New multi-target-directed ligands as potential therapeutic agents for Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of dementia, clinically characterized by loss of memory and progressive deficits in different cognitive domains. An emerging disease-modifying approach to face the multifactorial nature of AD may be represented by the development of Multi-Target-Directed Ligands (MTDLs), i.e., single compounds which may simultaneously modulate different targets involved in the neurodegenerative AD cascade (Cavalli, 2008). In parallel, since a significant number of therapeutic targets of AD reside inside cells and intracellular organelles, subcellular targeting strategies for drug design and delivery now represent a considerable drug discovery challenge (Rajendran, 2010). In the search of new rationally designed MTDLs against AD, we synthesized cystamine-tacrine dimer, based on structure of the acetylcholinesterase (AChE) inhibitor tacrine (Minarini, 2012). “In vitro” assays were performed on the new dimer to determine inhibition of human AChE and butyrylcholinesterase (BChE) and beta-amyloid (Aβ) aggregation, neuronal viability of neuroblastoma SH-SY5Y cell line, effect on intracellular ROS formation, and the role of ERK1/2 and Akt pathways in neuroprotection. Results: In this study we demonstrated that the cystamine-tacrine dimer is endowed with a low toxicity, it is able to inhibit AChE, BChE, AChE-induced Aβ aggregation and exerts a neuroprotective action on SH-SY5Y cell line against H2O2-induced oxidative injury, by activating kinase 1 and 2 (ERK1/2) and Akt/protein kinase B (PKB) pathways. Cystamine-tacrine dimer emerged as a new MTDL which may be potentially useful in AD treatment, thanks to its well balanced biological profile as cholinesterases inhibitor and cytoprotective agent.