Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute an important pharmacotherapeutic class that, over the past decade, have expanded in application to a panoply of medical conditions. They have been tested for neurodegenerative diseases such as Alzheimer's to reduce inflammation and also in the attempt to abrogate amyloid deposition. However, the use of NSAIDs as aggregation inhibitors has not been extensively studied in pancreatic amyloid deposition. Pancreatic amyloidosis involves the misfolding of islet amyloid polypeptide (IAPP) and contributes to the progression of type-2 diabetes in humans and felines. To ascertain their antiamyloidogenic activity, several NSAIDs were tested using fluorometric thioflavin-T assays, circular dichroism, photo-induced cross-linking assays, and cell culture. Celecoxib, diclofenac, indomethacin, meloxicam, niflumic acid, nimesulide, phenylbutazone, piroxicam, sulindac, and tenoxicam reduced fibrillization at a molar ratio of 1:10. The circular dichroism spectra of diclofenac, piroxicam, and sulindac showed characteristic spectral signatures found in predominantly α-helical structures. The oligomerization of human IAPP was abrogated with diclofenac and sulindac at a molar ratio of 1:5. The cytotoxic effects of pre-incubated human IAPP on cultured INS-1 cells were noticeably reduced in the presence of diclofenac, meloxicam, phenylbutazone, sulindac, and tenoxicam at a molar ratio of 1:10. Our results demonstrate that NSAIDs can provide chemical scaffolds to generate new and promising antiamyloidogenic agents that can be used alone or as a coadjuvant therapy.

• Authors: Jessica S Fortin, Marie-Odile Benoit-Biancamano
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 94 Issue 1 Pg. 35-48 (Jan 2016) ISSN: 1205-7541 [Electronic] Canada
• PMID: 26524404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Islet Amyloid Polypeptide
• Protein Aggregates

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology)
• Cats
• Cell Line
• Humans
• In Vitro Techniques
• Islet Amyloid Polypeptide (chemistry, drug effects, toxicity)
• Protein Aggregates (drug effects)
• Protein Aggregation, Pathological (prevention & control)
• Protein Multimerization (drug effects)
• Protein Structure, Secondary (drug effects)
• Rats
• Structure-Activity Relationship