ABSTRACT
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 Aß1-42 was treated with the compounds to evaluate their ability to delay Aß-induced paralysis. Expression of skn-1mRNA was examined on nematodes treated with selected efficacious compounds. In vitro Aß 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 Aß 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 Aß toxicity with an improved BBB permeability.
