Kavalactones as inhibitors of advanced glycation endproducts (AGEs) formation

The end-products of a complex series of non-enzymatic reactions involving glycation of proteins are the AGEs. Elevated levels of AGEs are associated with diabetic complications (nephropathy, retinopathy, cataract), atherosclerosis, neurological disorders and the normal ageing process.

In this study DL-kawain (1), methysticin (2) and dihydromethysticin (3), all belonging to the group of kavalactones, were identified as AGEs inhibitors. With IC₅₀ values of 0.87 ± 0.02 mM and 0.90 ± 0.03 mM for 1 and 2, respectively, the compounds inhibited the in vitro protein glycation significantly better than aminoguanidine (IC₅₀= 4.62 ± 0.23 mM; p= 0.01). Compound 3 showed lower inhibitory activities (IC₅₀= 11.28 ± 0.87 mM). Furthermore, compounds 1 and 2 inhibited the formation of fructosamine, which is an intermediate in the process of AGEs formation. Moreover, 1 and aminoguanidine prevented AGEs formation by chelating Cu²⁺ and Fe³⁺. However, these compounds showed less entrapment of the reactive carbonyl species (RCS), glyoxal and methylglyoxal, compared to aminoguanidine. These data indicate that kavalactones prevent early and advanced glycation, partly through metal chelation, and partly through the entrapment of RCS.

Fig. 1