Neuroprotective Multifunctional Iron Chelators: From Redox-Sensitive Process to Novel Therapeutic Opportunities

Abstract

Accumulating evidence suggests that many cytotoxic signals occurring in the neurodegenerative brain can initiate neuronal death processes, including oxidative stress, inflammation, and accumulation of iron at the sites of the neuronal deterioration. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent hydroxyl radical formation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron chelators is associated with their ability to upregulate or stabilize the transcriptional activator, hypoxia-inducible factor-1α (HIF-1α). HIF-1α stability within the cells is under the control of a class of iron-dependent and oxygen-sensor enzymes, HIF prolyl-4-hydroxylases (PHDs) that target HIF-1α for degradation. Thus, an emerging novel target for neuroprotection is associated with the HIF system to promote stabilization of HIF-1α and increase transcription of HIF-1–related survival genes, which have been reported to be regulated in patient's brains afflicted with diverse neurodegenerative diseases. In accordance, a new potential therapeutic strategy for neurodegenerative diseases is explored, by which iron chelators would inhibit PHDs, target the HIF-1–signaling pathway and ultimately activate HIF-1–dependent neuroprotective genes. This review discusses two interrelated approaches concerning therapy targets in neurodegeneration, sharing in common the implementation of iron chelation activity: antioxidation and HIF-1–pathway activation. Antioxid. Redox Signal. 13, 919–949.

Introduction

Brain-Iron Homeostasis, Oxidative Stress, and Neurodegeneration

• Parkinson's disease

• Alzheimer's disease

• Amyotrophic lateral sclerosis

Iron, HIF-1 System, and Neuroprotection

• HIF/PHD pathway and HIF-target genes

• Hypoxic preconditioning

• HIF-1 pathway and neurodegenerative diseases

Iron-Chelating Compounds; Neuroprotection Through HIF-1 Activation

• Multifunctional, iron-chelating neuroprotective drugs

• Flavonoids

Conclusions and Future Perspectives