Laquinimod prevents cuprizone-induced demyelination independent of Toll-like receptor signaling
| Autor: | Nadine Kramann, Wolfgang Brück, Uwe-Karsten Hanisch, Liat Hayardeny, Lena Menken |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Pathology Biology Article 03 medical and health sciences chemistry.chemical_compound Myelin 0302 clinical medicine Internal medicine medicine Receptor Microglia Multiple sclerosis medicine.disease Oligodendrocyte 030104 developmental biology Endocrinology medicine.anatomical_structure Neurology chemistry TRIF TLR4 Neurology (clinical) Laquinimod 030217 neurology & neurosurgery |
| Zdroj: | Neurology® Neuroimmunology & Neuroinflammation |
| ISSN: | 2332-7812 |
| Popis: | Objective: To test whether Toll-like receptor (TLR) signaling plays a key role for reduced nuclear factor B (NF-κB) activation after laquinimod treatment in the model of cuprizone-induced demyelination, oligodendrocyte apoptosis, inflammation, and axonal damage. Methods: Ten-week-old C57BL/6J, TLR4 −/− , and MyD88 −/− mice received 0.25% cuprizone for 6 weeks and were treated daily with 25 mg/kg laquinimod or vehicle. After 6 weeks of demyelination, extent of demyelination, oligodendrocyte density, microglia infiltration, and axonal damage were analyzed in the corpus callosum. Additionally, we analyzed primary mouse astrocytes from C57BL/6J, TLR4 −/− , MyD88 −/− , and TRIF −/− mice for alteration in NF-κB signaling. Results: Vehicle-treated controls from C57BL/6J, TLR4 −/− , and MyD88 −/− mice displayed extensive callosal demyelination as well as microglial activation. In contrast, mice treated with 25 mg/kg laquinimod showed mainly intact callosal myelin. The demyelination score was significantly higher in all untreated mice compared to mice treated with laquinimod. There were significantly fewer APP-positive axonal spheroids, Mac3-positive macrophages/microglia, and less oligodendrocyte apoptosis in the corpus callosum of laquinimod-treated mice in comparison to untreated controls. Stimulated primary mouse astrocytes from laquinimod-treated groups show reduced NF-κB activation compared to vehicle-treated controls. Conclusions: Our results confirm that laquinimod prevents demyelination in the cuprizone mouse model for multiple sclerosis via downregulation of NF-κB activation. This laquinimod effect, however, does not involve upstream Toll-like receptor signaling. |
| Databáze: | OpenAIRE |
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