Saturday, 20 April 2013

Research: Active part of Gilenya saving nerves

Fingolimod Phosphate Attenuates Oligomeric Amyloid β-Induced Neurotoxicity via Increased Brain-Derived Neurotrophic Factor Expression in Neurons. Doi Y, Takeuchi H, Horiuchi H, Hanyu T, Kawanokuchi J, Jin S, Parajuli B, Sonobe Y, Mizuno T, Suzumura A. PLoS One. 2013 Apr 12;8(4):e61988. Print 2013.

The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P) receptor (S1PR) agonist fingolimod phosphate (FTY720-P)-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF) in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease.

When Gilenya is injested it is gains phosphorous and this phosphrylated form of the drug is the major active part of the drug.
We know that the major way that the drug works is to stop white blood cells leaving lymph glands such that they do not get into the blood and this stops them getting in the brain and this stops relapsing MS. This works via S1P1 receptor, but in the brain cells alot more S1P receptors such as S1P5, are found. 

Furthermore, fingolimod phosphate easily gets in the brain and it has been suggested by the makers of the drug that Gilenya may have nerve protecting effects in addition to the immune-influencing affect.

In this study they used the amyloid protein. Amyloid precursor protein (APP) is an membrane protein concentrated in the synapses ofneurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export. APP is best known as the precursor molecule whose breakdown generates beta amyloid (Aβ), whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease.

 This study used this to trigger nerve damage and it was found that active component from gilenya could save nerves. This effect was mediated by stimulation of brain derived neutrophopic factor, which is a nerve growth factor. If this gets stimulated in MS, it could promote nerve survival. This is in part a reason why Novartis are developing these types of drugs for progressive MS.

CoI: None

1 comment:

  1. But MouseDoc, you said that the basic science to support fingolimod's effectiveness in preventing further neurological damage in PPMS was tenuous. Have you changed your view?

    Apparently Novartis has spent like a 100 million dollars on trialling fingolimod in PPMS. Sure hope it was worth it.


Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.