scholarly journals Chelators in the Treatment of Iron Accumulation in Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Ross B. Mounsey ◽  
Peter Teismann
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Iron Homeostasis ◽  
Essential Element ◽  
Experimental Models ◽  
Iron Accumulation ◽  
Natural Iron ◽  
Iron Redox ◽  
Brain Iron Homeostasis

Iron is an essential element in the metabolism of all cells. Elevated levels of the metal have been found in the brains of patients of numerous neurodegenerative disorders, including Parkinson's disease (PD). The pathogenesis of PD is largely unknown, although it is thought through studies with experimental models that oxidative stress and dysfunction of brain iron homeostasis, usually a tightly regulated process, play significant roles in the death of dopaminergic neurons. Accumulation of iron is present at affected neurons and associated microglia in the substantia nigra of PD patients. This additional free-iron has the capacity to generate reactive oxygen species, promote the aggregation ofα-synuclein protein, and exacerbate or even cause neurodegeneration. There are various treatments aimed at reversing this pathologic increase in iron content, comprising both synthetic and natural iron chelators. These include established drugs, which have been used to treat other disorders related to iron accumulation. This paper will discuss how iron dysregulation occurs and the link between increased iron and oxidative stress in PD, including the mechanism by which these processes lead to cell death, before assessing the current pharmacotherapies aimed at restoring normal iron redox and new chelation strategies undergoing research.

scholarly journals Iron Redox Chemistry and Implications in the Parkinson’s Disease Brain

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Dinendra L. Abeyawardhane ◽  
Heather R. Lucas
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Iron Homeostasis ◽  
Substantia Nigra Pars Compacta ◽  
Biochemical Alterations ◽  
Redox Active ◽  
Cellular Inclusions ◽  
Iron Redox ◽  
Presynaptic Protein

The etiology of Parkinson’s disease (PD) is linked with cellular inclusions in the substantia nigra pars compacta region of the brain that are enriched in the misfolded presynaptic protein α-synuclein (αS) and death of the dopaminergic neurons. Brain iron homeostasis governs both neurotransmission and neurodegeneration; hence, the role of iron in PD progression and neuronal health is apparent. Elevated iron deposits become prevalent in the cerebral region upon aging and even more so in the PD brain. Structural as well as oxidative modifications can result from coordination of αS with redox active iron, which could have functional and/or pathological implications. In this review, we will discuss iron-mediated αS aggregation, alterations in iron metabolism, and the role of the iron-dopamine couple. Moreover, iron interactions with N-terminally acetylated αS, the physiologically relevant form of the human protein, will be addressed to shed light on the current understanding of protein dynamics and the physiological environment in the disease state. Oxidative pathways and biochemical alterations resulting from aberrant iron-induced chemistry are the principal focus of this review in order to highlight the plethora of research that has uncovered this emerging dichotomy of iron playing both functional and disruptive roles in PD pathology.

scholarly journals Parkinson’s Disease: The Mitochondria-Iron Link

2016 ◽  
Vol 2016 ◽  
pp. 1-21 ◽  
Author(s):  
Yorka Muñoz ◽  
Carlos M. Carrasco ◽  
Joaquín D. Campos ◽  
Pabla Aguirre ◽  
Marco T. Núñez
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Iron Chelation ◽  
Causal Link ◽  
Iron Accumulation ◽  
Published Evidence

Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson’s disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences—mitochondrial dysfunction, iron accumulation, and oxidative damage—generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson’s disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation—by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways—is a viable therapy for retarding this cycle.

scholarly journals Shared Mechanisms of Neurodegeneration in Alzheimer’s Disease and Parkinson’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Anmu Xie ◽  
Jing Gao ◽  
Lin Xu ◽  
Dongmei Meng
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Iron Homeostasis ◽  
Noradrenergic Neurons ◽  
Genetic Studies ◽  
Brain Iron Homeostasis

Alzheimer’s disease (AD) and Parkinson’s disease (PD) have markedly different clinical and pathological features, but these two diseases are the most common neurodegenerative disorders. Previous studies have showed that there are common mechanisms in AD and PD. Several genetic studies have revealed mutations in genes associated with the risk of AD and PD. Circumstantial evidences have shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation and results in AD as well as PD.α-Synuclein and tau take part in the mechanisms of these diseases by oxidative stress and mitochondrial dysfunction. Some studies indicated that the loss of LC noradrenergic neurons may occur early in the progression of AD and PD. Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of pentameric ligand-gated ion channels; some evidence showed that nicotinic receptors may be associated with AD and PD. These experimental and clinical studies may provide a scientific foundation for common shared mechanisms in AD and PD.

scholarly journals Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Satoru Oshiro ◽  
Masaki S. Morioka ◽  
Masataka Kikuchi
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Lateral Sclerosis

Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs). Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD) and Parkinson's disease (PD), circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS). Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.

scholarly journals Natural Phytochemicals as Novel Therapeutic Strategies to Prevent and Treat Parkinson’s Disease: Current Knowledge and Future Perspectives

2021 ◽  
Vol 2021 ◽  
pp. 1-32
Author(s):  
Rengasamy Balakrishnan ◽  
Shofiul Azam ◽  
Duk-Yeon Cho ◽  
In Su-Kim ◽  
Dong-Kug Choi
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Comprehensive Evaluation ◽  
Current Knowledge ◽  
Antioxidant Response ◽  
Experimental Models ◽  
Protein Accumulation ◽  
Related Factor ◽  
Therapeutic Benefits

Parkinson’s disease (PD) is the second-most common neurodegenerative chronic disease affecting both cognitive performance and motor functions in aged people. Yet despite the prevalence of this disease, the current therapeutic options for the management of PD can only alleviate motor symptoms. Research has explored novel substances for naturally derived antioxidant phytochemicals with potential therapeutic benefits for PD patients through their neuroprotective mechanism, targeting oxidative stress, neuroinflammation, abnormal protein accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, neurotrophic factor deficit, and apoptosis. The aim of the present study is to perform a comprehensive evaluation of naturally derived antioxidant phytochemicals with neuroprotective or therapeutic activities in PD, focusing on their neuropharmacological mechanisms, including modulation of antioxidant and anti-inflammatory activity, growth factor induction, neurotransmitter activity, direct regulation of mitochondrial apoptotic machinery, prevention of protein aggregation via modulation of protein folding, modification of cell signaling pathways, enhanced systemic immunity, autophagy, and proteasome activity. In addition, we provide data showing the relationship between nuclear factor E2-related factor 2 (Nrf2) and PD is supported by studies demonstrating that antiparkinsonian phytochemicals can activate the Nrf2/antioxidant response element (ARE) signaling pathway and Nrf2-dependent protein expression, preventing cellular oxidative damage and PD. Furthermore, we explore several experimental models that evaluated the potential neuroprotective efficacy of antioxidant phytochemical derivatives for their inhibitory effects on oxidative stress and neuroinflammation in the brain. Finally, we highlight recent developments in the nanodelivery of antioxidant phytochemicals and its neuroprotective application against pathological conditions associated with oxidative stress. In conclusion, naturally derived antioxidant phytochemicals can be considered as future pharmaceutical drug candidates to potentially alleviate symptoms or slow the progression of PD. However, further well-designed clinical studies are required to evaluate the protective and therapeutic benefits of phytochemicals as promising drugs in the management of PD.

Mitochondria as an Easy Target to Oxidative Stress Events in Parkinson's Disease

2012 ◽  
Vol 11 (4) ◽  
pp. 430-438 ◽  
Author(s):  
Marcella Reale ◽  
Mirko Pesce ◽  
Medha Priyadarshini ◽  
Mohammad A Kamal ◽  
Antonia Patruno
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease

scholarly journals The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4676
Author(s):  
Katja Badanjak ◽  
Sonja Fixemer ◽  
Semra Smajić ◽  
Alexander Skupin ◽  
Anne Grünewald
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Cytokine ◽  
Population Ageing ◽  
Future Research ◽  
Cytokine Release ◽  
Vicious Cycle ◽  
Inflammatory Processes ◽  
Great Evidence

With the world’s population ageing, the incidence of Parkinson’s disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of PD patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, a-synuclein accumulation, and pro-inflammatory cytokine release. Hence, investigating the involvement of microglia is of great importance for future research and treatment of PD. The purpose of this review is to highlight recent findings concerning the microglia-neuronal interplay in PD with a focus on human postmortem immunohistochemistry and single-cell studies, their relation to animal and iPSC-derived models, newly emerging technologies, and the resulting potential of new anti-inflammatory therapies for PD.

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