Changes in serotonin neurotransmission as assayed by microdialysis after acute, intermittent or chronic ethanol administration and withdrawal.

Background: The serotonergic neurotransmitter system is involved in many ethanol-induced changes, including many behavioural alterations, as well as contributing to alcohol dependence and its withdrawal.

Aims: This review has evaluated microdialysis studies where alterations in the serotonin system, that is, serotonin, 5-HT, or its metabolite 5-hydroxyindoleacetic acid, 5-HIAA, have been reported during different ethanol intoxication states, as well as in animals showing alcohol preference or not. Changes in 5-HT receptors and the 5-HT transporter are briefly reviewed to comprehend the significance of changes in microdialysate 5-HT concentrations.

Iron, Neuroinflammation and Neurodegeneration.

Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs).

Changes in Brain Dopamine Extracellular Concentration after Ethanol Administration; Rat Microdialysis Studies.

Aims: The purpose of this review is to evaluate microdialysis studies where alterations in the dopaminergic system have been evaluated after different intoxication states, in animals showing preference or not for alcohol, as well as during alcohol withdrawal.

Methods: Ethanol administration induces varying alterations in dopamine microdialysate concentrations, thereby modulating the functional output of the dopaminergic system.

Results: Administration of low doses of ethanol, intraperitoneally, intravenously, orally or directly into the nucleus accumbens, NAc, increases mesolimbic dopamine, transmission, as shown by increases in dopamine content.

Is Chelation Therapy a Potential Treatment for Parkinson's Disease?

Iron loading in some brain regions occurs in Parkinson's Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that iron is sequestered within cells as a result of the "anaemia of chronic disease" and remains unavailable to the chelator. In this review, the extent of neuroinflammation in PD is discussed together with the role played by glia cells, specifically microglia and astrocytes, in controlling iron metabolism during inflammation, together with the results of MRI studies.

Iron and inflammation: in vivo and post-mortem studies in Parkinson's disease.

In these present studies, in vivo and and post-mortem studies have investigated the association between iron and inflammation. Early-stage Parkinson's disease (PD) patients, of less than 5 years disease duration, showed associations of plasmatic ferritin concentrations with both proinflammatory cytokine interleukin-6 and hepcidin, a regulator of iron metabolism as well as clinical measures. In addition ratios of plasmatic ferritin and iron accumulation in deep grey matter nuclei assessed with relaxometry T2* inversely correlated with disease severity and duration of PD.

The Efficacy of Iron Chelators for Removing Iron from Specific Brain Regions and the Pituitary-Ironing out the Brain.

Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g.

Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology.

Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI).

Alcohol Hangover: Underlying Biochemical, Inflammatory and Neurochemical Mechanisms.

Aim: To review current alcohol hangover research in animals and humans and evaluate key evidence for contributing biological factors.

Method: Narrative review with alcohol hangover defined as the state the day after a single episode of heavy drinking, when the alcohol concentration in the blood approaches zero.

Results: Many of the human studies of hangover are not well controlled, with subjects consuming different concentrations of alcohol over variable time periods and evaluation not blinded.

Ironing out the Brain.

Our understanding of the broad principles of cellular and systemic iron homeostasis in man are well established with the exception of the brain. Most of the proteins involved in mammalian iron metabolism are present in the brain, although their distribution and precise roles in iron uptake, intracellular metabolism and export are still uncertain, as is the way in which systemic iron is transferred across the blood-brain barrier. We briefly review current concepts concerning the uptake and distribution of iron in the brain, before turning to the ways in which brain iron homeostasis might be regulated.

Quantitative comparison of different iron forms in the temporal cortex of Alzheimer patients and control subjects.

We present a quantitative study of different molecular iron forms found in the temporal cortex of Alzheimer (AD) patients. Applying the methodology we developed in our previous work, we quantify the concentrations of non-heme Fe(III) by Electron Paramagnetic Resonance (EPR), magnetite/maghemite and ferrihydrite by SQUID magnetometry, together with the MRI transverse relaxation rate [Formula: see text], to obtain a systematic view of molecular iron in the temporal cortex. Significantly higher values of [Formula: see text], a larger concentration of ferrihydrite, and a larger magnetic moment of magnetite/maghemite particles are found in the brain of AD patients.

Changes in Pro-Inflammatory Markers in Detoxifying Chronic Alcohol Abusers, Divided by Lesch Typology, Reflect Cognitive Dysfunction.

Aim: To investigate pro-inflammatory markers in the blood and associate with cognitive impairment.

Methods: Il-6 and ferritin were assayed in the blood of 27 patients, divided according to Lesch typology, at the commencement and after 21 days of detoxification, together with a battery of cognitive tests.

Results: A significantly higher mean level of IL-6 was present in the blood of patients with Lesch typology 1 compared to the other typologies 2 and 3 on admission to the Detoxification Ward which did not alter significantly after detoxification.

Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease.

Parkinson's disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months.

Ageing, neuroinflammation and neurodegeneration.

During ageing, different iron complexes accumulate in specific brain regions which are associated with motor and cognitive dysfunction. In neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in local iron homoeostasis result in altered cellular iron distribution and accumulation, ultimately inducing neurotoxicity. The use of iron chelators which are able to penetrate the blood brain barrier and reduce excessive iron accumulation in specific brain regions have been shown to reduce disease progression in both Parkinson's disease and Friedreich's Ataxia.

Neurodegenerative diseases and therapeutic strategies using iron chelators.

This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies.

The role of iron in brain ageing and neurodegenerative disorders.

In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment.

Influence of adolescent heavy session drinking on the systemic and brain innate immune system.

Aims: The aim of the study was to evaluate rat models of intermittent alcohol abuse (heavy session/'heavy session' drinking) in relation to inflammatory changes in specific brain regions as well as in the periphery. Furthermore, the study was aimed to assess whether there are inflammatory changes in the blood of human intermittent alcohol abusers who might be associated with changes in neuronal circuitry in the brain, as assessed by functional magnetic resonance imaging (fMRI), which cause adverse effects on memory and learning.

Methods: Various regimes of intermittent alcohol administration have been used in rat models, which vary with respect to the dose and duration of ethanol administration as well as the time of abstinence.

Increased cortical activity in binge drinkers during working memory task: a preliminary assessment through a functional magnetic resonance imaging study.

Background: Cerebral dysfunction is a common feature of both chronic alcohol abusers and binge drinkers. Here, we aimed to study whether, at equated behavioral performance levels, binge drinkers exhibited increased neural activity while performing simple cognitive tasks.

Methods: Thirty-two participants (16 binge drinkers and 16 matched controls) were scanned using functional magnetic resonance imaging (fMRI) while performing an n-back working memory task.

Binge drinking +/- chronic nicotine administration alters extracellular glutamate and arginine levels in the nucleus accumbens of adult male and female Wistar rats.

Aims: The effect of 'binge drinking' coupled or not with chronic nicotine administration on nucleus accumbens (NAc) glutamate, arginine, taurine and hydroxyl radical levels has been investigated in these present studies.

Methods And Results: Ethanol, 2 or 3 g/kg, has been administered to male or female adult rats in a 'binge-type' regime for 3 weeks, +/- nicotine, and changes in glutamate, arginine and taurine content in the NAc, assayed by microdialysis after a further dose of ethanol. The basal concentration of NAc glutamate increased 8-fold in the female adult rats but did not change significantly after further doses of ethanol.

Anti-inflammatory actions of a taurine analogue, ethane β-sultam, in phagocytic cells, in vivo and in vitro.

The ability of a taurine prodrug, ethane β-sultam, to reduce cellular inflammation has been investigated, in vitro, in primary cultures of alveolar macrophages and an immortilised N9 microglial cell line and in vivo in an animal model of inflammation and control rats. Ethane β-sultam showed enhanced ability to reduce the inflammatory response in alveolar macrophages, as assayed by the lipopolysaccharide-stimulated-nitric oxide release, (LPS stimulated-NO), in comparison to taurine both in vitro (10 nM, 50 nM) and in vivo (0.15 mmol/kg/day by gavage).

Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson's disease after peripheral administration.

The iron content of the substantia nigra pars compacta increases in the brains of Parkinson's disease patients. Hence, its removal by iron chelators may retard the progression of the disease. However, information on the ability of clinically available iron chelators to cross the blood brain barrier and be neuroprotective is limited.

Iron and the immune system.

Iron and immunity are closely linked: firstly by the fact that many of the genes/proteins involved in iron homoeostasis play a vital role in controlling iron fluxes such that bacteria are prevented from utilising iron for growth; secondly, cells of the innate immune system, monocytes, macrophages, microglia and lymphocytes, are able to combat bacterial insults by carefully controlling their iron fluxes, which are mediated by hepcidin and ferroportin. In addition, lymphocytes play an important role in adaptive immunity. Thirdly, a variety of effector molecules, e.

Brain iron metabolism and its perturbation in neurological diseases.

Metal ions are of particular importance in brain function, notably iron. A broad overview of iron metabolism and its homeostasis both at the cellular level (involving regulation at the level of mRNA translation) and the systemic level (involving the peptide 'hormone' hepcidin) is presented. The mechanisms of iron transport both across the blood-brain barrier and within the brain are then examined.

Neuro-inflammation induced in the hippocampus of 'binge drinking' rats may be mediated by elevated extracellular glutamate content.

The neuropathological and immune changes induced in the brain by 'binge drinking' have been investigated in a rat model. Evidence of neuro-inflammation was identified in the 'binge drinking' rat model of alcohol abuse after 3 weeks of administration of 2 or 3 g/kg ethanol (EtOH), three times per day for two consecutive days, followed by 5 days of abstinence: Firstly, alveolar macrophages, isolated from these animals, showed significant increases in inducible nitric oxide synthase, as assayed by nitrite release, both before and after lipopolysaccaharide stimulation. Secondly, significant numbers of activated microglia were present in the dentate gyrus region of the hippocampus of the 'binge drinking' model, after major histocompatibility complex class II staining, by comparison with the control.

The influence of chronic nicotine administration on behavioural and neurochemical parameters in male and female rats after repeated binge drinking exposure.

Aims: The possible interaction between nicotine and 'binge drinking' in eliciting changes in behavioural patterns of 'binge drinking' rats as well as nucleus accumbens (NAc) glutamate levels has been investigated in these present studies.

Methods: Adult or adolescent male and female rats received ethanol, 2 g/kg or 3 g/kg, by gavage in a 'binge drinking' regimen (3 times/day over a 6 h period, for 2 days followed by 5 days of abstinence) combined with or without nicotine, 0.3 g/kg, for either a 5-week (adult) or a 4-week (adolescent) period.

Biochemical and neurotransmitter changes implicated in alcohol-induced brain damage in chronic or 'binge drinking' alcohol abuse.

The brain damage, which occurs after either chronic alcoholization or binge drinking regimes, shows distinct biochemical and neurotransmitter differences. An excessive amount of glutamate is released into specific brain regions during binge drinking (in excess of 4- to 5-fold of the normal basal concentration) that is not evident during periods of excessive alcohol consumption in chronic alcohol abusers. Increases in glutamate release are only observed during the initial stages of withdrawal from chronic alcoholism ( approximately 2- to 3-fold) due to alterations in the sensitivities of the NMDA receptors.