Download DMD reviews 95 - Action Duchenne

Research Review No. 95.
Tadalafil Amelioration of Duchenne Muscular Dystrophy
The Studies:
The authors of the publication (1) from Rome, Italy, examined the effects
of treating mdx mice, i.e. mice having a mutation in their dystrophin gene, which
are used as a model for Duchenne Muscular Dystrophy (DMD), with tadalafil.
Due to the adverse side effects that corticosteroids, which are currently the drugs
of choice for ameliorating DMD, can have on patients, the authors investigated
the effect of different types of non-steroidal anti-inflammatory drugs (NSAIDs) on
mdx mice. A study reported in 2012 “revealed that these compounds have a
beneficial effect on dystrophic muscle morphology that is comparable to
glucocorticoid treatment”.
As a result of extensive biochemical and physiological studies, the authors
concluded that agents which affected a family of enzymes called
phosphodiesterases (PDEs), which are “extensively used in human therapy, and
much is known regarding their toxicology, potential side effects, drug regimens,
and pharmacoepidemiology, as well as regarding tolerance to their long-term
use. PDE5 plays a critical role in heart physiology”. It had been observed in
earlier studies that “following PDE5 inhibition, an improvement of vascular activity
in dystrophic mice and a reduction of skeletal myofibril damage were observed”.
The authors therefore investigated the molecular alterations that could possibly
contribute to the therapeutic effects of drugs blocking PDE5 on mdx mice.
The results of these studies are well presented especially in the colourful
graphs, which show that mdx mice treated with tadalafil work on the treadmill
nearly as well as wild-type mice. Also they note that “more than 200 genes are
up-regulated and approximately 140 genes are downregulated in dystrophic
muscles following tadalafil treatment.”
These are the first studies that reveal “critical pathways implicated in
tadalafil-based therapy in muscular dystrophy”, they also show most importantly,
that “tadalafil can compensate the loss of functional dystrophin in muscle cells by
metabolic reprogramming of myofibers towards a profile more resistant to
contraction-induced damage”. This beneficial effect is explained by detailed
biochemistry of the role of tadalafil.
References:
1) De Arcangelis, V., Strimpakos, G., Gabanella, F., Corbi, N., Luvisetto, S.,
Magrelli, A., Onori, A., Passananti, C., Pisani, C., Rome, S., Severini, C., Naro,
F., Mattei, E., Di Certo, M.G. & Monaco, L. (2016) Pathways Implicated in
Tadalafil Amelioration of Duchenne Muscular Dystrophy. Journal of Cellular
Physiology. 231(1):224-232.
2) Serra, F., Quarta, M., Canato, M., Toniolo, L., De Arcangelis, V,., Trotta, A.,
Spath, L., Monaco, L., Reggiani, C. & Naro, F. (2012) Inflammation in muscular
dystrophy and the beneficial effects of non-steroidal anti-inflammatory drugs.
Muscle and Nerve. 46:773–784.
Karl A. Bettelheim
23.10.2015