Nitric oxide and ibuprofen treatment of mice with muscular dystrophy
What is the idea behind this study?
Muscle dystrophies are heritable diseases that result from defects in muscle proteins. These defects cause progressive muscle damage, and in the most severe cases, can lead to paralysis and death, due to heart and/or breathing difficulties.
Nitric oxide is a compound that is made by the body, and normally functions to activate cells surrounding muscle fibres, called satellite cells. Satellite cells have the ability to make new muscle fibres to repair muscle damage from normal daily activity. However, nitric oxide is found to be misplaced and thus not active in people with muscular dystrophy. As a result, the satellite cells become exhausted, and eventually lose their ability to make new muscle fibres. This leads to breakdown of muscle fibres, and inflammation. The deteriorating muscle becomes replaced with scar tissue. Eventually, symptoms worsen leading to muscle weakness and muscle breakdown.
To counteract these effects, previous studies have shown that a drug capable of releasing nitric oxide within the muscle tissue can reduce muscle breakdown. Administration of an anti-inflammatory drug, such as ibuprofen, reduces inflammation. Together, the two drugs are known to preserve the activity of satellite cells to make new muscle fibres that restore the health of the muscle.
This study is to test a new drug, called NCX 320 that can simultaneously release both nitric oxide, and ibuprofen, in mice with muscular dystrophy. The effect of the drug in reducing muscle breakdown, inflammation, and improving satellite cell activity can be evaluated.
What did this study show?
The effects of NCX 320 were tested in the lab, and then in mice. The lab work showed that NCX 320 inhibits two of the main inflammatory pathways (COX-1 and COX-2). NCX 320 also releases nitric oxide, to cause vasodilation (which is the relaxation of arteries and capillaries to allow more blood flow).
Mice that have been genetically engineered to have muscular dystrophy very similar to humans were treated orally with NCX 320 for 8 months. During treatment, blood levels of nitric oxide and ibuprofen were found to be appropriate.
After 8 weeks, muscle function was tested using a running wheel and a treadmill. This revealed the mice treated with NCX 320 performed significantly better than the untreated mice. Further, NCX 320 resulted in a reduction of signs in the blood for both muscle damage and inflammation to an extent greater than when the mice were treated with ibuprofen alone, or with no treatment.
Moreover, analysis of the muscle revealed that in mice treated with NCX 320, there are more healthy muscle fibres. Also, the activity of satellite cells in replacing damaged muscle fibres with healthy fibres was preserved in mice treated with NCX 320.
What does this mean for patients?
Current therapy for muscular dystrophy is based on steroid treatment (corticosteroids such as prednisone/prednisolone or deflazacort) that is mainly only able to delay the progression of the disease. There are currently many approaches scientists and clinicians are considering, but most are either not yet experimentally tested or are not broadly effective on most patients.
NCX 320, a drug that releases both nitric oxide and ibuprofen, holds a lot of promise for treatment of people with muscular dystrophy. This is because it is well known that nitric oxide helps improve muscle function and health. Further, ibuprofen is known to reduce inflammation, and is well tolerated in patients who require long-term treatment.
This study demonstrates that the combination of nitric oxide and ibuprofen through administration of the drug NCX 320 significantly improves muscle health in mice with muscular dystrophy. However, to know how helpful this will be in humans, clinical studies must be performed. However, the reason NCX 320 holds promise is that both the individual compounds nitric oxide and ibuprofen have been shown to be broadly helpful in many different people. Ibuprofen is already widely used as an anti-inflammatory by people for headaches and pain.
A large clinical randomized control trial on NCX 320 for treatment of muscular dystrophy must be performed before it is approved for treatment. This may take several years, but will provide more convincing evidence to support whether the drug will be helpful, and whether it will be safe.
Further information and links
The full original paper was published in the Journal of Pharmacological Research in 2011. Link to access the full article (free): http://www.ncbi.nlm.nih.gov/pubmed/21609764
Previous studies demonstrating the effect of combined nitric oxide and ibuprofen therapy for muscular dystrophy:
Brunelli S et al. Nitric oxide release combined with nonsteroidal anti-inflammatory activity prevents muscular dystrophy pathology and enhances stem cell therapy.
Published in the Proceedings of the National Academy of Sciences USA, in 2007.
Link to access the full article (free): http://www.pnas.org/content/104/1/264.full.pdf
Sciorati C et al. Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans. Published in the British Journal of Pharmacology, in 2010.
Link to access the full article (free): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938824/
Muscular Dystrophy Campaign website: http://www.muscular-dystrophy.org/
Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. You can find out more about the scientists in this programme and the work they do at:
This summary was written by Long Nyugen