Platelet-Activating Factor Deteriorates Lysophosphatidylcholine-Induced Demyelination Via Its Receptor-Dependent and -Independent Effects.
Mol Neurobiol
; 57(10): 4069-4081, 2020 Oct.
Article
em En
| MEDLINE
| ID: mdl-32661728
ABSTRACT
Accumulating evidence suggests that platelet-activating factor (PAF) increases the inflammatory response in demyelinating diseases such as multiple sclerosis. However, PAF receptor (PAFR) antagonists do not show therapeutic efficacy for MS, and its underlying mechanisms remain poorly understood. In the present study, we investigated the effects of PAF on an ex vivo demyelination cerebellar model following lysophosphatidylcholine (LPC, 0.5 mg/mL) application using wild-type and PAFR conventional knockout (PAFR-KO) mice. Demyelination was induced in cerebellar slices that were cultured with LPC for 18 h. Exogenous PAF (1 µM) acting on cerebellar slices alone did not cause demyelination but increased the severity of LPC-induced demyelination in both wild-type and PAFR-KO mice. LPC inhibited the expression of PAF-AH, MBP, TNF-α, and TGF-ß1 but facilitated the expression of IL-1ß and IL-6 in wild-type preparations. Of note, exogenous PAF stimulated microglial activation in both wild-type and PAFR-KO mice. The subsequent inflammatory cytokines TNFα, IL-1ß, and IL-6 as well as the anti-inflammatory cytokine TGF-ß1 demonstrated a diverse transcriptional profile with or without LPC treatment. PAF promoted TNF-α expression and suppressed TGF-ß1 expression indiscriminately in wild-type and knockout slices; however, transcription of IL-1ß and IL-6 was not significantly affected in both slices. The syntheses of IL-1ß and IL-6 were significantly increased in LPC-induced demyelination preparations without PAF but showed a redundancy in PAF-treated wild-type and knockout slices. These data suggest that PAF can play a detrimental role in LPC-induced demyelination probably due to a redundant response of PAFR-dependent and PAFR-independent effects on inflammatory cytokines.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator de Ativação de Plaquetas
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Glicoproteínas da Membrana de Plaquetas
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Doenças Desmielinizantes
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Receptores Acoplados a Proteínas G
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Neurobiol
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Ano de publicação:
2020
Tipo de documento:
Article