoneally administrated (2 mg/kg/day) for two weeks. The anti-inflammatory and anti-oxidative functions of SF were investigated biochemically, histologically, and immunohistochemically. CPZ increased serum levels of cardiac troponin 1 (CTn1), aspartate amino transaminase (AST), alanine amino transaminase (ALT), and alkaline phosphatase (ALP). In addition, serum levels of inflammatory interferon-gamma (IFN-γ), and pro-inflammatory interleukin 1ß (IL-1ß) were significantly elevated. Moreover, CPZ administration provoked oxidative stress as manifested by declined serum levels of total antioxidant capacity (TAC), as well as, stimulated lipid peroxidation and decreased catalase activities in both cardiac and hepatic tissues. SF treatment reversed all these biochemical alterations through exerting anti-oxidative and anti-inflammatory activities, and this was supported by histopathological investigations in both cardiac and hepatic tissues. This SF-triggered modulation of oxidative stress and inflammation is strongly associated with Nrf-2 activation, as evidenced by activated immunoexpression in both cardiac and hepatic tissues. This highlights the cardioprotective and hepatoprotective activities of SF via Nrf-2 activation and enhancing catalase function.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Cuprizona , Animais , Masculino , Ratos , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Cardiotoxicidade/metabolismo , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cuprizona/metabolismo , Cuprizona/farmacologia , Cuprizona/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/metabolismo , Fígado/patologia , Estresse Oxidativo , Ratos Wistar
2.
Neurosci Lett ; 792: 136936, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341924

RESUMO

Multiple sclerosis (MS) is a potentially disabling disease of the brain and spinal cord (central nervous system). The aim of this study was to investigate the effect of 6 weeks of aerobic training on the main proteins of myelin including myelin basic protein (MBP), myelin oligodendrocyte (MOG), myelin associated glycoprotein (MAG), and myelin proteolipid protein (PLP) at hippocampus of C57BL/6 mouse model of cuprizone-induced MS. Twenty-eight female C57BL/6 mice (23 ± 3 g) were randomly divided into four groups (n = 7 per group): control, exercise (Exe), cuprizone (CPZ), and cuprizone with exercise (CPZ + Exe). Exercise groups performed treadmill aerobic exercise training 5 days a week, 15-22 m/min, and 15-60 min, during 6 weeks. Cuprizone were fed to mice at CPZ and CPZ + Exe groups for 6 weeks. Animals were sacrificed after 6 weeks. Biochemical and molecular biology analyses were performed. Mice at CPZ group had decreased myelination of nerve cells in the hippocampus. In addition, the use of CPZ in the hippocampus caused a decrease in the MBP, MOG gene expression, as well as a decrease in the MAG and PLP gene and protein expression compared to the healthy control group. However, performing aerobic exercise with CPZ consumption increased MBP gene expression and increased MAG and PLP protein expression, as well as increased myelination of nerve cells in the hippocampus compared to the CPZ group (p < 0.05). It seems that regular aerobic exercise in the MS model controls the destruction of myelin in the nerve cells of hippocampus by upregulating MBP, MAG and PLP, which can have positive effects on cognitive and motor performance.


Assuntos
Cuprizona , Esclerose Múltipla , Animais , Camundongos , Feminino , Cuprizona/toxicidade , Bainha de Mielina/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Hipocampo , Caminhada , Modelos Animais de Doenças
3.
Neurobiol Dis ; 176: 105951, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36493975

RESUMO

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.


Assuntos
Doenças Desmielinizantes , Microbiota , Esclerose Múltipla , Animais , Camundongos , Encéfalo/metabolismo , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Nervo Vago/metabolismo
4.
Int J Mol Sci ; 23(24)2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36555825

RESUMO

Huperzine A (HupA) is a natural acetylcholinesterase inhibitor (AChEI) with the advantages of high efficiency, selectivity as well as reversibility and can exhibit significant therapeutic effects against certain neurodegenerative diseases. It is also beneficial in reducing the neurological impairment and neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a classic model for multiple sclerosis (MS). However, whether HupA can directly regulate oligodendrocyte differentiation and maturation and promote remyelination has not been investigated previously. In this study, we have analyzed the potential protective effects of HupA on the demylination model of MS induced by cuprizone (CPZ). It was found that HupA significantly attenuated anxiety-like behavior, as well as augmented motor and cognitive functions in CPZ mice. It also decreased demyelination and axonal injury in CPZ mice. Moreover, in CPZ mice, HupA increased mRNA levels of the various anti-inflammatory cytokines (Arg1, CD206) while reducing the levels of different pro-inflammatory cytokines (iNOS, IL-1ß, IL-18, CD16, and TNF-α). Mecamylamine, a nicotinic acetylcholinergic receptor antagonist, could effectively reverse the effects of HupA. Therefore, we concluded that HupA primarily exerts its therapeutic effects on multiple sclerosis through alleviating demyelination and neuroinflammation.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Cuprizona/toxicidade , Doenças Neuroinflamatórias , Acetilcolinesterase , Esclerose Múltipla/tratamento farmacológico , Citocinas/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Comportamento Animal , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
5.
Mol Neurodegener ; 17(1): 82, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36514132

RESUMO

BACKGROUND: Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia respond and regulate demyelination is not fully understood. METHODS: To understand how microglia respond during demyelination, we fed mice cuprizone-a potent demyelinating agent-and assessed the dynamics of genetically fate-mapped microglia. We then used single-cell RNA sequencing to identify and track the microglial subpopulations that arise during demyelination. To understand how microglia contribute to the clearance of dead oligodendrocytes, we ablated microglia starting at the peak of cuprizone-induced cell death and used the viability dye acridine orange to monitor apoptotic and lytic cell morphologies after microglial ablation. Lastly, we treated serum-free primary microglial cultures to model distinct aspects of cuprizone-induced demyelination and assessed the response. RESULTS: The cuprizone diet generated a robust microglial response by week 4 of the diet. Single-cell RNA sequencing at this time point revealed the presence of several cuprizone-associated microglia (CAM) clusters. These clusters expressed a transcriptomic signature indicative of cytokine regulation and reactive oxygen species production with altered lysosomal and metabolic changes consistent with ongoing phagocytosis. Using acridine orange to monitor apoptotic and lytic cell death after microglial ablation, we found that microglia preferentially phagocytose lytic carcasses. In culture, microglia exposed to lytic carcasses partially recapitulated the CAM state, suggesting that phagocytosis contributes to this distinct microglial state during cuprizone demyelination. CONCLUSIONS: Microglia serve multiple roles during demyelination, yet their transcriptomic state resembles other neurodegenerative conditions. The phagocytosis of cellular debris is likely a universal cause for a common neurodegenerative microglial state.


Assuntos
Cuprizona , Doenças Desmielinizantes , Animais , Camundongos , Cuprizona/toxicidade , Cuprizona/metabolismo , Microglia/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Transcriptoma , Laranja de Acridina/efeitos adversos , Laranja de Acridina/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
6.
Int J Mol Sci ; 23(24)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36555733

RESUMO

Remyelination therapies, which are currently under development, have a great potential to delay, prevent or even reverse disability in multiple sclerosis patients. Several models are available to study the effectiveness of novel compounds in vivo, among which is the cuprizone model. This model is characterized by toxin-induced demyelination, followed by endogenous remyelination after cessation of the intoxication. Due to its high reproducibility and ease of use, this model enjoys high popularity among various research and industrial groups. In this review article, we will summarize recent findings using this model and discuss the potential of some of the identified compounds to promote remyelination in multiple sclerosis patients.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Remielinização , Humanos , Animais , Camundongos , Cuprizona/efeitos adversos , Bainha de Mielina , Doenças Desmielinizantes/induzido quimicamente , Reprodutibilidade dos Testes , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
7.
Int J Mol Sci ; 23(23)2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36499195

RESUMO

Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming oligodendrocytes, a process driven by microglia-OPC crosstalk. Through conducting a transcriptomic analysis of microarray studies on the demyelination-remyelination cuprizone model and using human samples of multiple sclerosis (MS), we identified molecules involved in this crosstalk. Differentially expressed genes (DEGs) of specific regions/cell types were detected in GEO transcriptomic raw data after cuprizone treatment and in MS samples, followed by functional analysis with GO terms and WikiPathways. Additionally, microglia-OPC crosstalk between microglia ligands, OPC receptors and target genes was examined with the NicheNet model. We identified 108 and 166 DEGs in the demyelinated corpus callosum (CC) at 2 and 4 weeks of cuprizone treatment; 427 and 355 DEGs in the remyelinated (4 weeks of cuprizone treatment + 14 days of normal diet) compared to 2- and 4-week demyelinated CC; 252 DEGs in MS samples and 2730 and 12 DEGs in OPC and microglia of 4-week demyelinated CC. At this time point, we found 95 common DEGs in the CC and OPCs, and one common DEG in microglia and OPCs, mostly associated with myelin and lipid metabolism. Crosstalk analysis identified 47 microglia ligands, 43 OPC receptors and 115 OPC target genes, all differentially expressed in cuprizone-treated samples and associated with myelination. Our differential expression pipeline identified demyelination/remyelination transcriptomic biomarkers in studies using diverse platforms and cell types/tissues. Cellular crosstalk analysis yielded novel markers of microglia ligands, OPC receptors and target genes.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Células Precursoras de Oligodendrócitos , Remielinização , Camundongos , Animais , Humanos , Células Precursoras de Oligodendrócitos/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Camundongos Endogâmicos C57BL , Remielinização/genética , Cuprizona/toxicidade , Oligodendroglia/metabolismo , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Diferenciação Celular/genética , Microglia/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Modelos Animais de Doenças
8.
Mol Neurodegener ; 17(1): 75, 2022 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-36419137

RESUMO

BACKGROUND: Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear. METHODS: To determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination. RESULTS: We demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice. CONCLUSIONS: Our findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.


Assuntos
Apolipoproteína E4 , Doenças Desmielinizantes , Animais , Camundongos , Apolipoproteína E2 , Apolipoproteína E4/genética , Microglia , Apolipoproteína E3 , Metabolismo dos Lipídeos , Cuprizona/toxicidade , Apolipoproteínas E
9.
Int J Mol Sci ; 23(19)2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36232643

RESUMO

Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system's white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Remielinização , Animais , Cuprizona/toxicidade , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Bainha de Mielina/patologia , Teste de Desempenho do Rota-Rod
10.
Pflugers Arch ; 474(12): 1275-1283, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36241864

RESUMO

The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is mainly being used to study demyelination and the mechanisms of remyelination, as well as the efficiency of compounds or therapeutics aiming at remyelination. Although early investigations using high dosages of cuprizone reported the occurrence of hydrocephalus, it has long been assumed that cuprizone feeding at lower dosages does not induce changes at the blood-brain barrier (BBB). Here, by analyzing BBB ultrastructure with high-resolution electron microscopy, we report changes at astrocytic endfeet surrounding vessels in the brain parenchyma. Particularly, edema formation around blood vessels and swollen astrocytic endfeet already occurred after feeding low dosages of cuprizone. These findings indicate changes in BBB function that will have an impact on the milieu of the central nervous system (CNS) in the cuprizone model and need to be considered when studying the mechanisms of de- and remyelination.


Assuntos
Cuprizona , Doenças Desmielinizantes , Animais , Camundongos , Cuprizona/toxicidade , Astrócitos/patologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
11.
ASN Neuro ; 14: 17590914221126367, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36114624

RESUMO

SUMMARY STATEMENT: The demyelinating effects of CPZ are not due to Cu deficiency but are instead consistent with acute toxicity of a CPZ + Cu complex.


Assuntos
Cuprizona , Doenças Desmielinizantes , Animais , Encéfalo , Cobre/toxicidade , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL
12.
Proc Natl Acad Sci U S A ; 119(40): e2204509119, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161894

RESUMO

Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in Rag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in S1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon-myelin unit.


Assuntos
Azetidinas , Compostos de Benzil , Esclerose Múltipla Crônica Progressiva , Oligodendroglia , Receptores de Esfingosina-1-Fosfato , Esfingosina , Animais , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Cuprizona , Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Oligodendroglia/efeitos dos fármacos , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Receptores de Esfingosina-1-Fosfato/metabolismo
13.
Int J Mol Sci ; 23(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36142668

RESUMO

Maintaining the normal function of oligodendrocyte precursor cells (OPCs) and protecting OPCs from damage is the basis of myelin regeneration in multiple sclerosis (MS). In this paper, we investigated the effect of stemazole, a novel small molecule, on the promotion of oligodendrocyte precursor cell survival and remyelination. The results show that stemazole enhanced the survival rate and the number of clone formation in a dose-dependent manner and decreased the percentage of cell apoptosis. In particular, the number of cell clones was increased up to 6-fold (p < 0.001) in the stemazole group compared with the control group. In vivo, we assessed the effect of stemazole on recovering the motor dysfunction and demyelination induced by cuprizone (CPZ). The results show that stemazole promoted the recovery of motor dysfunction and the repair of myelin sheaths. Compared with the CPZ group, the stemazole group showed a 30.46% increase in the myelin area (p < 0.001), a 37.08% increase in MBP expression (p < 0.01), and a 1.66-fold increase in Olig2 expression (p < 0.001). Histologically, stemazole had a better effect than the positive control drugs. In conclusion, stemazole promoted OPC survival in vitro and remyelination in vivo, suggesting that this compound may be used as a therapeutic agent against demyelinating disease.


Assuntos
Doenças Desmielinizantes , Células Precursoras de Oligodendrócitos , Remielinização , Animais , Diferenciação Celular , Cuprizona/efeitos adversos , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Hidrazinas , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Oxidiazóis
14.
Acta Histochem ; 124(7): 151953, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36116321

RESUMO

Multiple Sclerosis (MS) is a chronic and autoimmune disease of the central nervous system that causes inflammation in the brain and spinal cord, progressive degeneration of central nervous system tissue, damage to neuronal axons, and loss of function of central nervous system neurons. Experimental encephalomyelitis is an alternative animal model of MS that can simulate the symptoms of this disease. Cuprizone is one of the factors creating this model. Various researchers are testing the use of different cells to reduce the symptoms of cuprizone-demyelinated mice. The different injection methods explained in this article include intracerebral, intraperitoneal, intravenous, and intranasal. The intracerebral method, in contrast to the intranasal method, was widely employed by researchers. In each technique, the researchers try to inject a specific type of stem cell (SC) and monitor their efficiency. For monitoring SCs various labeling procedures are available, however, there is an upward trend in using magnetic resonance imaging (MRI). Two main barriers to using this method are high cost and complexity. In the current review, we try to make review cell therapy in the cuprizone model of MS.


Assuntos
Cuprizona , Esclerose Múltipla , Animais , Encéfalo/patologia , Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia
15.
Neurotox Res ; 40(5): 1415-1426, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36053462

RESUMO

Intranasal mesenchymal stem cells (MSCs) delivery is a non-invasive method that has received interests for treatment of neurodegenerative diseases, such as multiple sclerosis (MS). The impact of intranasal MSCs on intermittent cuprizone model of demyelination was a focus of this study. C57/BL6 mice were fed with 0.3% cuprizone in an intermittent or single ways. Luxol fast blue (LFB), Rotarod test, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and western blot (WB) were used for interpretation of outcomes. MSCs effectively homed to the corpus callosum area, were able to improve motor coordination and to promote myelin recovery in the intermittent cuprizone (INTRCPZ/MSCs). Astrogliosis (GFAP+ cells) and microgliosis (Iba-1+ cells) were hampered, and more mature oligodendrocyte cells (APC+ cells) were identified in mice receiving INTRCPZ/MSCs. Such treatment also considerably reduced markers related to the macrophage type 1 (M1) cells, namely iNOS and CD86, but it recovered the M2 markers MRC-1 and TREM-2. In addition, a remarkable decrease in the expressions of pro-inflammatory IL-1ß and TNFα but an increase in the rate of anti-inflammatory TGF-ß and IL-10 were identified in mice that underwent INTRCPZ/MSCs therapy. Finally, microvascular changes were evaluated, and a noticeable increase in the expression of the endothelial cell marker CD31 was found in the INTRCPZ/MSCs-treated mice (p < 0.05 for all). The outcomes are representative of the efficacy of intranasal MSCs delivery in intermittent cuprizone model of MS for reshaping macrophage polarity along with modification of glial, inflammatory, and angiogenic markers in favor of therapy.


Assuntos
Doenças Desmielinizantes , Células-Tronco Mesenquimais , Esclerose Múltipla , Animais , Corpo Caloso/metabolismo , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/terapia , Modelos Animais de Doenças , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Mol Neurobiol ; 59(12): 7278-7292, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36175823

RESUMO

Astrocytes display an active, dual, and controversial role in multiple sclerosis (MS), a chronic inflammatory demyelination disorder. However, mesenchymal stem cells (MSCs) can affect myelination in demyelinating disorders. This study aimed to investigate the effect of single and combination therapies of astrocyte ablation and MSC transplantation on remyelination in the cuprizone (CPZ) model of MS. C57BL/6 mice were fed 0.2% CPZ diet for 12 weeks. Astrocytes were ablated twice by L-a-aminoadipate (L-AAA) at the beginning of weeks 13 and 14 whereas MSCs were injected in the corpus callosum at the beginning of week 13. Motor coordination and balance were assessed through rotarod test whereas myelin content was evaluated by Luxol-fast blue (LFB) staining and transmission electron microscopy (TEM). Glial cells were assessed by immunofluorescence staining while mRNA expression was evaluated by quantitative real-time PCR. Combination treatment of ablation of astrocytes and MSC transplantation (CPZ + MSC + L-AAA) significantly decreased motor coordination deficits better than single treatments (CPZ + MSCs or CPZ + L-AAA), in comparison to CPZ mice. In addition, L-AAA and MSCs treatment significantly enhanced remyelination compared to CPZ group. Moreover, combination therapy caused a significant decrease in the number of GFAP+ and Iba-1+ cells, whereas oligodendrocytes were significantly increased in comparison to CPZ mice. Finally, MSC administration resulted in a significant upregulation of BDNF and NGF mRNA expression levels. Our data indicate that transient ablation of astrocytes along with MSCs treatment improve remyelination through enhancing oligodendrocytes and attenuating gliosis in a chronic demyelinating mouse model of MS.


Assuntos
Doenças Desmielinizantes , Transplante de Células-Tronco Mesenquimais , Esclerose Múltipla , Remielinização , Animais , Camundongos , Cuprizona/toxicidade , Astrócitos/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/terapia , Doenças Desmielinizantes/metabolismo , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Modelos Animais de Doenças , Esclerose Múltipla/terapia , Esclerose Múltipla/metabolismo , RNA Mensageiro/metabolismo
17.
J Ethnopharmacol ; 298: 115622, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35964820

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Astragali is a traditional Chinese medicine with various pharmacological effects. Total astragalosides (TA), the main effective ingredients in Radix Astragali, exert properties including anti-oxidative stress, anti-neuroinflammation, and neuroprotection. We previously found that TA alleviated experimental autoimmune encephalomyelitis (EAE) progression, a widely used animal model of multiple sclerosis (MS). As a chronic demyelination disease, MS generally manifests myelin loss and fails to myelin regeneration. Regulation of oligodendrocyte progenitor cells (OPCs) differentiation and remyelination is the fundamental strategy for MS treatment. However, whether TA could directly promote OPCs differentiation and remyelination is still unknown. AIMS OF THE STUDY: This study was aimed to investigate pro-differentiation and myelin regeneration effects of TA on OPCs and Cuprizone (CPZ)-induced demyelination mice, an animal model of MS, and to explore mechanism underlying from regulation of OPCs differentiation and maturation. MATERIALS AND METHODS: Mice were orally given CPZ (400 mg/kg) daily for 4 weeks to induce myelin loss, and then treated with TA (25 and 50 mg/kg) daily for 1 week. Cell proliferation assay, Western blot, RT-PCR, immunocytochemistry and immunohistochemistry were performed to explore the mechanisms. The role of TA in oligodendrocyte differentiation and maturation was evaluated using MO3.13, a human oligodendrocytic hybrid cell line. RESULTS: TA was shown to mitigate behavioral impairment in CPZ-induced mice. It markedly ameliorated myelin loss and enhanced remyelination in the corpus callosum of mice, evidenced by increased expression of myelin basic protein (MBP) and the number of CC1+ newly generated oligodendrocytes (OLs). TA also enhanced the expression of MBP at both mRNA and protein levels in MO3.13 cells. In CPZ-induced mice and MO3.13 cells, TA remarkably promoted the activation of GSK3ß, repressed the phosphorylation of ß-catenin, reduced the expression of transcription factor 4 and inhibitor of DNA binding 2. The agonist of ß-catenin, SKL2001, partially abolished the pro-differentiation effect of TA in MO3.13 cells. CONCLUSIONS: Taken together, we clarified that TA could effectively enhance the differentiation and maturation of OPCs and accelerate remyelination in CPZ-induced mice through inhibition of Wnt/ß-catenin signaling pathway. This study provides new insight into the beneficial effect of TA in the treatment of MS.


Assuntos
Encefalomielite Autoimune Experimental , Células Precursoras de Oligodendrócitos , Remielinização , Animais , Diferenciação Celular , Cuprizona/metabolismo , Cuprizona/toxicidade , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
18.
Phytomedicine ; 106: 154309, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35994846

RESUMO

BACKGROUND: Inefficient differentiation of oligodendrocyte precursor cells (OPCs) is one of the significant pathological obstacles of myelin repair and provides an essential therapeutic target against behavioral dysfunction in various neurodegenerative diseases, especially in secondary progressive multiple sclerosis (SPMS). Ginsenoside Rg1 (Rg1) has traditionally been recognized as a protector of neuronal damages, preventing its degeneration. PURPOSE: We investigated the effects of Rg1 on myelin regeneration-mediated by OPCs and its therapeutic significance in SPMS. METHODS: A cuprizone (CPZ) model was established and then administered with Rg1 specific for evaluations of functional recovery and remyelination. In vitro, the primary mouse OPCs were isolated and cultured for examining their ability of myelin repair. Furthermore, a chronic experimental autoimmune encephalomyelitis (EAE) model was utilized to assess the therapeutic value on SPMS. RESULTS: We found that Rg1 promoted functional recovery of the demyelinated mice, including spatial memory, motor function, and anxiety-like behavior. Histologically, Rg1 enhanced myelin-genesis as proven by myelin staining and microstructures of myelin observed by transmission electron microscope. Furthermore, Rg1 significantly increased Olig2+ oligodendrocyte lineage cells in callosum, implying that the pro-remyelination effect of Rg1 was closely correlated to the enhanced differentiation of OPCs. We further demonstrated that Rg1 increased the survival and proliferation of OPCs as well as induced maturation in oligodendrocytes (OLs). Molecular analysis showed that Rg1 transduced the pro-differentiation signaling programmed by the GSK3ß/ß-Catenin pathway. Notably, relying on its pro-remyelination effects, Rg1 ameliorated severity and histopathology of EAE disease. CONCLUSION: By paving the way for OPCs differentiation, Rg1 could maintain the integrity of myelin and is a promising candidate for functional recovery in demyelinating diseases.


Assuntos
Encefalomielite Autoimune Experimental , Células Precursoras de Oligodendrócitos , Remielinização , Animais , Diferenciação Celular , Cuprizona/metabolismo , Cuprizona/farmacologia , Cuprizona/uso terapêutico , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ginsenosídeos , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Remielinização/fisiologia , beta Catenina/metabolismo
19.
Int J Med Mushrooms ; 24(9): 15-24, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36004706

RESUMO

Epidemiologic studies have shown a high prevalence of multiple sclerosis (MS) in Europe and North America, and a low prevalence in East Asia. Mushrooms contain various biological response modifiers (BRMs) and are widely used in traditional Chinese medicine in East Asian countries. To investigate whether mushrooms have potential beneficial effects on MS, we administered mushrooms to cuprizone (bis-cyclohexanone-oxalyldihydrazone, CPZ)-induced MS model mice. This model is used to study the processes of demyelination in the CNS. The CPZ-induced demyelination is involved in the apoptotic death of mature oligodendrocytes, neuroinflammation, and motor dysfunction. Mice were fed a powdered diet containing 5% each mushroom and CPZ diet for 5 weeks, which coincides with peak demyelination. We measured the body weight of the mice, evaluated their motor function using a rotarod, and quantified the myelin levels using Black-Gold II staining. Ganoderma lucidum and Hericium erinaceus treatments showed recovery from weight loss. Pleurotus eryngii, G. lucidum, and Flammulina velutipes treatments significantly improved CPZ-induced motor dysfunction. P. eryngii, G. lucidum, F. velutipes, and H. erinaceus treatments effectively suppressed CPZ-induced demyelination. The four medicinal mushrooms may be promising BRMs for prevention and alleviation of the symptoms of MS.


Assuntos
Agaricales , Doenças Desmielinizantes , Esclerose Múltipla , Animais , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Modelos Animais de Doenças , Carpóforos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico
20.
Cell Rep ; 40(8): 111189, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-36001972

RESUMO

Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding oligodendrocyte activation states would shed light on disease processes. We identify three distinct activation states of oligodendrocytes from single-cell RNA sequencing (RNA-seq) of mouse models of Alzheimer's disease (AD) and multiple sclerosis (MS): DA1 (disease-associated1, associated with immunogenic genes), DA2 (disease-associated2, associated with genes influencing survival), and IFN (associated with interferon response genes). Spatial analysis of disease-associated oligodendrocytes (DAOs) in the cuprizone model reveals that DA1 and DA2 are established outside of the lesion area during demyelination and that DA1 repopulates the lesion during remyelination. Independent meta-analysis of human single-nucleus RNA-seq datasets reveals that the transcriptional responses of MS oligodendrocytes share features with mouse models. In contrast, the oligodendrocyte activation signature observed in human AD is largely distinct from those observed in mice. This catalog of oligodendrocyte activation states (http://research-pub.gene.com/OligoLandscape/) will be important to understand disease progression and develop therapeutic interventions.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Doenças Neurodegenerativas , Animais , Cuprizona/uso terapêutico , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Oligodendroglia
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