title: Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor.
abstract: Laquinimod is a promising, orally available compound that has been successfully evaluated in placebo-controlled phase II/III studies of relapsing-remitting multiple sclerosis (MS). Studies are ongoing to further define laquinimod's modulatory mechanisms. Analyses in the animal model of experimental autoimmune encephalomyelitis (EAE) demonstrate that laquinimod reduces infiltration of leukocytes into the central nervous system, induces a Th1 to Th2/3 shift, and suppresses Th17 responses. To evaluate the potential neuroprotective capacity of laquinimod via modulation of brain-derived neurotrophic factor (BDNF), we analyzed the expression of BDNF in blood samples from 203 MS patients treated with laquinimod. Furthermore, we investigated the effect of laquinimod in EAE using a conditional BDNF knockout strain lacking BDNF expression in myeloid cells and T cells (LLF mice). Treatment with laquinimod resulted in a significant and persistent increase in BDNF serum levels of MS patients when compared to baseline and placebo-treated patients. LLF mice treated with laquinimod display a more severe EAE disease course in comparison to wild-type mice. Furthermore, laquinimod-treated wild-type monocytes secreted an anti-inflammatory cytokine pattern in comparison to untreated wild-type monocytes and treated LLF monocytes. Adoptive transfer of laquinimod stimulated monocytes into mice with EAE ameliorated the disease course. Consistent with immunomodulatory properties, laquinimod skewed monocytes toward a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients.
authors.affiliation: Department of Neurology at St. Josef Hospital, Group for Molecular Cell Biology, Ruhr-University Bochum, Bochum, Germany. jan_thoene@gmx.de
authors.forename: Jan
authors.initials: J
authors.lastname: Thöne
authors.forename: Gisa
authors.initials: G
authors.lastname: Ellrichmann
authors.forename: Silvia
authors.initials: S
authors.lastname: Seubert
authors.forename: Isabella
authors.initials: I
authors.lastname: Peruga
authors.forename: De-Hyung
authors.initials: DH
authors.lastname: Lee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Conrad
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiese
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Linker
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D009103:Multiple Sclerosis / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D018696:Neuroprotective Agents; D015363:Quinolones; C476223:laquinimod