Aspirin, diabetes, and amyloid: re-examination of the inhibition of amyloid formation by aspirin and ketoprofen.
The loss of β-cell function and β-cell death are key features of diabetes. A range of mechanisms are thought to contribute to β-cell loss, including islet amyloid formation by the neuropancreatic hormone amylin (islet amyloid polypeptide, IAPP). Islet amyloid deposition also contributes to the failure of islet transplants. There are no therapeutic strategies for the treatment or prevention of islet amyloidosis. Aspirin and the nonsteroid anti-inflammatory drug (NSAID) ketoprofen, at clinically relevant doses, have been proposed to inhibit amyloid formation by amylin and thus may hold promise for treatment of islet amyloidosis. These compounds are potentially attractive given the importance of inflammation in islet amyloidosis and given the fact that there are no anti-islet amyloid agents in the clinic. We show that aspirin, even in 20-fold excess, has no effect on the kinetics of amyloid formation by amylin as judged by thioflavin-T binding, right angle light scattering, and transmission electron microscopy, nor does it alter the morphology of resulting amyloid fibrils. Aspirin showed no ability to disaggregate preformed amylin amyloid fibrils under the conditions of these studies, 25 °C and pH 7.4. Ketoprofen is similarly ineffective at inhibiting amylin amyloid formation. The compounds do, however, interfere with circular dichroism- and Congo Red-based assays of amylin amyloid formation. This study highlights the importance of using multiple methods to follow amyloid formation when screening inhibitors.
Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Ling-Hsien
LH
Tu
Harris
H
Noor
Ping
P
Cao
Daniel P
DP
Raleigh
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000648:ultrastructure; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism* / Q000648:ultrastructure; D007660:Ketoprofen / Q000494:pharmacology*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000378:metabolism
D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D058228:Islet Amyloid Polypeptide; D007660:Ketoprofen; D001241:Aspirin