Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and protects pancreatic β-cells from human islet amyloid polypeptide/amylin-induced cytotoxicity

• Published in: Biochemical journal Vol. 476; no. 5; p. 889
• Main Authors: Dubey, Richa, Patil, Ketaki, Dantu, Sarath C, Sardesai, Devika M, Bhatia, Parnika, Malik, Nikita, Acharya, Jhankar D, Sarkar, Soham, Ghosh, Soumadwip, Chakrabarti, Rajarshi, Sharma, Shilpy, Kumar, Ashutosh
• Format: Journal Article
• Language: English
• Published: England 15.03.2019
• Subjects: Amyloid - chemistry; Amyloid - metabolism; Amyloidosis - drug therapy; Amyloidosis - metabolism; Amyloidosis - pathology; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Humans; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - metabolism; Limonins - pharmacology; Molecular Dynamics Simulation; Oxidative Stress - drug effects; pancreatic β-cell; apoptosis; amyloid; Azadirachtin; hIAPP; molecular dynamics
• ISSN: 1470-8728
• DOI: 10.1042/BCJ20180820

The human islet amyloid polypeptide (hIAPP) or amylin is the major constituent of amyloidogenic aggregates found in pancreatic islets of type 2 diabetic patients that have been associated with β-cell dysfunction and/or death associated with type 2 diabetes mellitus (T2DM). Therefore, developing and/or identifying inhibitors of hIAPP aggregation pathway and/or compound that can mediate disaggregation of preformed aggregates holds promise as a medical intervention for T2DM management. In the current study, the anti-amyloidogenic potential of Azadirachtin (AZD)-a secondary metabolite isolated from traditional medicinal plant Neem ( )-was investigated by using a combination of biophysical and cellular assays. Our results indicate that AZD supplementation not only inhibits hIAPP aggregation but also disaggregates pre-existing hIAPP fibrils by forming amorphous aggregates that are non-toxic to pancreatic β-cells. Furthermore, AZD supplementation in pancreatic β-cells ( ) resulted in inhibition of oxidative stress; along with restoration of the DNA damage, lipid peroxidation and the associated membrane damage, endoplasmic reticulum stress and mitochondrial membrane potential. AZD treatment also restored glucose-stimulated insulin secretion from pancreatic islets exposed to hIAPP. All-atom molecular dynamics simulation studies on full-length hIAPP pentamer with AZD suggested that AZD interacted with four possible binding sites in the amyloidogenic region of hIAPP. In summary, our results suggest AZD to be a promising candidate for combating T2DM and related amyloidogenic disorders.