Metal-Protein Attenuating Compounds (MPACs): An Emerging Approach for the Treatment of Neurodegenerative Disorders

Aberrant interactions of redox-active transition metals Cu2+, Zn2+ and Fe3+ in the central nervous system (CNS) with metal-binding proteins such as amyloid-β (Aβ), neuromelanin, etc., with concomitant increase in oxidative stress leading to consequential neuronal damage are central to the pathology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and others. The therapeutic significance of metal dysregulation in neurodegenerative disorders has been a subject of intense debate recently. Of the several approaches related to the life cycle of Aβ, metal-protein attenuating compounds (MPACs) represent an emerging therapeutic approach leading to restoration of metal homeostasis, decreased oxidative stress and thereby reversing or slowing the disease progression. MPACs compete with Aβ for binding with redox-active metal ions, subsequently preventing Aβ oligomerization. Clioquinol (CQ), a retired antibiotic, is a prototype MPAC, which has shown encouraging efficacy from early clinical evaluation for the treatment of AD supporting its use. CQ-metal complexes were reported to up-regulate matrix metalloprotease (MMP) activity in vitro. This elevated MMP activity resulted in enhanced degradation of secreted Aβ peptide with additional effect in preventing its aggregation. Few experiments involving mouse model of PD showed neuroprotective effects of clioquinol. This review discusses various issues related to the scientific rationale, scope, evaluation, limitations and applications of MPACs as a novel therapeutic option for the treatment of neurodegenerative diseases.