Two FDA-approved treatments for high blood pressure, diuretics called indapamide and hydrochlorothiazide, might also treat diseases associated with amyloid deposits, such as familial amyloid polyneuropathy (FAP), a study suggests.
Diuretics are medicines that help a person excrete more water and salt from their system to lower blood pressure.
People worldwide are affected by diseases marked by protein misfolding and the buildup of insoluble protein aggregates. In FAP, a type of hereditary amyloidosis, abnormal transthyretin (TTR) protein aggregates, called amyloids, accumulate in peripheral nerves.
“A lot of research has been done to develop suitable cure for amyloid associated diseases. Although reports provide evidences of the inhibitory effects of small organic compounds on fibril formation by different proteins but the finding of exact treatment is still progressing,” the researchers wrote.
Evidence suggests that medications to lower high blood pressure help to reduce the risk of developing Alzheimer’s disease, where protein aggregates, or clumps, also accumulate in the nervous system. In fact, diuretics have been shown to promote the degradation and to suppress the production of amyloids in Alzheimer’s disease.
Researchers at Aligarh Muslim University, in India, investigated whether the FDA-approved thiazide diuretics, namely indapamide (INDP) and hydrochlorothiazide (HCTZ), could lessen or prevent the formation of protein aggregates.
Instead of studying TTR directly, researchers used human serum albumin (HSA) and human lysozyme protein (HL) — both of which form amyloid-like aggregates — as models to study whether the diuretic therapies could be protective against clumping.
Using fluorescence to examine protein aggregation, they observed that both HSA and HL changed their structure in the presence of INDP and HCTZ. More specifically, they found that these compounds are able to bind HSA and HL.
Researchers then incubated both proteins at 65º Celsius (about 150º Fahrenheit), in an optimal pH (7.4) for 120 hours to promote aggregate formation. Rayleigh light scattering measurements — a way of measuring the degree of protein clumping — showed that after the incubation, the HSA protein reached a scattering maximum, indicative of aggregate formation.
When they added increasing doses of INDP (from 50 up to 2,000 micromolars), they saw lesser scattering, supporting a therapeutic potential for INDP. Similar results were obtained when using HCTZ.
Another set of tests also showed that adding INDP or HCTZ reduced the formation of HSA and HL fibrils.
At the molecular level, the team demonstrated that the two diuretics were able to bind to HSA and HL, and that these interactions blocked the formation of amyloid fibrils.
Fewer aggregation was also observed by transmission electron microscopy, a high resolution technique that allows researchers to observed very small structures, like fibrils.
Finally, the research showed that use of these diuretics prevented damage to red blood cells, which is triggered by amyloid aggregates. The level of hemolysis (red blood cell rupturing) fell in a dose-dependent manner.
“Our work demonstrates that both INDP and HCTZ are effective in preventing amyloid aggregation in vitro [in the lab],” the researchers wrote.
However, “much more in vivo research is required to validate INDP and HCTZ as a useful and clinically viable drug,” they added.
“With the diuretics identified as a potent aggregation inhibitor, there is possibility for further expansion of the pool of potential therapeutics for amyloidosis” like FAP, the study concluded.
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