Targeting multiple Alzheimer's disease etiologies with multimodal neuroprotective and neurorestorative iron chelators.
Dysregulation of brain iron homeostasis is central to early neuropathological events in Alzheimer's disease (AD), including oxidative stress, inflammatory processes, amyloid deposition, tau phosphorylation, and neuronal cell cycle regulatory failure, leading to apoptosis. Also, there is a direct link between iron metabolism and AD pathogenesis, demonstrated by the presence of an iron-responsive element in the 5' UTR of the amyloid precursor protein transcript. As a consequence of these findings, a new paradigm is emerging that includes the development of iron-chelating neuroprotective-neurorescue drugs with multimodal functions, acting at various pathological brain targets. This concept is challenging the widely held assumption that "silver bullet" agents are superior to "dirty drugs" in drug therapy for neurodegenerative diseases. At best, the so-called magic bullets exhibit moderate symptomatic activity without modifying the course of disease progression. The present review elaborates on conventional and novel therapeutic targets of various multifunctional iron-chelating drugs (e.g., chemically designed compounds; natural polyphenols) that address multiple central nervous system etiologies in AD, aimed at preventing or slowing disease evolution. A similar approach in drug design is being investigated for treatment of cancer, AIDS, cardiovascular diseases, and depression.
Eve Topf Center of Excellence for Neurodegenerative Diseases Research, Department of Pharmacology, Faculty of Medicine, Technion, Faculty of Medicine, Haifa, Israel.
Tamar
T
Amit
Yael
Y
Avramovich-Tirosh
Moussa B H
MB
Youdim
Silvia
S
Mandel
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016716:PC12 Cells; D010879:Piperazines / Q000494:pharmacology; D051381:Rats
C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D016564:Amyloid beta-Protein Precursor; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D010879:Piperazines; C505060:5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol; D002392:Catechin; C045651:epigallocatechin gallate; D007501:Iron