A Galantamine-Curcumin Hybrid Decreases the Cytotoxicity of Amyloid-Beta Peptide on SH-SY5Y Cells

Misfolded amyloid beta (A beta) peptides aggregate and form neurotoxic oligomers. Membrane and mitochondrial damages, calcium dysregulation, oxidative stress, and fibril deposits are among the possible mechanisms of A beta cytotoxicity. Galantamine (GAL) prevents apoptosis induced by A beta mainly through the ability to stimulate allosterically the alpha 7 nAChRs and to regulate the calcium cytosolic concentration. Here, we examined the cytoprotective effects of two GAL derivatives, namely compounds 4b and 8, against A beta cytotoxicity on the human neuroblastoma cell line SH-SY5Y. The protective effects were tested at simultaneous administration, pre-incubation and post-incubation, with A beta. GAL and curcumin (CU) were used in the study as reference compounds. It was found that 4b protects cells in a similar mode as GAL, while compound 8 and CU potentiate the toxic effects of A beta. Allosteric stimulation of alpha 7 nAChRs is suggested as a possible mechanism of the cytoprotectivity of 4b. These and previous findings characterize 4b as a prospective non-toxic multi-target agent against neurodegenerative disorders with inhibitory activity on acetylcholinesterase, antioxidant, and cytoprotective properties.

Automated summary

Compound 4b, similar to GAL, exhibits cytoprotective effects against Aβ cytotoxicity, while compound 8 and CU enhance the toxic effects of Aβ. Allosteric stimulation of alpha 7 nAChRs is suggested as a possible mechanism for the cytoprotectivity of 4b.