Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in a Transgenic Rat Model of Type 2 Diabetes

Abstract

Protein aggregation is associated with a large number of human protein-misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid (RA) as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200–300 nM). Structure–function relationship analysis of RA showed the additive effects of the two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin but rather lead to nontoxic, remodeled protein aggregates. RA has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of RA treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein-misfolding diseases.

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

“…Oral administration of rutin delayed diabetes onset and ameliorated disease severity and progression in hA-transgenic mice ( Aitken et al, 2017 ). Similarly, in a study using transgenic HIP rats, 4-month dietary supplementation of rosmarinic acid reduced pancreatic amyloid deposition, serum hA oligomer levels and non-fasting blood glucose, and increased serum insulin levels ( Wu et al, 2021 ).…”

“…Compounds that have demonstrated hA aggregation-inhibitory properties in vitro include: resveratrol ( Mishra et al, 2009 ; Tu et al, 2015 ); EGCG ( Meng et al, 2010 ; Cao and Raleigh, 2012 ; Franko et al, 2018 ); rutin and quercetin ( Aitken et al, 2017 ; Chen, S. et al, 2020 ); curcumin ( Daval et al, 2010 ); baicalein ( Velander et al, 2016 ), oleuropein ( Rigacci et al, 2010 ; Wu et al, 2017 ); caffeic acid ( Sun et al, 2019 ); and rosmarinic acid ( Sun et al, 2019 ; Wu et al, 2021 ). Some, but not all, of these compounds have been shown to be capable of disaggregating pre-formed hA fibrils, including EGCG ( Meng et al, 2010 ); rutin ( Aitken et al, 2017 ); rosmarinic acid ( Wu et al, 2021 ); baicalein ( Velander et al, 2016 ), oleuropein ( Wu et al, 2017 ), and morin ( Noor et al, 2012 ).…”

“…Both EGCG and rosmarinic acid can disaggregate pre-formed hA fibrils to amorphous, off-pathway aggregates. This disaggregation pathway was not the reverse of fibril formation and hA monomers were not formed ( Wu et al, 2021 ).…”

“…Oleuropein has shown a cytoprotective effect against hA in INS-1 ( Wu et al, 2017 ; Chaari, 2020 ) and RIN-m5F cells ( Rigacci et al, 2010 ). Rosmarinic acid formed nontoxic aggregates with hA that neutralized hA-induced cytotoxicity in INS-1 cells ( Wu et al, 2021 ). Similarly, baicalein also prevented hA-induced cytotoxicity in INS-1 cells ( Velander et al, 2016 ).…”

“…Compounds containing two catechol moieties appear to be more effective at both inhibition of hA aggregation and disaggregation than analogues comprising only one catechol moiety ( Nomoto et al, 2021 ). For example, the efficacy of rosmarinic acid was similar to the additive effects of its two substituents, caffeic acid and salvianic acid, on the inhibition of fibril formation and hA-induced cytotoxicity ( Wu et al, 2021 ).…”