A new study, from scientists at Harvard Medical School and the University of Cambridge, has described how drugs traditionally developed to treat erectile dysfunction may also improve the brain’s ability to clear toxic misfolded proteins linked with neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Sildenafil, commonly known as Viagra, was originally discovered in the late 1980s while scientists were investigating novel treatments for cardiovascular chest pain. The drug works by inhibiting the activity of an enzyme known as PDE5.
In the 1990s these PDE5-inhibiting drugs became well-known as treatments for erectile dysfunction. However, as time passed, researchers began to understand the broader systemic effects of PDE5 inhibition, and one of the more interesting areas of study has been in the potential for these drugs to prevent age-related cognitive decline.
A number of observational and preclinical studies have suggested PDE5 inhibitors could improve cognitive function in subjects suffering from neurodegeneration. A systematic review of the current research, published earlier this year, concluded there is enough evidence to warrant a clinical trial testing sildenafil in Alzheimer’s patients.
The new research set out to investigate exactly how a PDE5 inhibitor could possibly prevent cognitive decline. The focus of the study was on how these drugs influence the body’s natural ability to destroy damaged, misfolded or toxic proteins in the brain.
When our body detects damaged or unnecessary proteins it enlists a garbage disposal mechanism involving protein complexes called proteasomes, which degrade and clear out those molecules. Proteasomes can identify the toxic proteins to remove because they are tagged with a molecule called ubiquitin. Prior studies have suggested dysfunction in this proteasome-ubiquitin mechanism can underpin neurodegenerative disease.
In human cell studies, the new research demonstrated how PDE5 inhibitors enhance levels of molecules that aid in the process of misfolded proteins being tagged with ubiquitin. This means drugs such as sildenafil can enhance proteasome activity, and help the body more effectively destroy and clear out toxic proteins.
The researchers then explored whether exploiting this mechanism could help clear toxic proteins in a zebrafish genetically engineered to model excessive accumulation of proteins linked with Huntington’s disease and Alzheimer’s disease. These experiments successfully found proteasome activity can be safely and effectively enhanced through this mechanism, and accumulation of these toxic proteins can be reduced.
“Our study indicates a new approach to combat the basic cause of many neurodegenerative diseases as well as certain rare cardiac and muscle diseases, which are due to the buildup of misfolded intracellular proteins,” says Alfred Goldberg, senior author on the new study.
Goldberg does note that although these results are very promising, they do not translate into Viagra being an immediate treatment for Alzheimer’s. Instead, the likely outcome is future research will explore more focused ways to harness this mechanism and enhance proteasome activity in the brain.
The new research was published in the journal PNAS.
Source: Harvard Medical School
