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1.
Mult Scler ; 30(1): 35-43, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37982154

RESUMEN

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). OBJECTIVE: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. METHODS: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. RESULTS: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = -0.113%, 95% confidence interval (CI): -0.204% to -0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. CONCLUSIONS: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Factores Inhibidores de la Migración de Macrófagos , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Femenino , Humanos , Masculino , Atrofia/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Factores Inhibidores de la Migración de Macrófagos/líquido cefalorraquídeo , Factores Inhibidores de la Migración de Macrófagos/uso terapéutico , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/patología
2.
Neurotherapeutics ; 20(4): 1229-1240, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37296356

RESUMEN

Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS). This study aimed to investigate whether a novel long-acting GLP-1R agonist, NLY01, could limit demyelination or improve remyelination as occurs in MS using the cuprizone (CPZ) mouse model. Herein, we assessed the expression of GLP-1R on oligodendrocytes in vitro and found that mature oligodendrocytes (Olig2+PDGFRa-) express GLP-1R. We further confirmed this observation in the brain by immunohistochemistry and found that Olig2+CC1+ cells express GLP-1R. We next administered NLY01 twice per week to C57B6 mice while on CPZ chow diet and found that NLY01 significantly reduced demyelination with greater weight loss than vehicle-treated controls. Because GLP-1R agonists are known to have anorexigenic effect, we then administered CPZ by oral gavage and treated the mice with NLY01 or vehicle to ensure the dose consistency of CPZ ingestion among mice. Using this modified approach, NLY01 was no longer effective in reducing demyelination of the corpus callosum (CC). We next sought to examine the effects of NLY01 treatment on remyelination after CPZ intoxication and during the recovery period using an adoptive transfer-CPZ (AT-CPZ) model. We found no significant differences between the NLY01 and vehicle groups in the amount of myelin or the number of mature oligodendrocytes in the CC. In summary, despite the promising anti-inflammatory and neuroprotective effects of GLP-1R agonists that have been previously described, our experiments provided no evidence to support a beneficial effect of NLY01 on limiting demyelination or enhancing remyelination. This information may be useful in selecting proper outcome measures in clinical trials of this promising class of drugs in MS.


Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple , Remielinización , Ratones , Animales , Cuprizona/toxicidad , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Vaina de Mielina , Esclerosis Múltiple/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL
3.
Front Mol Neurosci ; 15: 995477, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36407761

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). In people with MS, impaired remyelination and axonal loss lead to debilitating long-term neurologic deficits. Current MS disease-modifying drugs mainly target peripheral immune cells and have demonstrated little efficacy for neuroprotection or promoting repair. To elucidate the pathological mechanisms and test therapeutic interventions, multiple animal models have been developed to recapitulate specific aspects of MS pathology, particularly the acute inflammatory stage. However, there are few animal models that facilitate the study of remyelination in the presence of inflammation, and none fully replicate the biology of chronic demyelination in MS. In this review, we describe the animal models that have provided insight into the mechanisms underlying demyelination, myelin repair, and potential therapeutic targets for remyelination. We highlight the limitations of studying remyelination in toxin-based demyelination models and discuss the combinatorial models that recapitulate the inflammatory microenvironment, which is now recognized to be a major inhibitor of remyelination mechanisms. These models may be useful in identifying novel therapeutics that promote CNS remyelination in inflammatory diseases such as MS.

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