[PD5.004] Laquinimod Induces Up-Regulation of BDNF in Serum of Patients with Relapsing-Remitting Multiple Sclerosis

Jan Thöne, Silvia Seubert, Rebecca Conrad, Bochum, NRW, Germany, Giancarlo Comi, Milan, Italy, Stefan Wiese, Bochum, NRW, Germany, Liat Hayardeny, Netanya, Israel, Ralf Gold, Ralf Andreas Linker, Bochum, NRW, Germany

OBJECTIVE: To evaluate the expression of neurotrophic factors in the serum of MS patients treated with laquinimod. BACKGROUND: Laquinimod is a new orally active compound for the treatment of multiple sclerosis (MS). In patients with relapsing-remitting MS (RRMS), 0.6 mg laquinimod per day significantly reduced disease activity measured by MRI in a phase II study (LAQ/5062). Although available data suggest immunomodulatory effects of laquinimod, further investigation is required. DESIGN/METHODS: 596 serum samples from RRMS patients participating in the LAQ/5062 trial were tested for the presence of neurotrophin (NT)-3 and brain derived neurotrophic factor (BDNF). Moreover, the expression of 19 different cytokines/chemokines was assayed in the same samples. Participants were treated with either placebo or laquinimod 0.6 mg/d. Blinded testing of sera was performed at baseline and after 3 and 9 months of treatment. Data on the expression of neurotrophic factors were correlated with functional activity in a neuronal survival assay and neuroimaging patterns, respectively. RESULTS: Treatment with 0.6 mg of laquinimod for 3 months resulted in a significant and specific increase (up to 11-fold) in BDNF serum levels as compared to baseline or placebo treatment (Total amount of mean SEM: 16088 760 pg/ml BDNF in the laquinimod-group vs. 12882 625 pg/ml in the placebo-group, p < 0.05 and vs. 14436 778 pg/ml at baseline, p < 0.05). However, neither NT-3 nor tested chemokines/cytokines were altered. This effect on BDNF was maintained at 9 months and when analyzing the relapse-free subgroup. Bioactivity of serum BDNF was demonstrated in a dorsal root ganglion survival assay. FACS analyses revealed a slight increase of BDNF in CD4 positive immune cells after stimulation with laquinimod in vitro. CONCLUSIONS/RELEVANCE: In addition to its immunomodulatory actions, laquinimod increases levels of the neurotrophic factor BDNF in vivo, possibly contributing to neuroprotection in MS patients. Supported by: TEVA Pharmaceuticals Industries Ltd.
Category - MS and Related Diseases - Clinical Science

Thursday, April 15, 2010 7:30 AM

Poster Discussion Session V: Multiple Sclerosis and Related Diseases: Drug Mechanisms (7:30 AM-12:00 PM)