Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease.
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PMID:Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. 756 81

Iron deposition in the substantia nigra in Parkinson's disease has been associated with an increase in lactoferrin receptors and a reduction in ferritin concentration. This accumulation of iron in the brain may accelerate free radical formation, lipid peroxidation, and neuronal death. Remarkably, there are few data available concerning systemic iron metabolism in Parkinson's disease. We measured total iron binding capacity and circulating iron, ferritin, transferrin, and transferrin receptors; calculated transferrin saturation; and estimated dietary iron intake in patients with idiopathic Parkinson's disease and in controls. Concentrations of circulating iron, ferritin, and transferrin as well as total iron binding capacity and transferrin saturation were significantly lower in patients than controls. There were no differences in transferrin receptors or dietary intake of iron. The decrease in levels of systemic ferritin and transferrin and the total iron binding capacity parallels observations in a Parkinson's disease brain, but the reductions in serum iron concentrations and transferrin saturation do not, and were unexpected. These results suggest the existence of a defect in the systems that regulate the synthesis of the major proteins of iron metabolism in the liver as well as the brain in Parkinson's disease that may, over time, expedite entry of iron into the brain and decrease iron in the extracellular compartment.
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PMID:Altered systemic iron metabolism in Parkinson's disease. 930 29

The presence of iron in brain tissue in increased concentrations in Parkinson's disease cases, where it might be responsible for oxidative stress, and the parallel observation that the iron transporter lactoferrin (Lf) was present in increased amounts in surviving neurons, led us to study the synthesis of Lf in a mouse model of Parkinson's disease. In this context, the origin and expression of brain Lf in normal, aged and MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine)-treated mice were investigated. Lf immunostaining was observed mainly on microvessels in the cerebral cortex of the adult mice and to a greater extent in older mice. Lf immunoreactivity was also present in the hippocampus only in the aged mouse brains, associated with structures which seemed to be pyramidal neurons and fibers. After RT-PCR (polymerase chain reaction), Lf transcripts were found in mouse brain tissue whatever the age of the animals studied but the level of their expression was very low. No up-regulation of Lf was detectable during aging. Lf distribution and expression in the MPTP-induced Parkinsonian mouse model were also investigated. A marked depletion of dopamine (DA) occurred in the high dose MPTP-treated mice. The level of Lf expression was found to be markedly increased in the same animals and this up-regulation occurred on the first day after MPTP administration. When the brain was stressed by the neurotoxin MPTP, Lf expression increased in line with antioxidant enzymes such as catalase and gamma-glutamylcysteine synthetase, which may permit the protection of brain tissue from oxidative damage induced by the drug.
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PMID:Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. 1052 77

Iron may play an important role in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that the iron-transporting glycoprotein lactoferrin (LF) and its receptor are increased in the substantia nigra (SN) in PD. We investigated whether plasma levels of LF are altered in dopa-responsive PD. Plasma LF was not different between patients with PD (n = 23; 306 +/- 116 [mean +/- standard deviation] ng/ml) and age- and sex-matched healthy control subjects (n = 15; 359 +/- 126 ng/ml ). However, LF was inversely correlated with PD severity (r = -0.68, P = 0.002), an association that remained significant after adjustment for treatment with levodopa, monoaminooxidase inhibitors, and dopa agonists (r = -0.53, P = 0.017). Plasma transferrin and ferritin levels were not different between groups and neither correlated with disease severity nor with LF levels. Together with the result of increased nigral lactoferrin, this finding is compatible with the hypothesis of an imbalance between LF levels in blood and SN in progressing PD. Larger and particularly longitudinal studies and measurements of LF in cerebrospinal fluid are warranted to further examine the role of LF in PD.
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PMID:Assessment of plasma lactoferrin in Parkinson's disease. 1121 73

We have conducted a case-control study in order to test for an association between 8 intragenic polymorphisms of 5 iron-related genes (transferrin, transferrin receptor1, HFE, frataxin and lactoferrin) and Parkinson disease. Comparison of genotypes and allele frequencies did not differ significantly between cases and controls for all studied polymorphisms except the G258S transferrin polymorphism, for which a higher frequency of the G allele was found among cases (p=0.033), particularly among cases with onset older than 60 (p=0.0017) and with negative family history (p=0.022). This finding suggests that genetic variations in the control of iron metabolism may contribute to the pathogenesis of the disease.
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PMID:Association study between iron-related genes polymorphisms and Parkinson's disease. 1214 Jun 59

Parkinson's disease (PD) is characterized by the death of dopaminergic neurons in the substantia nigra. This neuronal degeneration is associated with a strong microglial activation and iron accumulation in the affected brain structures. The increased iron content may result from an increased iron penetration into the brain parenchyma due to a higher expression of lactoferrin and lactoferrin receptors at the level of the blood vessels and dopaminergic neurons in the substantia nigra in PD. Iron may also accumulate in microglial cells after phagocytosis of dopaminergic neurons. These effects may be reinforced by a lack of up-regulation of the iron storage protein ferritin, as suggested by an absence of change in iron regulatory protein 1 (IRP-1) control of ferritin mRNA translation in PD. Thus, a dysregulation of the labile iron pool may participate in the degenerative process affecting dopaminergic neurons in PD.
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PMID:Altered regulation of iron transport and storage in Parkinson's disease. 1744 30

The health-relevant functionality of Mucuna pruriens was improved by priming the seeds with elicitors of the pentose phosphate pathway (PPP) such as fish protein hydrolysates (FPHs), lactoferrin (LF) and oregano extract (OE) followed by dark germination. FPH elicited the highest phenolic content of 19 mg/g FW on day 1, which was 38% higher than control sprouts. OE enhanced Parkinson's disease-relevant L-DOPA content by 33% on day 1 compared to control sprouts. Anti-diabetes-relevant alpha-amylase inhibition percent (AIP) and alpha-glucosidase inhibition percent (GIP) were high in the cotyledons and decreased following elicitation and sprouting. For potential anti-diabetic applications, low AIP and high GIP with moderate L-DOPA content on day 4 of dark germination could be optimal. Improved L-DOPA concentrations in a soluble phenolic and antioxidant-rich M. pruriens background on day 1 sprouts have potential for Parkinson's disease management.
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PMID:Improved health-relevant functionality in dark germinated Mucuna pruriens sprouts by elicitation with peptide and phytochemical elicitors. 1945 56

Dopaminergic cell death in the substantia nigra (SN) is central to Parkinson's disease (PD) but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic neurons and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation and neuronal death. However, the mechanisms involved in iron accumulation remain unclear. In previous studies we excluded a role of transferrin and its receptor in iron accumulation while we showed that lactoferrin receptors were overexpressed in blood vessels and dopaminergic neurons in Parkinson's disease. We recently also described an increase in the expression of the divalent metal transporter 1 (DMT1/Nramp2/Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increased in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress and dopaminergic cell loss. A mutation in DMT1 that impairs iron transport protected rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine (6-OHDA). This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.
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PMID:Iron transport in Parkinson's disease. 2008 92

Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is upregulated in dopamine (DA) neurons resistant to degeneration in Parkinson disease (PD). To study how this could possibly relate to disease progression, we used midbrain cultures and experimental settings that model the progressive loss of DA neurons in this disorder. Human lactoferrin of either recombinant or natural origin provided robust protection to vulnerable DA neurons in a culture paradigm in which these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of glial cell line-derived neurotrophic factor, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans on the cell surface of DA neurons and subsequently to partial inactivation of focal adhesion kinase (FAK), a major effector kinase of integrins. We established that FAK inactivation served to unmask a prosurvival phosphoinositide 3-kinase/AKT-dependent signaling pathway that stimulates calcium shuttling from endoplasmic reticulum to mitochondria. DA neurons exposed to the mitochondrial toxin 1-methyl-4-phenylpyridinium were also partially protected by lactoferrin, further supporting the view that mitochondria may represent a downstream target for lactoferrin protective actions. Finally, we found that the iron binding capability of lactoferrin intervened in DA cell rescue only when neurodegeneration was consecutive to iron-catalyzed oxidative stress. Overall, our data suggest that the accumulation of lactoferrin in PD brains might be evidence of an attempt by the brain to minimize the consequences of neurodegeneration.
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PMID:The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis. 2407 68

Amyotrophic lateral sclerosis (ALS) has a multitude of factors implicated in its etiology. The complex neuro-etiology and the restrictive nature of the blood-brain barrier (BBB) have significantly hindered the drug therapy of ALS. Riluzole, a moderately performing drug, is the only agent approved for treating ALS. However, several promising nanocarrier approaches are surfacing that can provide more efficient drug delivery. In addition, biologicals such as stem cells are able to carry neurotrophic factors to their target site, providing motor neurons with the benefits of both, stem cells and neurotrophic factors. This review examines the current drug delivery strategies investigated for optimally treating ALS and related neurodegenerative disorders. Examples include cerium oxide nanoparticles in Alzheimer's disease, odorranalectin, and lactoferrin-coupled PEG-PLGA nanoparticles for urocortin transportation in Parkinson's disease that can also be employed in ALS to bypass the BBB and increase drug bioavailability. A concise incursion into the progress (and lack thereof) made in ALS clinical trials is also discussed. Nanocarriers can potentially eliminate the challenges of poor drug bioavailability in ALS as they have been proven to cross the BBB and reach target sites while minimizing systemic side-effects. Nanocarrier-based delivery of ALS drugs is an area that requires much needed investigation.
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PMID:A review of the potential role of nano-enabled drug delivery technologies in amyotrophic lateral sclerosis: lessons learned from other neurodegenerative disorders. 2555 87


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