MS patients may reap neuroprotection benefit from laquinimod
MedWire News: The beneficial therapeutic effect of the oral immunomodulator laquinimod on relapsing remitting multiple sclerosis (RRMS) may be due to the stimulation of brain-derived neurotrophic factor (BDNF) production, researchers report. <
BDNF plays a role in nerve cell development and maintenance within the central nervous system, say the investigators in the American Journal of Pathology.
They therefore suggest that increasing the action of BDNF may boost protection and survival of neurons that typically die in RRMS.
Jan Thöne (Ruhr-University Bochum, Germany) and co-investigators assessed BDNF levels in blood samples obtained from 203 RRMS patients enrolled in phase II clinical trials for laquinimod. Of these, 104 were treated with laquinimod 0.6 mg per day and 99 received placebo for 16 weeks.
The team found that BDNF levels increased significantly among 76% of the patients given laquinimod, and this group had BDNF levels up to 11-fold higher than those of placebo-treated patients by the end of treatment.
Thöne and team found that BDNF elevation was not associated with relapse rate, age, gender, or baseline RRMS severity.
The researchers then conducted a mouse model-based assessment of the drug's properties by comparing its effects in normal mice with a condition similar to RRMS, experimental autoimmune encephalomyelitis (EAE), with its effects in BDNF-deficient mice with EAE.
The team found that laquinimod reduced the occurrence and severity of EAE in normal mice but not in BDNF-deficient mice. The former group of mice also exhibited greater preservation of neuronal axons and less nerve-based inflammation than the latter group.
This, say Thöne and colleagues, indicates "the beneficial effect of directly administered BDNF or BDNF gene transfer for enhanced survival of injured neurons and regenerative capacity."
Further investigation with mouse models demonstrated that laquinimod targets monocytes and encourages phagocyte differentiation into a regulatory cell type that facilitates immunomodulation.
The researchers therefore conclude: "Pharmacological modulation of BDNF secretion or stimulation of BDNF transcription is a promising goal in MS.
"In contrast to licensed immunomodulatory therapies and pipeline drugs for MS, which primarily target the immune system, laquinimod may provide both immunomodulatory and neuroprotective mechanisms of action."
By Lauretta Ihonor