Abstract:Background and purpose
Several studies suggested a role or iron in the pathogenesis or Parkinson's disease (PD), and substantia nigra iron concentrarions have been found increased in PD. However, the results on cerebrospinal (CSF) and serum/plasma iron levels in PD patients have been controversial. The aim of this systematic review and meta‐analysis was to establish the CSF and serum/plasma levels of iron and iron‐related proteins (ferritin, transferrin, lactoferrin, haptoglobin, and hepcidine) levels, and the… Show more
“…However, there are still many questions to be answered regarding the increase in the naturally Lf levels in the PD brain. First, the expression of Lf was detected in neurons, microglia and oligodendrocytes in PD patients [ 43 ]; however, there was no significant difference in the level of Lf in the plasma/serum or even in the cerebrospinal fluid (CSF) between PD patients and controls [ 105 ]. A case-control study further suggested the existence of endogenous Lf.…”
Section: Lf In Neurodegenerative Diseasesmentioning
Central nervous system (CNS) diseases are currently one of the major health issues around the world. Most CNS disorders are characterized by high oxidative stress levels and intense inflammatory responses in affected tissues. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein, plays a significant role in anti-inflammatory, antibacterial, antiviral, reactive oxygen species (ROS) modulator, antitumor immunity, and anti-apoptotic processes. Previous studies have shown that Lf is abnormally expressed in a variety of neurological diseases, especially neurodegenerative diseases. Recently, the promotion of neurodevelopment and neuroprotection by Lf has attracted widespread attention, and Lf could be exploited both as an active therapeutic agent and drug nanocarrier. However, our understanding of the roles of Lf proteins in the initiation or progression of CNS diseases is limited, especially the roles of Lf in regulating neurogenesis. This review highlights recent advances in the understanding of the major pharmacological effects of Lf in CNS diseases, including neurodegenerative diseases, cerebrovascular disease, developmental delays in children, and brain tumors.
“…However, there are still many questions to be answered regarding the increase in the naturally Lf levels in the PD brain. First, the expression of Lf was detected in neurons, microglia and oligodendrocytes in PD patients [ 43 ]; however, there was no significant difference in the level of Lf in the plasma/serum or even in the cerebrospinal fluid (CSF) between PD patients and controls [ 105 ]. A case-control study further suggested the existence of endogenous Lf.…”
Section: Lf In Neurodegenerative Diseasesmentioning
Central nervous system (CNS) diseases are currently one of the major health issues around the world. Most CNS disorders are characterized by high oxidative stress levels and intense inflammatory responses in affected tissues. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein, plays a significant role in anti-inflammatory, antibacterial, antiviral, reactive oxygen species (ROS) modulator, antitumor immunity, and anti-apoptotic processes. Previous studies have shown that Lf is abnormally expressed in a variety of neurological diseases, especially neurodegenerative diseases. Recently, the promotion of neurodevelopment and neuroprotection by Lf has attracted widespread attention, and Lf could be exploited both as an active therapeutic agent and drug nanocarrier. However, our understanding of the roles of Lf proteins in the initiation or progression of CNS diseases is limited, especially the roles of Lf in regulating neurogenesis. This review highlights recent advances in the understanding of the major pharmacological effects of Lf in CNS diseases, including neurodegenerative diseases, cerebrovascular disease, developmental delays in children, and brain tumors.
“…Some support for the hypothesis that Fe accumulation in the brain causes disease can be found from a study in anemic Korean older adults, who showed lower risk of developing PD [294]. On the other hand, a meta-analysis showed mildly decreased serum Fe levels in PD patients compared to controls [107]. A recent study found that in the SN of elderly individuals, oligodendroglial and astroglial cells contained the highest cellular Fe concentrations, whereas in PD, the Fe concentrations were increased in most cell types, including neurons in the SN [112].…”
Section: Iron Accumulation and Pathology In Sporadic Neurodegenerativ...mentioning
confidence: 95%
“…Parkinson Disease ↓ Fe in serum/plasma [107] ↑ Fe in substantia nigra [108,109] ↑ Fe in neurons and adjacent neuropil, microglia, perivascularly in extracellular deposits [110][111][112] Fe bound to neuromelanin in dopaminergic neurons [112,113] Alzheimer Disease ↓ Fe in serum/plasma [114][115][116] ↑ Fe in (mostly temporal) cortex, globus pallidus, caudate, putamen [117][118][119][120][121][122] ↑ Fe in amyloid plaques, microglia, along myelinated fibers [117,[123][124][125] Fe bound to amyloid partially composed of magnetite nanoparticles [126,127] Amyotrophic Lateral Sclerosis ↑ ferritin, ↓ transferrin in serum [128] ↑ Fe in liver, kidneys [129] ↑ Fe in spinal cord [130,131] ↑ Fe in motor cortex, caudate, subthalamic nucleus, globus pallidus, substantia nigra, red nucleus [132][133][134] ↑ Fe in spinal cord neuron nuclei [135] ↑ Fe in microglia in motor cortex [136] n.a.…”
Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.
“…Peripheral iron metabolism, on the other hand, was generally found to be unrelated to the risk of parkinsonism. A meta-analysis of all quantitative reports of iron in the substantia nigra and biofluids in Parkinson disease concluded that cerebrospinal iron levels were non-significantly higher and serum/plasma levels somewhat lower in parkinsonism, while CSF and serum/plasma ferritin and transferrin and serum/plasma lactoferrin and haptoglobin concentrations are similar in people with Parkinson disease and controls (reviewed: Jiménez-Jiménez et al 2021 ). Fig.…”
Section: ‒2000: Part 1 Building a Case For Iron And Neurodegenerationmentioning
Iron has a long and storied history in Parkinson disease and related disorders. This essential micronutrient is critical for normal brain function, but abnormal brain iron accumulation has been associated with extrapyramidal disease for a century. Precisely why, how, and when iron is implicated in neuronal death remains the subject of investigation. In this article, we review the history of iron in movement disorders, from the first observations in the early twentieth century to recent efforts that view extrapyramidal iron as a novel therapeutic target and diagnostic indicator.
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