Repurposing of Copper(II)-chelating drugs for the treatment of neurodegenerative diseases.

Background: There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews has exhaustively described either the molecular or clinical aspects of neurodegenerative diseases as Alzheimer’s (AD) and Parkinson’s (PD). Conversely, reports outlining how known drugs in use for other diseases can be also effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) interacting molecules as potential drug candidates in neurodegeneration. Methods: Starting from the well-known harmful relationships existing between the dys-homeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, that deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature data bases and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) interacting features of the selected drugs. Results: Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis is crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repositioning copper(II) interacting drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repositioning, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. Conclusions: In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over de novo drug discovery since repositioned drugs had already passed the safety and toxicity tests. Promising drug candidates in neurodegenerative diseases may be represented by copper chelating classes of drugs, provided that sufficient details on their mechanism of action are available to encourage further investigations and clinical trials.