Curcumin and a hemi‐analogue with improved blood–brain barrier permeability protect against amyloid‐beta toxicity in Caenorhabditis elegans via SKN‐1/Nrf activation

Objectives This study aims to investigate the blood–brain barrier (BBB) permeability of curcumin analogues with shortened linkers and their ability to protect against amyloid‐beta toxicity in a whole organism model. Method Four curcumin analogues were synthesized. These analogues and curcumin were evaluated for their BBB permeability in the parallel artificial membrane permeability assay. The transgenic Caenorhabditis elegansGMC101 that expresses human Aβ1–42 was treated with the compounds to evaluate their ability to delay Aβ‐induced paralysis. Expression of skn‐1mRNA was examined on nematodes treated with selected efficacious compounds. In vitro Aβ aggregation in the presence of the compounds was performed. Key findings The four analogues showed improved BBB permeability vs curcumin in the PAMPA with the hemi‐analogue C4 having the highest permeability coefficient. At 100 μm, analogues C1 and C4 as well as curcumin significantly prolonged the survival of the nematodes protecting against Aβ toxicity. However, only curcumin and C4 showed protection at lower concentrations. skn‐1mRNA was significantly elevated in nematodes treated with curcumin and C4 indicating SKN‐1/Nrf activation as a possible mode of action. Conclusions Analogue C4 provides a new lead for the development of a curcumin‐based compound for protection against Aβ toxicity with an improved BBB permeability.