December 8, 2011

Reducing Brain Damage

(Ivanhoe Newswire) — Save the neurons! A new study suggests laquinimod triggers immune cells within the central nervous system produce and release brain-derived neurotrophic factor, BDNF, contributing to the repair or survival of neurons; therefore limiting brain damage.

Laquinimod is an orally available synthetic compound for the treatment of relapsing-remitting multiple sclerosis.

"Our data are indicative of a direct and sustained effect of laquinimod on the up-regulation of bioactive BDNF in patients with RRMS. Additionally, we demonstrate that laquinimod targets monocytes and skews the phagocyte population towards a regulatory phenotype, which in turn mediates immune modulation in vivo," Jan Thöne, MD, of the Department of Neurology at St. Josef-Hospital Bochum and Ruhr-University Bochum, Germany was quoted as saying.

Neurotrophins, such as BDNF, are essential for the development and maintenance of neurons and axons in the central nervous system. Although BDNF is mainly produced by neurons, several types of immune cells also secrete BDNF, suggesting a role in neuroprotection.

Researchers evaluated levels of BDNF in the serum of RRMS patients treated with laquinimod. A significant and robust BDNF increase occurred in 76 percent of the laquinimod-treated patients, with a high increase in BDNF serum levels observed in individual patients.

Despite BDNF elevation independent of relapse rate, and the no correlation between levels, age, gender or baseline disability; the source of serum BDNF subsequent to treatment remained questionable.

To investigate whether laquinimod-treated monocytes mediate immune modulation in vivo, laquinimod-stimulated monocytes were injected into WT mice at an early experimental autoimmune encephalomyelitis, EAE, a model of MS, disease stage. The mice showed less severe disease course than controls. Transfer of laquinimod-treated cells derived from mice with a conditional BDNF deficiency in immune cells, into wild-type mice with ongoing EAE did not influence disease course. The cells also secrete significantly less IL-10, an immunomodulatory cytokine that is associated with the generation of regulatory monocytes.

"Consistent with immunomodulatory properties, laquinimod skewed monocytes towards a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients," Thöne was quoted as saying. "To date, selective targeting of monocytes has not been described for any other MS pipeline drug, highlighting an innovative mechanism of action of laquinimod."

SOURCE: American Journal of Pathology, December 7, 2011