title: Laquinimod prevents cuprizone-induced demyelination independent of Toll-like receptor signaling.
abstract: 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.
authors.affiliation: Institute of Neuropathology (N.K., L.M., U.-K.H., W.B.), University Medical Center Göttingen, Germany; and Teva Pharmaceutical Industries (L.H.), Netanya, Israel.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kramann
authors.affiliation: Institute of Neuropathology (N.K., L.M., U.-K.H., W.B.), University Medical Center Göttingen, Germany; and Teva Pharmaceutical Industries (L.H.), Netanya, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Menken
authors.affiliation: Institute of Neuropathology (N.K., L.M., U.-K.H., W.B.), University Medical Center Göttingen, Germany; and Teva Pharmaceutical Industries (L.H.), Netanya, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.affiliation: Institute of Neuropathology (N.K., L.M., U.-K.H., W.B.), University Medical Center Göttingen, Germany; and Teva Pharmaceutical Industries (L.H.), Netanya, Israel.
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.affiliation: Institute of Neuropathology (N.K., L.M., U.-K.H., W.B.), University Medical Center Göttingen, Germany; and Teva Pharmaceutical Industries (L.H.), Netanya, Israel.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück