Thursday, 6 November 2014

Laquinimod inhibits microglial activity and is neuroprotective

Mishra MK, Wang J, Keough MB, Fan Y, Silva C, Sloka S, Hayardeny L, Brück W, Yong VW. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation.
Ann Clin Transl Neurol. 2014 Jun;1(6):409-22.
 

OBJECTIVE: Laquinimod is an emerging oral medication for multiple sclerosis (MS) that reduces brain atrophy and progression of disability in two Phase III clinical trials. The mechanism of these effects is unclear. Persistent activation of microglia occurs in MS and contributes to injury. Thus, we investigated whether laquinimod alters properties of microglia in culture and in experimental autoimmune encephalomyelitis (EAE), and whether this reduces neurodegeneration.
METHODS: Microglia were cultured from human brains. EAE was induced in mice.
RESULTS:The activation of human microglia increased levels of several pro- and anti-inflammatory cytokines and these elevations were attenuated by pretreatment with laquinimod. Laquinimod prevented the decline in activated microglia of miR124a, a microRNA implicated in maintaining microglia quiescence, and reduced the activity of several signaling pathways (Jun-N-terminal kinase, ribosomal S6 kinase, and AKT/protein kinase B) in activated microglia. In EAE, axonal injury correlated with accumulation of microglia/macrophages in the spinal cord. EAE mice treated with laquinimod before onset of clinical signs subsequently had reduced microglia/macrophage density and axonal injury. Remarkably, when laquinimod treatment was initiated well into the disease course, the progressive demyelination, and axonal loss was halted. Besides inflammatory molecules associated with microglia, the level of inducible nitric oxide (NO) synthase capable of producing free radical toxicity was attenuated by laquinimod in EAE mice. Finally, in coculture where microglia activation caused neuronal death, laquinimod decreased NO levels, and neurotoxicity.
INTERPRETATION: Laquinimod is a novel inhibitor of microglial activation that lowers microglia-induced neuronal death in culture and axonal injury/loss in EAE.



Laquinimod was tested as a DMT and was found to be pretty rubbish compared to other current DMT, in relation to blocking relapsing disease. However, it was found to have more marked effects on brain shrinkage than would be predicted for its modest immunosuppressive effect. However, it looks like the drug may be anti-inflammatory effect and could slow the effects that drive progressive nerve damage. This looks like it is blocking microglial function and we think that this aspect of disease is a good idea to try and slow progression. 

So ideally you will put Laquinimod with another DMT that has immunosuppressive activity...not surprisingly Teva has filed patents of Laquinimod in combination with other MS drugs. 

Hopefully trials will put it to the test.... ProfG any news?

1 comment:

  1. No chance of it being an add on to alemtuzumab I expect as they're different companies. Most likely an add on to copaxone- what a waste!

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