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Nitric oxide and cognitive function

Nitric oxide and cognitive function

Cignitive the similar cognltive occurs to produce NO. The use, distribution ckgnitive reproduction in other forums is permitted, provided the oxid author Sports nutrition consultations and Brown rice for breakfast copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. High total cholesterol levels in late life associated with a reduced risk of dementia. Another case for targeting iron homeostasis is inhibiting DMT1 function. Posted December 11,

Research from the Medical Research Council MRC Toxicology Unit at the University coggnitive Leicester shows cognitibe nitric oxide NO can Sports nutrition consultations the clgnitive ability of the brain. Sports nutrition consultations cognktive has implications for Nitric oxide and cognitive function treatment of neurodegenerative diseases such fucntion Alzheimer's Disease and ajd understanding of brain function more generally.

The research is ufnction Nitric oxide and cognitive function Professor Ian Forsythe cognitivs is reported in the journal Neuron on 26th November. Professor Forsythe, of the MRC Toxicology Unit, explains: "It is well known that nerve cells communicate via Nitric oxide and cognitive function Cayenne pepper supplements — the site at which cogntiive messengers neurotransmitters such as acetylcholine or Sports nutrition consultations are packaged and then Mental agility exercises under tight control to influence their neighbours.

However, because it is normally released in such minute quantities and is so labile, it is very difficult to study. Normally these ion-channels keep electrical potentials very short-lived, but nitric oxide shifts their activity, slowing the electrical potentials and reducing information passage along the pathway, acting as a form of gain control.

Such a function is ideal for tuning neuronal populations to global activity. On the other hand, too much nitric oxide is extremely toxic and will cause death of nerve cells; so within the kernel of this important signaling mechanism are the potential seeds for neurodegeneration, which if left unchecked contribute to the pathologies of stroke and dementias.

In the future Professor Forsythe's research group will be trying to understand how these signalling mechanisms are applicable elsewhere in the brain and will investigate how aberrant signalling contributes to neurodegenerative disease processes such as in Alzheimer's disease.

Professor Ian D. Forsythe Toxicity at the Synaptic Interface MRC Toxicology Unit University of Leicester Leicester. LE1 9HN. email: idf le. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Journal Neuron.

: Nitric oxide and cognitive function

Functions and dysfunctions of nitric oxide in brain

Indeed, most of the literature related to circulatory dysfunction associated with AD was focused on the cortical areas, which are primarily affected in AD Du et al. Our data Figures 2 , 3 are in agreement with recent reports of a coupling between cortical hypoperfusion and a reduction of blood flow from ICA Maalikjy Akkawi et al.

Moreover, the recognition of ICA blood flow reduction in parallel to AD severity implies an exacerbated cortical hypo perfusion in this population. These findings suggest that cortical perfusion changes measured via ASL are strongly dependent on abnormal inflow from extracranial arteries Clark et al.

Along with cortical alteration of blood flow, few studies reported evidence that peripheral vascular dysfunction determined by ankle-to-brachial index, flow-mediated dilation, intima-media thickness, and endothelial microvascular response to acetylcholine are associated with AD Dede et al.

This literature suggests that systemic vascular impairments are determined by AD, or from a different point of view, that systemic vascular dysfunctions may trigger AD De La Torre, In this complex cause-effect scenario, the peripheral vascular difference between the vascular dementia and AD has been accounted, and AD appears, per se , to be associated with a significant reduction of systemic vascular function.

Data from the current study Figures 3 — 5 confirm this view and extend the relationship between AD onset and circulatory impairment up to the more advanced phases of the disease. Nitric oxide, an unstable free radical endogenously synthesized by several cell-types, exerts various biological regulatory functions at peripheral level in the nervous and cardiovascular systems Loscalzo and Welch, ; Calabrese et al.

Indeed, depletion of NO and endothelial nitric oxide synthase enzymatic activity, as a major endogenous source of NO, are one of the mechanisms in the pathogenesis of endothelial dysfunction in both cerebral and peripheral blood vessels Katusic and Austin, Interestingly, recent literature has underlined the key role of NO depletion in the early stage of neurodegenerative disorders, as well as in their progression Katusic and Austin, In a recent murine study, Merlini and coauthors Merlini et al.

Interestingly, and similarly to the data retrieved in our human model, endothelium-dependent vasorelaxation was significantly impaired in both basilar and femoral arteries of month-old Swedish arctic SweArc transgenic AD mice compared with that of age-matched wild-type and 6-month-old SweArc.

This vascular impairment was accompanied by significantly reduced levels of cyclic GMP, demonstrating the central role of NO bioavailability in the pathogenesis and development of AD. Due to the transitory and unstable nature of this free radical, several studies have determined the bioavailability of NO via plasma levels of nitrite and nitrate Casey et al.

Interestingly, this literature indicates a strong positive relationship between plasma level of nitrite and nitrate and systemic vascular function Casey et al. The present data are in agreement with the above-mentioned animal and human studies, and support the hypothesis that, in humans, the depletion in NO bioavailability is correlated with reduction of cortical, extracranial, and peripheral blood flow during aging and in parallel to AD severity Figures 4 — 6.

The recent literature underlined that augmenting physical activity and fitness can protect NO bioavailability, attenuating the deleterious effects of advancing age on vascular function Groot et al.

Therefore, particular attention on the determination of the physical activity level is needed in order to better describe the net effect of aging and AD to the systemic vascular function. As expected, our results indicate that in comparison to the YG, healthy elderly and patients with AD, were more sedentary Table 1.

These data suggest that the reduction of systemic vascular function and NO bioavailability of these groups are likely affected by their low-level of physical activity. However, it is important to note that the IPAQ values among OLD, MCI, AD1, AD2, and AD3 were similar, implicating that in these age-matched groups, aging and level of physical activity are not responsible of the progressive reduction of NO bioavailability and vascular dysfunction.

Another physiological factor important to mention in relation to the cerebral blood flow assessment is the level of CO 2. In fact, due to its vasodilatory effect on the conduit intra- and extracranial arteries, hypercapnia is routinely utilized for the evaluation of maximal cerebral perfusion.

Therefore, the determination of ExpCO 2 is required in order to normalize the cerebral blood flow. The data of resting ExpCO 2 Table 1 were similar in the 6 groups, implicating that ExpCO 2 did not play a role in the changes of cerebral blood flow in our subjects.

Indeed, resting blood flow to a specific organ is affected by its volume of metabolically active tissue. Indeed, basal metabolism is another important physiological factor affected by aging Venturelli et al.

Interestingly, our data of resting oxygen uptake Table 1 indicate similar basal metabolism in the six groups of subjects, suggesting that this physiological factor is not playing a direct role in the progressive changes of brain and skeletal muscle blood flow.

It is important to mention that NO is a free radical playing several positive regulatory functions at cellular and systemic level. However, it is well established that elevated levels of free radicals have a plethora of deleterious effects on the vascular and nervous system during aging and AD, primarily associated with mitochondrial dysfunction.

It is believed that mitochondrial dysfunction precedes Aβ formation, increasing reactive oxygen species ROS and oxidative stress, which, in turn, may facilitate overproduction of Aβ Morris et al. In AD, mitochondrial damage is characterized by decreased respiratory chain complexes activities, where complexes III and IV are typically involved, causing ROS overproduction and reduced ATP synthesis Marques-Aleixo et al.

In this regard, brain tissues are metabolically very active and are particularly susceptible to the damaging effects by ROS.

In case of AD, ROS have been reported within those brain regions, such as the cerebral cortex and hippocampus, which undergo selective neurodegeneration Bhat et al. Interestingly, a large body of evidence shows that AD patients have oxidative metabolism dysfunction in both the central nervous system CNS and peripheral tissues i.

Moreover, recent studies suggest that mitochondria ROS overproduction contribute to accelerate the development of the senescent phenotype in endothelial cells, impairing regenerative and angiogenic capacity of the endothelium, promoting atherosclerosis by altering the secretion of cytokines, growth factors, and protease in the vascular wall Dai et al.

Other potential confounding factors that may have influenced, at least in part, our findings include the deconditioning due to AD, the age-related aortic stiffness and progressive impairment in diastolic heart functions Pase et al.

MV performed the experiments, analyzed the data, prepared the figures, and drafted the manuscript. APe performed the experiments, analyzed the data, and drafted the manuscript. IB performed the experiments, analyzed the data, and drafted the manuscript.

CF performed the experiments, analyzed the data, and drafted the manuscript. NS interpreted the results of experiments, and drafted the manuscript.

ST performed the experiments, interpreted the results of experiments, and drafted the manuscript. EM performed the experiments, interpreted the results of experiments, and drafted the manuscript. LC performed the experiments, interpreted the results of experiments, and drafted the manuscript.

AS performed the experiments, interpreted the results of experiments, and drafted the manuscript. APi performed the experiments, interpreted the results of experiments, and drafted the manuscript.

MR interpreted the results of experiments, and drafted the manuscript. FP interpreted the results of experiments, and drafted the manuscript. FS edited, revised, and approved the final version of manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We thank all the study participants and Dr. Scarsini R. for their support and dedication to the research project. Albert, M. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

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Professor Ian D. Forsythe Toxicity at the Synaptic Interface MRC Toxicology Unit University of Leicester Leicester. LE1 9HN. email: idf le. Kapil, V. Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role for Nitrite-Derived NO Hypertension, AHA Journals, 56 2 , Shirley, B Nitric Oxide and Mental Health.

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Causes of Memory Malfunction Article CAS PubMed PubMed Central Google Scholar Anstey KJ, Cherbuin N, Budge M, Young J. Back Magazine. Pre-processed Control and Label volumes were then surround subtracted and averaged to obtain perfusion-weighted images. Nitric oxide-induced calcium release via ryanodine receptors regulates neuronal function. Zhou, Z. Cardiovascular disease risk models and longitudinal changes in cognition: a systematic review.
How does Nitric Oxide improve mood and enhance immunity? Iron and dopamine: cognutive toxic couple. Central and peripheral contributors cognitie Sports nutrition consultations muscle hyperemia: Mindful snacking tips to passive limb cognutive. Cochlear compound action potentials thresholds were recorded with NOS inhibitor and glutamate exposed conditions. Secondly, it modified the function of iron-related protein directly via S-nitrosylation. About us About us. Anxiety disorders are the most frequently diagnosed psychiatric conditions and can cause a diminished quality of life.
The Radical Role of Nitric Oxide in Learning Also, deficiencies in protein, healthy fats, vitamin B1 and B12 specifically affect memory function. Kelleher RJ, Soiza RL. Moreover, the recognition of ICA blood flow reduction in parallel to AD severity implies an exacerbated cortical hypo perfusion in this population. Kakizawa, S. Lancet Neurol.
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Abstract Nitric oxide NO works as a retrograde neurotransmitter in synapses, allows the brain blood flow and also has important roles in intracellular signaling in neurons from the regulation of the neuronal metabolic status to the dendritic spine growth.

Publication types Research Support, Non-U. Gov't Review. Substances Proteins Peroxynitrous Acid Nitric Oxide. Flow-mediated dilation and neurocognition: systematic review and future directions. Psychosom Med. Scuteri A, Wang H. Pulse wave velocity as a marker of cognitive impairment in the elderly.

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Physiol Behav. Download references. Institute of Health and Society and Newcastle University Institute for Ageing, Newcastle University, Newcastle Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne,, NE4 5PL, UK.

Department of Rehabilitation, Aged and Extended Care, Faculty of Medicine, Nursing and Health Sciences, School of Health Sciences, Flinders University, Adelaide, Australia. Cognitive Ageing and Impairment Neurosciences Laboratory, School of Psychology, Social Work and Social Policy, University of South Australia, Adelaide, Australia.

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You can also search for this author in PubMed Google Scholar. Correspondence to Blossom C. Blossom CM Stephan, Stephanie L. Harrison, Hannah Keage, Abrar Babateen, Louise Robinson and Mario Siervo declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

This article is part of the Topical Collection on Psychological Aspects of Cardiovascular Diseases. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions.

Stephan, B. et al. Cardiovascular Disease, the Nitric Oxide Pathway and Risk of Cognitive Impairment and Dementia. Curr Cardiol Rep 19 , 87 Download citation. Published : 11 August Anyone you share the following link with will be able to read this content:.

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Download PDF. Abstract Purpose of Review In this review, we summarise the evidence on the association between cardiovascular disease CVD and cognitive impairment and explore the role of the nitric oxide NO pathway as a causal mechanism.

Recent Findings Evidence from epidemiological studies suggests that the presence of CVD and its risk factors in midlife is associated with an increased risk of later life cognitive impairment and dementia. Summary CVDs and dementia are major challenges to global health worldwide.

Cognitive assessment tools for mild cognitive impairment screening Article 14 August Use our pre-submission checklist Avoid common mistakes on your manuscript. Introduction Midlife cardiovascular disease CVD and vascular risk factors have been consistently associated with an increased risk of later life cognitive impairment and dementia [ 1 , 2 , 3 ].

Structural and Functional Brain Changes Associated with CVD and Vascular Risk Factors: Links to Cognitive Impairment and Dementia CVD can alter the brain structure and functioning including an increase in white matter lesions, small vessel disease, micro-bleeds, cerebral infarcts, grey matter atrophy and regional structural alterations e.

Inflammation and Oxidative Stress In all age groups, including the very old, a significant and increased risk of cognitive decline and dementia has been associated with high inflammation e. Physiological Roles of Nitric Oxide Production in Brain Function NO is a reactive gas secreted in endothelial cells by the endothelial isoform of the enzyme NO synthase and is tonically released to control systemic vascular tone i.

Full size image. Endothelial Dysfunction, NO and Cognitive Impairment Endothelial function is closely linked to the control of cerebrovascular reactivity, which is essential for creating a favourable environment for neurons, by maintaining energy-dependent processes and removing metabolic waste [ 54 , 55 , 56 ].

NO-Targeted Nutritional Interventions The biosynthesis of NO is highly dependent on arginine and inorganic nitrate intake since they are the main substrates for the enzymatic and non-enzymatic pathways, respectively.

Table 1 Examples of human studies investigating the effect of inorganic nitrate on cerebral blood flow CBF Full size table. Implications for Research The findings highlight that CVDs and vascular risk factors are major risks for the onset of cognitive decline and dementia. Conclusions With a rapidly ageing population, CVDs and dementia are major challenges to global health and future health care provision.

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Article PubMed Google Scholar Hanon O, Haulon S, Lenoir H, Seux ML, Rigaud AS, Safar M, et al. Ferritin, a major iron storage protein in the brain, compromises the H- or L-ferritin monomers.

Neurons and oligodendrocyte express H-ferritin, which have a high iron metabolite rate. Microglia express L-ferritin, which is associated with iron storage Connor et al.

Although oligodendrocytes have the highest iron accumulation in normal aging brain, there is little effect on myelination and oligodendrocyte in neurodegenerative diseases. Oligodendrocytes have high levels of ferritin expression Connor et al.

Fpn needs to couple with ferroxidase to export iron. Astrocytes express ceruloplasmin, while oligodendrocytes express another ferroxidase, hephaestin, to facilitate iron export from oligodendrocyte Schulz et al.

Oligodendrocytes down regulate TfR1 to reduce iron uptake after maturation Han et al. These iron level-regulating mechanisms protect oligodendrocytes in neurodegenerative diseases.

The iron absorbed from blood during different age is more than what is accumulated in the brain, indicating that there is a iron efflux mechanism in the brain. The iron export from brain to blood maybe through the cerebrospinal fluid Moos et al.

Figure 1. Iron homeostasis in the brain. The iron was uptake from blood through brain capillary epithelial cells. Neurons express TfR, DMT1 and Fpn; absorb iron from brain interstitium and export excess iron. Astrocytes form intimate contact with brain capillary epithelial cells through end-feet and may influence iron transport between blood and brain.

Astrocytes express TfR1, DMT1 and ZIP; and efflux iron via Fpn partnered with ceruloplasmin Cp. Astrocytes may also efflux iron via endothelial cells into blood. Microglia can acquire iron via TfR1, DMT1 from brain intermedium. Microglia are unable to efflux iron as Fpn is internalized from the cell surface.

In aged or neurodegenerative brain, microbleeds may occur. Hemoglobin is released after haemolysis. Haptoglobin binds with hemoglobin form a tight complex. The Hb:Hp complex is bound with the receptor CD and undergo endocytosis.

The complex are degraded after endocytosis and the iron is absorbed into intracellular iron pool and stored in ferritin. The iron flow direction is indicated by black arrows. In addition, the highest iron load in the brain is seen in relation to chronic microbleeds.

Cerebral microbleeds are likely to be caused by cerebral atherosclerosis in aged people or people with neurodegenerative diseases Martinez-Ramirez et al. The iron from hemolysis of erythroid cells may be the major source of iron load in aged or neurogenerative brain Figure 1. Erythroid cells contain most of the body iron in hemoglobin Hb.

Hb is not restricted in erythroid cells, but expressed in glia, macrophage and neurons. Hb is an oxygen reservoir inside the cell and regulate mitochondria function.

While Hb mainly exists intracellularly, it will be released extracellularly during hemolysis. Haptoglobin Hp is mostly produced by hepatic cell and binds free Hb in plasma with very high affinity Wicher and Fries, In the brain, Hp is produced locally by oligodendrocyte Zhao et al.

The Hb—Hp complex has a membrane receptor CD The interaction between them leads to internalization of CD Figure 1 , Hb dissociating from Hp, Hb heme degradation, and iron being absorbed into the intracellular iron pool.

Following intravascular hemorrhage, hippocampal and cortical neurons express CD in the brain Garton et al. Although rodent models are widely used for iron study, it is noteworthy that iron accumulation and cellular storage are different between humans and experimental rodent models.

Rodent generally have a lower basal level of iron deposition in the brain, especially in young animals less than one year old , as shown by several groups Jeong and David, ; Liu et al.

In AD, iron hemostasis is disrupted. Transferrin has been shown to be decreased consistently, and in particular in the white matter, White matter is thought to play a major role in neurodegeneration, and increased peroxidative damage to white matter is known to take place in AD Connor et al.

High concentration of iron is accumulated in Aβ plaques and tau tangles which is characteristic of AD. The Aβ plaques contain a fairly large amount of labile iron, while the neighboring cells express significant levels of ferritin and transferrin receptors Connor et al.

Moreover, iron influence APP translation via IRP-IRE system. Lei et al. showed that tau deficiency caused iron accumulation in brain and dopaminergic neuron degeneration, which led to parkinsonism in mice with dementia. Tau promotes the export of neuronal iron by facilitating the trafficking of APP to the plasma membrane.

The study suggested that Alzheimer disease, Parkinson disease and tauopathies that are associated with the iron toxicity due to the loss of soluble tau could in principle be rescued by a pharmacological agent such as clioquinol, an iron chelator Lei et al. Several studies reported that iron deposition was increased in the substantia nigra according to the severity of the disease in PD patients SN Dexter et al.

The researchers used plasma spectroscopy to detect iron concentration quantitatively in various brain regions Dexter et al. In PD brain, histology studies showed that iron accumulate in neurons and glia in SN Jellinger et al.

Furthermore, there are reports that a dysfunction in the IRP-IRE system that results in iron accumulation gave rise to α-Syn-induced toxicity Li et al. Similarly, in almost all PD patient brains the Lewy bodies contained aggregated α-Syn Wakabayashi et al.

The reason for iron accumulation in SN is unclear. Several hypotheses proposed include increased brain-blood-barrier BBB permeability Faucheux et al. Cellular iron accumulation in PD brain may be caused by elevated influx or decreased efflux.

Inflammation could contribute to iron accumulation by either increasing DMT1 uptake activity or TfR transport activity. In a mouse model, DMT1 activity was increased to mediate the iron uptake Salazar et al. NO is a gaseous signaling molecule that initially was thought as a dilator in blood vessels, with guanylyl cyclase as the major effector.

NO binds to the heme group of guanylyl cyclase and activates it in the presence of iron. High cGMP level are associated with release of neurotransmitters including glutamate, acetylcholine and glycine.

NO participates in tumor and bacteria immunity and in the central nervous system, it acts as a retrograde neurotransmitter.

In the nervous system, NO has both physiological and pathological functions. For example, NO contributes to long-term potentiation LTP and long-term depression LTD , and thus it plays a role in learning and memory Schuman and Madison, ; Shibuki and Okada, ; Lev-Ram et al.

NO enhances CREB expression to mediate the response to brain-derived neurotrophic factor Riccio et al. The synaptic NMDARs mediate neuroprotection, while the extrasynaptic NMDARs mediate neurodegeneration Talantova et al. NO also binds to other iron-containing proteins, such as mitochondrial aconitase.

The interaction between mitochondrial aconitase and superoxidase are the major cause to mitochondrial damage Vasquez-Vivar et al. Most of the cytotoxicity of NO is attributed to the production of peroxynitrite Pacher et al.

Peroxynitrite is produced from the diffusion-controlled reaction between NO and superoxide in vivo Squadrito and Pryor, Peroxynitrite is a strong oxidant and it interacts with electron-rich groups, including Fe—S cluster.

Peroxynitrite is an important intermediator for protein nitration and oxidation, lipid peroxidation, mitochondria dysfunction, and finally causes apoptosis and necrosis Radi, NO is produced by NOS through the conversion of L-arginine to citrulline. Three distinct NOS isoforms have been identified in the brain Forstermann et al.

Neuronal NOS nNOS is expressed in neurons, while endothelial eNOS is expressed in brain endothelial cells. Inducible NOS iNOS is expressed in glia cells upon brain injury or inflammation. Inducible NOS produces a large amount of NO upon stimulation by proinflammatory cytokines over a long period of time Green et al.

In human immune response, NO is produced by phagocytes such as monocytes, macrophages, and neutrophils. In phagocytes, interferon-gamma IFN-γ or tumor necrosis factor TNF activates iNOS Green et al. On the other hand, transforming growth factor-beta TGF-β , interleukin-4 IL-4 or IL weakly inhibits iNOS.

As such, phagocytes contribute to inflammatory and immune responses via NO Green et al. In an immune response, NO is secreted as free radicals that is toxic to intracellular pathogens. The modes of action are via DNA damage Wink et al. The molecular effects of NO depend on two kinds of reactions: S-nitrosylation of thiols and the nitrosylation of some metalloenzymes.

Guanylate cyclase, a NO activated heme-containing enzyme, is an essential component of the relaxing function of NO on smooth muscles Derbyshire and Marletta, In addition to neuro-inflammatory stimuli, induction of iNOS expression in astrocytes, macrophages, and microglia by Aβ oligomers or by toxins such as 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP have been reported to increase NO levels in the degenerating brain Liberatore et al.

However, in the Tg APP AD mouse model, ablation of iNOS exacerbated spatial learning and memory and tau pathology, providing evidence that NO may have a neuroprotective role Wilcock et al. NO targeted proteins have been partially characterized. NO can interact with Fe—S cluster containing protein and influence their enzyme activity.

Cytosolic iron concentrations sensed by IRPs could post-transcriptionally adjust the expression of iron metabolizing genes to optimize the availability of labile iron.

IRPs bind to iron-responsive elements IRE , which are specific non-coding mRNA sequences, to control iron metabolism. IREs are of 30 nucleotide in length found along RNA motifs, and they contain the CAGUGN sequence the classic IRE motif that form a stem-loop structure Molokanova et al.

IRP1 and IRP2 are examples of two RNA-binding proteins that interact with IRE to modulate the translation of either the ferritin or Fpn mRNA, and they also control the stability of TfR and DMT1 mRNAs. The binding of IRPs and IREs is regulated by free iron concentration.

Therefore, IRPs can act as either a translation enhancer or inhibitor Pantopoulos, ; Piccinelli and Samuelsson, The decreased expression of ferritin and Fpn reduces free iron binding and export, leading to an increased in availability of labile iron for use by the cell.

Examples of transcripts that contain IREs include those that encode the ferritin subunits L and H, TfR, Fpn, DMT1, mitochondrial aconitase, succinate dehydrogenase, erythroid aminolevulinic acid synthetase, amyloid precursor protein and a-synuclein.

These downstream genes suggest that iron has close regulation of iron metabolism, redox and neurodegeneration via the IRP-IRE system.

NO could regulate IRP-IRE binding, which in turn regulates many iron metabolism-related proteins Figure 2. Similarly, NO can regulate ferritin, Fpn and TfR via regulating the interaction of IRP-IRE binding, and hence regulate iron metabolism Figure 3.

Another report also showed that NO can enhance iron deposition in the brain via decreasing APP expression Ayton et al. The authors reported obvious decrease in expression of APP in substantia nigra of PD brain. APP KO mice have iron-dependent dopaminergic neuron loss, while APP overexpressing mice have protection effect in MPTP mouse model, as APP facilitates iron efflux.

NO decreases APP expression via the IRP-IRE system and this may explain how NO leads to dopaminergic neuron loss in PD. Figure 2. Schematic chart showing how NO regulate iron homeostasis. NO regulates IRP-IRE binding through redox reaction with Fe—S cluster in IRP, hence regulates the transcription of iron-metabolism-related proteins, and elevates intracellular iron level.

NO also directly S-nitrosylates DMT1, which enhances DMT1 transporter function. In addition, NO S-nitrosylates Dexras 1 and enhances the binding of Das1-PAP7-DMT1 complex and finally enhances iron uptake. Figure 3. The regulation of NO on iron homeostasis in the brain during neuroinflammation.

Large amount of NO was produced by microglia and astrocytes upon activation of iNOS during neuroinflammation. NO enhanced the translation of TfR and DMT1 and decreased the translation of Fpn, hence increased iron accumulation in neurons.

The iron accumulation leads to oxidative stress and finally caused neurodegeneration. NO also regulates iron metabolism-related proteins in other ways, such as S-nitrosylation Figure 2.

Recently, we have shown that NO directly modulated DMT1 and enhanced its function via S-nitrosylation. This is unexpected as S-nitrosylation of proteins important in PD such as Parkin and XIAP resulted in compromised functions. Besides, many S-nitrosylated proteins have been identified in the past decade, and of note, those that have been functionally characterized have a loss-of-function Nakamura et al.

The potential therapeutic use of iron chelators gained much attention in recent years Ward et al. The strategy to target iron deposition is either to chelate iron directly or to regulate iron homeostasis, including NO-regulated iron absorption.

The candidate compounds should be BBB-permeant and easily penetrate cell membrane, chelate free iron and minimize the side effect to normal iron metabolism. Several iron chelators were used to deplete excessive iron and yielded promising clinical outcome.

The syndrome was improved and the iron content in SN significantly decreased as monitored by MRI Devos et al. Deferiprone seems quite promising so far, and is waiting to be tested in further clinical trial in larger population.

Furthermore, in several in vivo PD models, iron chelators, including deferasirox, deferrioxamine, VAR and D, have been used to significantly attenuate DA neuronal loss Ghosh et al.

Desferrioxamine has been shown to decelerate AD progression Rogers and Lahiri, However, as DFO is unstable with poor BBB permeability Bandyopadhyay et al. As clioquinol has side effects associated with myelopathies Zhang et al.

However, in another Phase II trial announced by the Australian company Prana Biotechnoloy in , PTB2 failed to improve brain amyloid deposition, neuronal function, brain atrophy and cognition in a one-year course treatment.

Besides direct chelation of iron, potent nontoxic IRE inhibitors with excellent BBB penetrating capacity were also thought to have high therapeutic significance in neurodegenerative diseases. The IRE inhibitors that down-regulate translation of APP and α-Syn and prevent protein aggregation can support survival of neurons.

To date, a few promising drug candidates of IRE inhibitors have been characterized and are being tested in various clinical trials for AD and PD patients Zhou and Tan, Posiphen is a natural product that has been shown to inhibit translation of both APP and a-synuclein proteins.

Furthermore, it is nontoxic and potent Rogers et al. The inhibitory effect has been validated by various experiments done in vitro and in vivo Lahiri et al.

The compound is still waiting for further clinical trials to test the efficacy for AD and PD Bandyopadhyay et al.

Another compound JTR, screened from a ,compound library, was identified to have a more potent effect on APP translation than posiphen. Another case for targeting iron homeostasis is inhibiting DMT1 function. To inhibit NO-mediated DMT1 functional increase, we used the NOS inhibitor L-name to reduce NO-mediated iron deposition in LPS-evoked mouse inflammatory model.

L-NAME significantly ameliorated SN dopaminergic neuron loss and LPS-induced behavior deficit Liu et al. Iron homeostasis is elaborately regulated in the human brain, and iron accumulation is closely associated with neurodegenerative diseases. NO regulates iron deposition at several levels. So far, therapeutic targeting of iron deposition has yielded some promising results, and further clinical trials in larger populations are still needed.

There are still some questions that remained unresolved. For example, how iron is transported through brain capillary epithelial cells and more specifically, how S-nitrosylation of DMT1 enhanced its transporter activity. A real-time, quantitative and in vivo detection technique will be extremely valuable for the field.

CL and MCL drafted the manuscript. TWS critically edited the manuscript. All authors approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Aisen, P. Chemistry and biology of eukaryotic iron metabolism. Cell Biol. doi: CrossRef Full Text Google Scholar.

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