Viagra stops demyelination

V


Sildenafil (Viagra) induces cyclicGMP accumulation through phosphodiesterase-5 (PDE5)
inhibition. cGMP-pathways protect oligodendrocytes and modulate
astroglial (which contain glial fibraillary acid protein = GFAP) and microglial (which express Iba-1) reactions. Microglia and astrocytes play an
important role in perpetuating multiple sclerosis
(MS), a chronic inflammatory disease characterized by demyelination.
Therefore, sildenafil can be a potential tool for MS treatment.

The
present study investigated the effects of sildenafil on the myelin
structure and astrocyte/microglia-mediated neuroinflammation in an
animal model of MS. Cuprizone-induced demyelination and
neuroinflammation in rodents has been widely used as a model for MS.Over
a 4-week period, the different groups of mice received the following: (1)
cuprizone (0.2%) mixed into the food (2) cuprizone in the food and
sildenafil (Viagra®; 3, 25 or 50mg/kg) in the drinking water; or (3)
pure food and water (control group). Cerebella were analyzed using
transmission electron microscopy, western blotting, immunohistochemistry
and luxol fast blue staining.


Cuprizone induced tissue damage, with an
increase in GFAP, Iba-1 and demyelination in comparison to the
control group. However, cuprizone did not affect the expression of
cytokines (TNF-α, IFN-γ, IL-1β and IL-2 = pro-inflammatory cytokines). Sildenafil reduced GFAP (25
and 50mg/kg) and Iba-1 expression (25mg/kg) in comparison to the
cuprizone group, indicating the modulation of astrocytes and microglia,
respectively. Sildenafil preserved myelin and axons ultrastructure and
strongly reduced IFN-γ, TNF-α, IL-1β, and IL-2 in
comparison to the control and/or cuprizone groups. The results
demonstrate a protective effect of sildenafil in the cerebellum. Thus,
well-designed clinical trials may demonstrate that the oral
administration of sildenafil can be suitable for individuals with MS and
other neuroinflammatory/neurodegenerative diseases, providing
additional benefits to current treatments.


We spoke about drugs having Janus-like effects recently where drugs can do one thing good and another  bad. Sometimes you could get more bang for your buck. We all know about the erectile effects of viagra, but this study is suggesting that it can prevent demyelination. Cuprizone is a copper containing compound that is toxic for oligodendrocytes in certain part of the brain and is given to mice so that they get demyelination in certain parts of the brain such as the cerebellulm. This is a part of the brain that co-ordinates movement. It is used to study demyelination and remyelination. 

This study suggests that viagra may limit demyelination, who it does this it is not clear.  It could be because the drug is working via PDE5 or something else. Alternatively is it because it tastes really bad and stresses the animals who do not want to drink and this may create a stress response that affects macrophage/astrocyte function. The drug is in the drinking water so you do not really know how much the animals may drink especially if they feel sick. 

In addition viagra tablets come in different sizes such as 25mg-100mg tablets. So this means people take about 0.3-1.5mg/kg. Now a mouse has faster metabolism than man so you can put a factor of 10-12 to get an equivalent dose so this is 3-15mg/kg where it did very little and required 25mg/kg. So does this mean the does is too low to have an effect on demyelination? 

What should have been done is a dose should have been selected such that it matches the drug levels, in blood, in humans and then see what it does. It costs alot to do a clinical trial and not so much to do an experiment such that it will better reflect how the drug is to be used in humans.

So this new action remains a theoretical but unproven possibility. 

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MouseDoctor

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  • The side-effect of course is that us gentlemen will be walking round with a permanent hat stand!

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