Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility?

Kaur, Deepinder; Andersen, Julie K.

doi:10.1046/j.1474-9728.2002.00001.x

Cited by 45 publications

(31 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another hallmark of PD is the aggregation of the protein ␣-synuclein. Such clustered ␣-synuclein has been shown, along with iron, to be a constituent of Lewy bodies in PD (157). Through an IRP1-dependent mechanism, MPTP administration caused upregulation of TfR, which preceded increased iron and oxidative stress (276).…”

Section: Iron Regulation and Neurodegenerationmentioning

confidence: 99%

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Mackenzie

Iwasaki

Tsuji

2008

Antioxidants & Redox Signaling

449

372

View full text Add to dashboard Cite

Section: Iron Regulation and Neurodegenerationmentioning

confidence: 99%

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Mackenzie

Iwasaki

Tsuji

2008

Antioxidants & Redox Signaling

449

372

View full text Add to dashboard Cite

“…Direct evidence that disrupted iron homeostasis contributes to injury rather than simply being caused by it has been obtained by treatment with low molecular weight iron chelators or by overexpression of iron storage proteins. Small molecule iron chelators such as deferoxamine mesylate (DFO) 2 inhibit neuronal injury in rodent models of stroke (21), Parkinson disease (22), and multiple sclerosis (23). Moreover, DFO and some other metal chelators such as clioquinol have been shown to slow the progression of Alzheimer disease in humans (24,25).…”

Section: Fibrogen Inc South San Francisco California 94080mentioning

confidence: 99%

Hypoxia-inducible Factor Prolyl 4-Hydroxylase Inhibition

Siddiq

Ayoub

Chávez

et al. 2005

Journal of Biological Chemistry

260

View full text Add to dashboard Cite

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron-and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1␣ and HIF-2␣. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1␣ and up-regulate HIF-dependent target genes (e.g. enolase, p21 waf1/cip1 , vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.Iron maintains a unique role in physiology via its ability to change readily its oxidation state in response to changes in its local environment. A general simplification of its primary function is that it mediates one-electron redox reactions. This chemical property of iron enables it to act as an essential component in several biological activities, including as a cofactor for enzymes such as tyrosine hydroxylase. Oxygen binding to biomolecules such as hemoglobin and myoglobin is also coordinated by iron. Indeed iron deficiency can lead to a host of disorders, including anemia and restless legs syndrome (1).Paradoxically, the biochemical properties that make iron beneficial in many biological processes appear to be a drawback when the balance between its accumulation/sequestration within cellular compartments and its release is disturbed in favor of iron accumulation (2). Indeed, iron overload is associated with several neurological conditions (3-5). For example, the iron content of nigral Lewy bodies is elevated in patients with Parkinson disease (6 -9). Alzheimer disease has also been found to be associated with an increase in the iron content of senile plaques (10 -15). Accumulation of mitochondrial iron has been shown to play a role in Friedrich ataxia (16,17). Similarly, changes in intracellular free iron levels have been observed in cerebral ischemia (18 -20). Direct evidence that disrupted iron homeostasis contributes to injury rather than simply being caused by it has been obtained by treatment with low molecular weight iron chelators or by overexpression of iron storage proteins. Small molecule iron chelators such as deferoxamine mesylate (DFO) 2 inhibit neuronal injury in rodent models of stroke (21), Parkinson disease (22), and multiple sclerosis (23). Moreover, DFO and some other metal chelators such as clioquinol have been shown to slow the progressi...

show abstract

“…Parkinson's disease (PD) is one of the major human neurodegenerative disorders characterized by a progressive loss of dopaminergic neurons and the formation of Lewy body aggregates (Hirsch et al 1997;Kaur and Andersen, 2002). Dopamine deficiency and defects in mitochondrial complex I activity play important roles in the manifestation of PD (Javitch et al 1985;Parker et al 1989).…”

Section: Introductionmentioning

confidence: 99%

Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity

et al. 2008

View full text Add to dashboard Cite

Parkinson's disease is a common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease. Thus, therapeutic approaches that improve mitochondrial function may prove to be beneficial. Previously, we have documented that near-infrared light via light-emitting diode (LED) treatment was therapeutic to neurons functionally inactivated by tetrodotoxin, potassium cyanide (KCN), or methanol intoxication, and LED pretreatment rescued neurons from KCN-induced apoptotic cell death. The current study tested our hypothesis that LED treatment can protect neurons from both rotenone-and MPP + -induced neurotoxicity. Primary cultures of postnatal rat striatal and cortical neurons served as models, and the optimal frequency of LED treatment per day was also determined. Results indicated that LED treatments twice a day significantly increased cellular ATP content, decreased the number of neurons undergoing cell death, and significantly reduced the expressions of reactive oxygen species and reactive nitrogen species in rotenone-or MPP + -exposed neurons as compared to untreated ones. These results strongly suggest that LED treatment may be therapeutic to neurons damaged by neurotoxins linked to Parkinson's disease by energizing the cells and increasing their viability.

show abstract

Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility?

Cited by 45 publications

References 32 publications

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Hypoxia-inducible Factor Prolyl 4-Hydroxylase Inhibition

Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity

Contact Info

Product

Resources

About