Characterization of the Neuroprotective Potential of Derivatives of the Iron Chelating Drug Deferiprone

Abstract

There is growing evidence for alterations in iron homeostasis during aging that are exacerbated in neurodegenerative diseases such as Alzheimer's disease. However, since essentially all neurodegenerative diseases are multi-factorial in the sense that there are a large number of mechanisms that can be identified as contributing to nerve cell death, iron chelators that have additional activities might be the most useful for the treatment of age-related CNS diseases. We have described a series of cell culture-based assays that define molecular toxicity pathways relevant to neurodegenerative diseases and have used these assays to identify potential therapeutic compounds for the treatment of these diseases. Deferiprone is a blood brain barrier permeable, low molecular weight iron chelator that has been used for many years to treat systemic iron disease. In this study, we describe the use of our cell culture-based screening assays to identify deferiprone derivatives with the greatest therapeutic potential for the treatment of CNS diseases. We show that several derivatives are much more potent than deferiprone at reducing oxidative stress and preventing nerve cell death induced by multiple, age-related insults. In addition, we show that both deferiprone and the derivatives modulate several distinct signaling pathways associated with neuroprotection. All of the compounds were able to both inhibit the activation of p38 MAP kinase and JNK kinase and prevent the loss of PI3 kinase activity in response to a toxic stress. These results strongly suggest that these compounds have significant potential for the treatment of CNS diseases.

Advances on Chelation and Chelator Metal Complexes in Medicine

“…Specific chelation targeting strategies are also required for the treatment of diseases associated with the excess accumulation of xenobiotic and essential metals in specific organs e.g., excess iron, copper, zinc and aluminium in the brain, all of which have been implicated in neurodegenerative diseases [1,17]. Such strategies should include the selection of specific chelators that can cross the blood-brain barrier such as deferiprone [18,19]. Substantial improvements have been observed in different categories of patients with neurodegenerative diseases using deferiprone including pantothenate kinase-associated neurodegeneration (PKAN) and Friedreich's Ataxia [12,[20][21][22][23][24].…”

Mitochondria‐targeted antioxidants

“…1). In addition to UVR‐induced iron‐mediated oxidative damage to key cellular constituents in skin, several studies have been published that support the role of iron accumulation and mitochondrial dysfunction in the development and progression of various neurodegenerative disorders, including Parkinson's and Alzheimer's disease (60, 61, 65, 66). Thomsen et al (59) showed recently that chronic inflammation in the substantia nigra ( in vivo rat model) is marked by a profound increase in intracellular iron levels.…”

“…In addition to providing further insight into the participation of iron in the molecular mechanisms underlying the initiation and progression of neurodegeneration, the researchers highlighted the potential iron‐scavenging role of microglia in reducing oxidative damage caused by iron‐mediated ROS formation. Maher and Kontoghiorghes (65) demonstrated, in rat pheochromocytoma (PC12) cells, that the iron‐chelating agent deferiprone and several derivatives of this compound confer neuroprotection. The reduction in neurodegeneration was mediated through the targeting of free iron, resulting in a decreased level of iron and inhibition of cell death.…”

Current Biomedical Use of Copper Chelation Therapy

“…Accordingly, a wide range of compounds have been proposed for PD therapy [70], including iron chelators [71]. For instance, deferiprone has been widely used for the treatment of systemic iron-related diseases and for neurological pathologies, including PD [72], due to its low molecular weight and ability to cross the blood-brain barrier. Different studies demonstrated deferiprone's ability to chelate not only iron but also copper, aluminum and zinc [73], reducing their free radical catalytic activity [74].…”