Tuesday, 25 December 2012

Research: Laquinimod prevents inflammation-induced synaptic alterations

Epub: Ruffini et al. Laquinimod prevents inflammation-induced synaptic alterations occurring in experimental autoimmune encephalomyelitis.Mult Scler. 2012 Dec. 

BACKGROUND: There are two generally accepted strategies for treating multiple sclerosis (MS), preventing central nervous system (CNS) damage indirectly through immunomodulatory interventions and/or repairing CNS damage by promoting remyelination. Both approaches also provide neuroprotection since they can prevent, indirectly or directly, axonal damage. OBJECTIVE Recent experimental and clinical evidence indicates that the novel immunomodulatory drug laquinimod can exert a neuroprotective role in MS. Whether laquinimod-mediated neuroprotection is exerted directly on neuronal cells or indirectly via peripheral immunomodulation is still unclear.

METHODS: C57BL/6 experimental autoimmune encephalomyelitis (EAE) mice, immunised with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, were treated for 26 days with subcutaneous daily injections of laquinimod (from 1 to 25 mg/kg). Patch clamp electrophysiology was performed on acute brain striatal slices from EAE mice treated with daily (25 mg/kg) laquinimod and on acute brain striatal slices from control mice bathed with laquinimod (1-30 ┬ÁM).

RESULTS: Both preventive and therapeutic laquinimod treatment fully prevented the alterations of GABAergic synapses induced by EAE, the first limiting also glutamatergic synaptic alterations. This dual effect might, in turn, have limited glutamatergic excitotoxicity, a phenomenon previously observed early during EAE and possibly correlated with later axonal damage. Furthermore, laquinimod treatment also preserved cannabinoid CB1 receptor sensitivity, normally lost during EAE. Finally, laquinimod per se was able to regulate synaptic transmission by increasing inhibitory post-synaptic currents and, at the same time, reducing excitatory post-synaptic currents.

CONCLUSIONS: Our data suggest a novel neuroprotective mechanism by which laquinimod might in vivo protect from neuronal damage occurring as a consequence of inflammatory immune-mediated demyelination.


Lacquinimod was one of the disappointments of 2012, this is an oral immunomodulator, which turned out to be not much of an imunomodulator and was worse than beta interferons t affecting relapses. The FDA wanted more trials to try and convince themselves that it was worthwhile. As an immunomodulator it was not that impressive but the effect on disability progression was much more impressive. Could they have found a neuroprotective drug? Put in on top of an immune modulator and you could have something useful, unfortunateyl they will not doubt put it on top of glaterimer acetate, as it is a Teva drug.

This study reports that lacquinimod promote nerve compensation, some of it will be "chicken and Egg" because in animals it can be n effective immunomodulator, so it stops EAE so it is not surprising that it will stop synapse formation. But this study shows it can do something apparently directly on nerves to promote synapse formation by stimulating the negative excitory nervous transmitter, whilst blocking the excitatory glutamatergic nerves. Time for a trial in progressive MSers!

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