
Laquinimod - an orally available synthetic compound triggers immune cells within the CNS to produce and release brain-derived neurotrophic factor (BDNF), contributing to the repair of neurons and thus limiting brain damage, show studies.
"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," explained Jan Thöne, MD, of the Department of Neurology at St. Josef-Hospital Bochum and Ruhr-University Bochum, Germany.
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.
Experiments with animal models corroborated the findings in human patients. Experimental autoimmune encephalomyelitis (EAE; a model of MS) was induced in mice with a conditional BDNF deficiency in immune cells (LLF mice) and in wild-type (WT) control mice. Treatment with laquinimod resulted in a significant reduction in EAE incidence and disease severity in the WT mice. The effect of laquinimod was significantly reduced in the LLF-mice.
Further studies showed that WT mice treated with a suboptimal dose of laquinimod demonstrated a significant reduction in the inflammatory area and level of demyelination. These mice also displayed a reduction of macrophage infiltration and a significant preservation of axonal densities in comparison with laquinimod-treated LLF mice and controls. The data suggest a BDNF-dependent mechanism of action for laquinimod in autoimmune demyelination.
To investigate whether laquinimod-treated monocytes mediate immune modulation in vivo, laquinimod-stimulated monocytes were injected into WT mice at an early EAE disease stage. The mice showed less severe disease course than controls. Transfer of laquinimod-treated cells derived from LLF mice into WT 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," said Dr. Thöne. "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: Eurekalert
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