Diuretics—often referred to as “water pills”—are frequently used to treat cardiac conditions such as congestive heart failure and high blood pressure, as well as water retention (edema) linked to kidney disease, diabetes, and liver disorders. These drugs help the body rid itself of excess salt and water, and some even function to widen the blood vessels themselves and lower blood pressure. Now, new research has found another purpose of a special class of diuretics that may have positive implications for people suffering from diseases caused by protein misfolding.
When proteins fail to fold correctly, they are often unable to carry out their responsibilities within the cell, which can lead to cell deterioration and death. Misfolded proteins tend to clump together, forming insoluble protein aggregates. Several neurodegenerative diseases have been linked to plaques formed by amyloid protein aggregates, including Alzheimer’s, Parkinson’s, and familial amyloid polyneuropathy (FAP).
Reducing the Effects of Neurodegenerative Diseases
With both FAP and Alzheimer’s, amyloid plaques gather in nerves, severely affecting the neurons’ ability to relay nerve signals. In Alzheimer’s, these plaques form in the central nervous system, affecting the patient’s cognitive skills. With FAP, plaques form in the peripheral nerves in bodily organs like the kidneys, eyes, and heart, seriously affecting how they function.
New research has shown that two diuretics that have historically been used to fight high blood pressure may be useful in preventing the formation of amyloid aggregations. The diuretics hydrochlorothiazide and indapamide could reduce patient risk of developing amyloid plaques. Evidence has also emerged showing that diuretics could degrade existing amyloid aggregations and suppress amyloid production.
Behind the Research
In order to compile the amount of data needed to evaluate the plaques in question, researchers at India’s Aligarh Muslim University utilized other human proteins that commonly form aggregates. Both human serum albumin (HSA) and human lysosomal protein (HL) have been known to aggregate similarly to amyloid. Researchers applied hydrochlorothiazide and indapamide to these proteins to gauge their response. Both HSA and HL were able to bind to the diuretics and changed their structures as a result.
Researchers isolated HSA and HL, increased the temperature to 150℉, and optimized the pH of the solution to promote the formation of aggregates. Once light scattering and fluorescence readings reached a maximum—indicating that protein aggregation had occurred—researchers administered diuretics in increasing concentrations. The diuretics were able to bind to HSA and HS, and showed less scattering, indicating a reduction in aggregation.
Similar tests indicated that the diuretics reduced the number of fibrils formed by the proteins, indicating that the proteins would be less likely to form aggregates in the future. Tellingly, both diuretics blocked the formation of protein aggregations. The diuretics also prevented the residual damage to red blood cells that frequently occurs when amyloid aggregations are present.
Hope for the Future
Currently, these experiments regarding diuretics and amyloid aggregations have only occurred in vitro in a laboratory environment. Much more research is necessary to determine if diuretics will have the same effect on the amyloid aggregations in the human body that contribute to neurodegenerative diseases. However, the findings indicate that diuretics may show vast potential as a therapeutic or preventive measure to combat devastating diseases like Parkinson’s, Alzheimer’s, and FAP in the future.