lactoferrin and Parkinson-Disease

Topics: Animals; Biological Transport; Central Nervous System; Ceruloplasmin; Ferritins; Humans; Iron; Lactoferrin; Mice; Parkinson Disease; Rats; Receptors, Transferrin; Transferrin

There are at least three major reasons for thinking that iron participates in the mechanism of nerve cell death in Parkinson's disease (PD): (1) Iron catalyzes the formation of highly toxic hydroxyl radicals through the Fenton reaction. (2) Evidence suggests that oxidative stress participates in the mechanism of nerve cell death in PD. (3) Increased iron concentrations have been observed in the substantia nigra of patients with PD. In this review, we report data suggesting that the vulnerable neurons in PD are particularly sensitive to oxidative stress that may be induced by iron and then discuss the mechanisms by which iron levels may be increased in dopaminergic neurons in PD.

Topics: Cell Death; Dopamine; Free Radicals; Humans; Hydroxyl Radical; Iron; Lactoferrin; Neurons; Parkinson Disease; Reactive Oxygen Species; Substantia Nigra; Transferrin

Topics: Animals; Dopamine; Ferritins; Free Radicals; Homeostasis; Humans; Iron; Lactoferrin; Neurons; Oxidative Stress; Parkinson Disease; Rats; Receptors, Cell Surface; Receptors, Transferrin; Substantia Nigra

Although Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra not all dopaminergic neurons degenerate in this disease. This suggests that some specific factors make subpopulations of dopaminergic neurons more susceptible to the disease. Here, we show that the most vulnerable neurons are particularly sensitive to oxidative stress and rise in intracellular calcium concentrations. Because both events seem to occur in Parkinson's disease this may explain why some dopaminergic neurons degenerate and other do not.

Topics: Calcium; Calpain; Cell Death; Dopamine; Humans; Lactoferrin; Nerve Degeneration; Neurons; Oxidative Stress; Parkinson Disease; Substantia Nigra

Overexpression of reactive oxygen species in the substantia nigra pars compacta destroys dopaminergic neurons and accelerates the pathological process of Parkinson's disease (PD). In this study, a new hydrophilic nano-bioconjugate, lactoferrin (Lf)-modified Au-Bi

Topics: Animals; Lactoferrin; Mice; Mitochondria; Oxygen; Parkinson Disease; Reactive Oxygen Species

The treatment of Parkinson's disease (PD) is hampered by the blood-brain barrier (BBB). As such, there is an urgent need for the development of a novel nanoplatform capable of penetrating the BBB in order to effectively treat PD. In the present study, we utilized black phosphorus nanosheets (BP) containing the brain-targeting ligand lactoferrin (Lf) and loaded with Paeoniflorin (Pae) to obtain Lf-BP-Pae. Through an effective photo-thermal effect, these Lf-BP-Pae particles were capable of traversing the BBB and effectively treating PD in a targeted manner. Importantly, this BP-based nanoplatform was capable of achieving satisfactory biocompatibility and biosafety with excellent anti-Parkinsonian efficacy, making it ideal for clinical applications.

Topics: Blood-Brain Barrier; Brain; Drug Delivery Systems; Humans; Lactoferrin; Nanoparticles; Nanostructures; Parkinson Disease; Phosphorus

Topics: Aged; alpha-Synuclein; Biomarkers; Case-Control Studies; Chemokine CCL2; Female; Humans; Lactoferrin; Male; Middle Aged; Parkinson Disease; Tears

Efficient delivery of brain-targeted drugs is highly important for successful therapy in Parkinson's disease (PD). This study was designed to formulate borneol and lactoferrin co-modified nanoparticles (Lf-BNPs) encapsulated dopamine as a novel drug delivery system to achieve maximum therapeutic efficacy and reduce side effects for PD. Dopamine Lf-BNPs were prepared using the double emulsion solvent evaporation method and evaluated for physicochemical and pharmaceutical properties.

Topics: Administration, Intranasal; Animals; Antiparkinson Agents; Brain; Camphanes; Cells, Cultured; Dopamine; Drug Delivery Systems; Lactoferrin; Nanoparticles; Parkinson Disease; Rats; Rats, Sprague-Dawley

Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD.. The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs.. Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference (. Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD.

Topics: Administration, Intranasal; Animals; Brain; Disease Models, Animal; Dopamine Agonists; Drug Carriers; Drug Delivery Systems; Lactoferrin; Male; Nanoparticles; Neuroprotective Agents; Nose; Parkinson Disease; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tetrahydronaphthalenes; Thiophenes; Tissue Distribution

Intestinal inflammation and increased intestinal permeability (both possibly fueled by dysbiosis) have been suggested to be implicated in the multifactorial pathogenesis of Parkinson's disease (PD). The objective of the current study was to investigate whether fecal markers of inflammation and impaired intestinal barrier function corroborate this pathogenic aspect of PD.. In a case-control study, we quantitatively analyzed established fecal markers of intestinal inflammation (calprotectin and lactoferrin) and fecal markers of intestinal permeability (alpha-1-antitrypsin and zonulin) in PD patients (n = 34) and controls (n = 28, group-matched for age) by enzyme-linked immunosorbent assay. The study design controlled for potential confounding factors.. Calprotectin, a fecal marker of intestinal inflammation, and two fecal markers of increased intestinal permeability (alpha-1-antitrypsin and zonulin) were significantly elevated in PD patients compared to age-matched controls. Lactoferrin, as a second fecal marker of intestinal inflammation, showed a non-significant trend towards elevated concentrations in PD patients. None of the four fecal markers correlated with disease severity, PD subtype, dopaminergic therapy, or presence of constipation.. Fecal markers reflecting intestinal inflammation and increased intestinal permeability have been primarily investigated in inflammatory bowel disease so far. Our data indicate that calprotectin, alpha-1-antitrypsin and zonulin could be useful non-invasive markers in PD as well. Even though these markers are not disease-specific, they corroborate the hypothesis of an intestinal inflammation as contributing factor in the pathogenesis of PD. Further investigations are needed to determine whether calprotectin, alpha-1-antitrypsin and zonulin can be used to define PD subgroups and to monitor the effect of interventions in PD.

Topics: Adult; Aged; alpha 1-Antitrypsin; Biomarkers; Case-Control Studies; Cholera Toxin; Feces; Female; Haptoglobins; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Lactoferrin; Leukocyte L1 Antigen Complex; Male; Middle Aged; Parkinson Disease; Permeability; Protein Precursors; Severity of Illness Index

Among the properties of lactoferrin (LF) are bactericidal, antianemic, immunomodulatory, antitumour, antiphlogistic effects. Previously we demonstrated its capacity to stabilize in vivo HIF-1-alpha and HIF-2-alpha, which are redox-sensitive multiaimed transcription factors. Various tissues of animals receiving recombinant human LF (rhLF) responded by expressing the HIF-1-alpha target genes, hence such proteins as erythropoietin (EPO), ceruloplasmin, etc. were synthesized in noticeable amounts. Among organs in which EPO synthesis occurred were brain, heart, spleen, liver, kidneys and lungs. Other researchers showed that EPO can act as a protectant against severe brain injury and status epilepticus in rats. Therefore, we tried rhLF as a protector against the severe neurologic disorders developed in rats, such as the rotenone-induced model of Parkinson's disease and experimental autoimmune encephalomyelitis as a model of multiple sclerosis, and observed its capacity to mitigate the grave symptoms. Moreover, an intraperitoneal injection of rhLF into mice 1 h after occlusion of the medial cerebral artery significantly diminished the necrosis area measured on the third day in the ischaemic brain. During this period EPO was synthesized in various murine tissues. It was known that EPO induces nuclear translocation of Nrf2, which, like HIF-1-alpha, is a transcription factor. In view that under conditions of hypoxia both factors demonstrate a synergistic protective effect, we suggested that LF activates the Keap1/Nrf2 signaling pathway, an important link in proliferation and differentiation of normal and malignant cells. J774 macrophages were cultured for 3 days without or in the presence of ferric and ferrous ions (RPMI-1640 and DMEM/F12, respectively). Then cells were incubated with rhLF or Deferiprone. Confocal microscopy revealed nuclear translocation of Nrf2 (the key event in Keap1/Nrf2 signaling) induced by apo-rhLF (iron-free, RPMI-1640). The reference compound Deferiprone (iron chelator) had the similar effect. Upon iron binding (in DMEM/F12) rhLF did not activate the Keap1/Nrf2 pathway. Added to J774, apo-rhLF enhanced transcription of Nrf2-dependent genes coding for glutathione S-transferase P and heme oxygenase-1. Western blotting revealed presence of Nrf2 in mice brain after 6 days of oral administration of apo-rhLF, but not Fe-rhLF or equivalent amount of PBS. Hence, apo-LF, but not holo-LF, induces the translocation of Nrf2 from cytoplasm to the nucle

Topics: Animals; Brain Ischemia; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Female; Humans; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Multiple Sclerosis; Neuroprotection; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease; Rats; Rats, Wistar; Recombinant Proteins

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.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Binding Sites; Calcium; Cell Death; Cells, Cultured; Dopamine; Focal Adhesion Kinase 1; Glial Cell Line-Derived Neurotrophic Factor; Homeostasis; Humans; Lactoferrin; Mesencephalon; Mitochondria; Nerve Degeneration; Neuroglia; Neurons; Parkinson Disease; Phosphatidylinositol 3-Kinases; Rats; Rats, Wistar; Recombinant Proteins

To investigate clinical features, iron metabolism and neuroinflammation in Parkinson's disease (PD) patients with sleep disorders (SD).. 211 PD patients were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a body of scales for motor symptoms and non-motor symptoms. 94 blood and 38 cerebral spinal fluid (CSF) samples were collected and iron and its metabolism-relating proteins, neuroinflammatory factors were detected and analyzed.. 136 cases (64.5%) of PD patients were accompanied by SD. Factor with the highest score in PSQI was daytime dysfunction. Depression, restless leg syndrome, autonomic symptoms and fatigue contributed 68.6% of the variance of PSQI score. Transferrin level in serum and tumor necrosis factor-α level in CSF decreased, and the levels of iron, transferrin, lactoferrin and prostaglandin E2 in CSF increased in PD patients with SD compared with those without SD. In CSF, prostaglandin E2 level was positively correlated with the levels of transferrin and lactoferrin, and tumor necrosis factor-α level was negatively correlated with the levels of iron, transferrin and lactoferrin in CSF.. Depression, restless leg syndrome, autonomic disorders and fatigue are the important contributors for the poor sleep in PD patients. Abnormal iron metabolism may cause excessive iron deposition in brain and be related to SD in PD patients through dual potential mechanisms, including neuroinflammation by activating microglia and neurotoxicity by targeting neurons. Hence, inhibition of iron deposition-related neuroinflammation and neurotoxicity may cast a new light for drug development for SD in PD patients.

Topics: Adult; Aged; Aged, 80 and over; Depression; Dinoprostone; Fatigue; Female; Humans; Iron; Lactoferrin; Male; Middle Aged; Parkinson Disease; Restless Legs Syndrome; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Transferrin; Tumor Necrosis Factor-alpha

A novel biodegradable brain drug delivery system, the lactoferrin (Lf) conjugated polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticle (Lf-NP) was constructed in this paper with its in vitro and in vivo delivery properties evaluated by a fluorescent probe coumarin-6. Lf was thiolated and conjugated to the distal maleimide function surrounding on the pegylated nanoparticle to form Lf-NP. TEM observation and ELISA analysis confirmed the existence of active Lf on the surface of Lf-NP. The results of qualitative and quantitative uptake studies of coumarin-6 incorporated Lf-NP showed a more pronounced accumulation of Lf-NP in bEnd.3 cells than that of unconjugated nanoparticle (NP). Further uptake inhibition study indicated that the increased uptake of Lf-NP was via an additional clathrin mediated endocytosis processes. Following intravenous administration, a near 3 fold of coumarin-6 was found in the mice brain carried by Lf-NP compared to that carried by NP. Intravenous injection of urocortin loaded Lf-NP effectively attenuated the striatum lesion caused by 6-hydroxydopamine in rats as indicated by the behavioral test, the immunohistochemistry test and striatal transmitter content detection results. The cell viability test and CD68 immunohistochemistry demonstrated the acceptable toxicity of the system. All these results demonstrated that Lf-NP was a promising brain drug delivery system with reasonable toxicity.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Brain; Cell Line; Cell Survival; Drug Carriers; Drug Compounding; Lactoferrin; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Nanoparticles; Parkinson Disease; Particle Size; Polyethylene Glycols; Polyglactin 910; Rats; Rats, Sprague-Dawley; Surface Properties; Tissue Distribution; Urocortins

Nonviral gene therapy of chronic degenerative diseases such as Parkinson's disease (PD) is a great challenge as a result of the low tranfection efficiency of nonviral gene vectors. We previously constructed a lactoferrin (Lf)-modified vector, which was demonstrated to be potential for brain gene delivery both in vitro and in vivo. In the present study, this type of vector was applied to load human glial cell line-derived neurotrophic factor gene (hGDNF).. A rat PD model was constructed by the unilateral lesion of striatum using 6-hydroxydopamine (6-OHDA). Lf-modified nanoparticles (NPs) were prepared and characterized. Neuroprotective effects of Lf-modified NPs were examined in the 6-OHDA-lesioned PD model via a regimen of multiple dosing intravenous administrations.. The size of Lf-modified NPs was 196 +/- 10.1 nm, whereas the zeta potential value was 29.35 +/- 3.27 mV. Lf-modified NPs could protect themselves from heparin displacement and DNase digestion. The results of the neuroprotective evaluation show that increasing the number of injections of Lf-modified NPs loading hGDNF improved locomotor activity, reduced dopaminergic neuronal loss and enhanced monoamine neurotransmitter levels in PD rats. Five injections of Lf-modified NPs loading hGDNF exhibited much more powerful neuroprotection than a single injection, indicating the effectiveness and feasibility of multiple dosing administrations. The results of toxicity tests demonstrated that the dosage of NPs used in the present study was safe enough for brain gene delivery.. The findings obtained in the present study suggest that Lf-modified NPs could be developed for potential nonviral gene therapy of chronic brain disorders.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Genetic Therapy; Glial Cell Line-Derived Neurotrophic Factor; Immunohistochemistry; Lactoferrin; Male; Nanoparticles; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley

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.

Topics: Dopamine; Female; Humans; Lactoferrin; Male; Middle Aged; Parkinson Disease; Severity of Illness Index; Substantia Nigra; Transferrin

Changes in the distribution of the iron-binding protein lactotransferrin have recently been described in the central nervous system during a variety of neurodegenerative disorders. To investigate whether lactotransferrin is associated with the neuropathological changes that characterize Parkinson's disease, we analyzed the distribution of this protein in the mesencephalon of neurologically normal individuals and patients affected with Parkinson's disease using quantitative immunohistochemical methods. High levels of lactotransferrin were observed in a large population of neurons in the substantia nigra of control cases. Lactotransferrin-positive neurons were severely affected by the neurodegenerative process that occurs in Parkinson's disease as indicated by a severe decrease in the number of immunolabeled neurons in all of these cases. Quantitative analysis also demonstrated higher immunolabeling levels of lactotransferrin in the surviving neurons in the substantia nigra and ventral tegmental area of Parkinson's disease cases compared to control cases. These results suggest that lactotransferrin may participate actively in the mechanism of neuronal degeneration in Parkinson's disease.

Topics: Aged; Aged, 80 and over; Carrier Proteins; Female; Humans; Immunohistochemistry; Iron-Binding Proteins; Lactoferrin; Male; Mesencephalon; Middle Aged; Parkinson Disease; Transferrin-Binding Proteins

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.

Topics: Aged; Aged, 80 and over; Antibody Specificity; Humans; Immunoblotting; Immunohistochemistry; Lactoferrin; Microcirculation; Neuroglia; Neurons; Parkinson Disease; Receptors, Cell Surface; Substantia Nigra