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Nady Braidy, Helene Rossez, Chai K Lim, Bat-Erdene Jugder, Bruce J Brew, Gilles J Guillemin
The kynurenine (KYN) pathway (KP) is a major degradative pathway of the amino acid, L-tryptophan (TRP), that ultimately leads to the anabolism of the essential pyridine nucleotide, nicotinamide adenine dinucleotide. TRP catabolism results in the production of several important metabolites, including the major immune tolerance-inducing metabolite KYN, and the neurotoxin and excitotoxin quinolinic acid. Dendritic cells (DCs) have been shown to mediate immunoregulatory roles that mediated by TRP catabolism. However, characterization of the KP in human DCs has so far only been partly delineated...
November 2016: Neurotoxicity Research
M Lukács, K Warfvinge, L S Kruse, J Tajti, F Fülöp, J Toldi, L Vécsei, L Edvinsson
BACKGROUND: Neurogenic inflammation has for decades been considered an important part of migraine pathophysiology. In the present study, we asked the question if administration of a novel kynurenic acid analogue (SZR72), precursor of an excitotoxin antagonist and anti-inflammatory substance, can modify the neurogenic inflammatory response in the trigeminal ganglion. METHODS: Inflammation in the trigeminal ganglion was induced by local dural application of Complete Freunds Adjuvant (CFA)...
December 2016: Journal of Headache and Pain
Anna Maria Tartaglione, Monica Armida, Rosa Luisa Potenza, Antonella Pezzola, Patrizia Popoli, Gemma Calamandrei
In the study of neurodegenerative diseases, rodent models provide experimentally accessible systems to study multiple pathogenetic aspects. The identification of early and robust behavioural changes is crucial to monitoring disease progression and testing potential therapeutic strategies in animals. Consistent experimental data support the translational value of rodent self-grooming as index of disturbed motor functions and perseverative behaviour patterns in different rodent models of brain disorders. Huntington's disease (HD) is a progressive neurodegenerative disorder, characterized by severe degeneration of basal ganglia, cognitive and psychiatric impairments and motor abnormalities...
October 15, 2016: Behavioural Brain Research
Denise F Happ, R Andrew Tasker
BACKGROUND: Organotypic hippocampal slice cultures (OHSCs) are an attractive in vitro model to examine mechanisms of neuronal injury, because the normal hippocampal architecture, function and cellular diversity are mostly preserved. The effects of exposure to excitotoxins such as N-methyl-d-aspartate (NMDA) on cell viability can be determined by propidium iodide (PI) staining. NEW METHOD: We describe a simple method to objectively quantify cell death in NMDA exposed slice cultures using PI that provides a standardized means of quantifying cell death in hippocampal subfields without the need to induce maximal cell death in each slice...
August 30, 2016: Journal of Neuroscience Methods
Rebecca A Kohnken, Denise J Schwahn
FVB/N mice with 'space cadet' syndrome are prone to audiogenic seizures and are considered excitotoxic 'sensitive' mice due to the neuronal damage that accompanies seizures. FVB/N mice found dead demonstrate acute neuronal cell death--attributed to a massive seizure episode--within the hippocampus and cerebrocortical laminae. However, the behavioral features of FVB/N mice and numerous studies using excitotoxins to induce seizure activity indicate that this strain experiences multiple sublethal seizures. To assess whether FVB/N mice develop histologically detectable lesions, we evaluated the brains of 86 aged (154-847 d) FVB/N mice without a history of seizures...
April 2016: Comparative Medicine
Michael D Lovelace, Bianca Varney, Gayathri Sundaram, Matthew J Lennon, Chai K Lim, Kelly Jacobs, Gilles J Guillemin, Bruce J Brew
The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-γ (IFN-γ), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production...
March 16, 2016: Neuropharmacology
Catherine A Blizzard, K M Lee, Tracey C Dickson
We report the methodology for the chronic delivery of an excitotoxin to the mouse spinal cord via surgically implanted osmotic mini-pumps. Previous studies have investigated the effect of chronic application of excitotoxins in the rat, however there has been little translation of this model to the mouse. Using mice that express yellow fluorescent protein (YFP), motor neuron and neuromuscular junction alterations can be investigate following targeted, long-term (28 days) exposure to the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor excitotoxin, kainic acid...
2016: Frontiers in Neuroscience
Shamsher Singh, Puneet Kumar
AIM: Quinolinic acid (QA) is an excitotoxin that induces Huntington's-like symptoms in animals and humans. Curcumin (CMN) is a well-known antioxidant but the major problem is its bioavailability. Therefore, the present study was designed to investigate the effect of CMN in the presence of piperine against QA-induced excitotoxic cell death in rats. MATERIAL AND METHODS: QA was administered intrastriatally at a dose of 200 nmol/2 µl saline, bilaterally. CMN (25 and 50 mg/kg/day, p...
2016: Pharmacology
Andrew J Gall, Dorela D Shuboni, Lily Yan, Antonio A Nunez, Laura Smale
The ventral subparaventricular zone (vSPVZ) receives direct retinal input and influences the daily patterning of activity in rodents, making it a likely candidate for the mediation of acute behavioral responses to light (i.e., masking). We performed chemical lesions aimed at the vSPVZ of diurnal grass rats (Arvicanthis niloticus) using N-methyl-D,L-aspartic acid (NMA), a glutamate agonist. Following NMA lesions, we placed grass rats in various lighting conditions (e.g., 12:12 light-dark, constant dark, constant light); presented a series of light pulses at circadian times (CT) 6, 14, 18, and 22; and placed them in a 7-h ultradian cycle to assess behavioral masking...
April 2016: Journal of Biological Rhythms
Frank van Bel, Floris Groenendaal
An adverse outcome is still encountered in 45% of full-term neonates with perinatal asphyxia who are treated with moderate hypothermia. At present pharmacologic therapies are developed to be added to hypothermia. In the present article, these potential neuroprotective interventions are described based on the molecular pathways set in motion during fetal hypoxia and following reoxygenation and reperfusion after birth. These pathways include excessive production of excitotoxins with subsequent over-stimulation of NMDA receptors and calcium influx in neuronal cells, excessive production of reactive oxygen and nitrogen species, activation of inflammation leading to inappropriate apoptosis, and loss of neurotrophic factors...
April 2016: Seminars in Perinatology
Diana M Roccaro-Waldmeyer, Alexandre Babalian, Annelies Müller, Marco R Celio
The parvafox nucleus is located ventrolaterally in the lateral hypothalamic area (LHA). Its core and shell are composed of neurons expressing the calcium-binding protein parvalbumin (PV) and the transcription factor Foxb1, respectively. Given the known functions of the LHA and that the parvafox nucleus receives afferents from the lateral orbitofrontal cortex and projects to the periaqueductal gray matter, a functional role of this entity in the expression of positive emotions has been postulated. The purpose of the present study was to ascertain whether the deletion of neurons in the parvafox nucleus influenced the tickling-induced 50-kHz calls, which are thought to reflect positive affective states, in rats...
February 1, 2016: Behavioural Brain Research
Sun Young Park, Yung Hyun Choi, Geuntae Park, Young-Whan Choi
α-Iso-cubebenol is a natural compound isolated from Schisandra chinensis, and is reported to have beneficial bioactivity including anti-inflammatory and anti-tumor activities. Glutamate-induced oxidative neuronal damage has been implicated in a variety of neurodegenerative disorders. Here we investigated the mechanisms of α-iso-cubebenol protection of mouse hippocampus-derived neuronal cells (HT22 cells) from apoptotic cell death induced by the major excitatory neurotransmitter, glutamate. Pretreatment with α-iso-cubebenol markedly attenuated glutamate-induced loss of cell viability and release of lactate dehydrogenase), in a dose-dependent manner...
September 2015: Environmental Toxicology and Pharmacology
Donika Gallina, Christopher Paul Zelinka, Colleen M Cebulla, Andy J Fischer
Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injections of GCR agonist or antagonist, assessed microglial reactivity, and the survival of retinal neurons following different damage paradigms...
November 2015: Experimental Neurology
K A L McAllister, A C Mar, D E Theobald, L M Saksida, T J Bussey
RATIONALE: It is becoming increasingly clear that the development of treatments for cognitive symptoms of schizophrenia requires urgent attention, and that valid animal models of relevant impairments are required. With subchronic psychotomimetic agent phencyclidine (scPCP), a putative model of such impairment, the extent to which changes following scPCP do or do not resemble those following dysfunction of the prefrontal cortex is of importance. OBJECTIVES: The present study carried out a comparison of the most common scPCP dosing regimen with excitotoxin-induced medial prefrontal cortex (mPFC) dysfunction in rats, across several cognitive tests relevant to schizophrenia...
November 2015: Psychopharmacology
Chi Hun Kim, Carola Romberg, Martha Hvoslef-Eide, Charlotte A Oomen, Adam C Mar, Christopher J Heath, Andrée-Anne Berthiaume, Timothy J Bussey, Lisa M Saksida
RATIONALE: The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships...
November 2015: Psychopharmacology
Sachiko Murase, Crystal L Lantz, Eunyoung Kim, Nitin Gupta, Richard Higgins, Mark Stopfer, Dax A Hoffman, Elizabeth M Quinlan
In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood...
July 2016: Molecular Neurobiology
Edwin B Yan, Tony Frugier, Chai K Lim, Benjamin Heng, Gayathri Sundaram, May Tan, Jeffrey V Rosenfeld, David W Walker, Gilles J Guillemin, Maria Cristina Morganti-Kossmann
UNLABELLED: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims...
2015: Journal of Neuroinflammation
Vincenzo Barrese, Maurizio Taglialatela, Iain A Greenwood, Colin Davidson
Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since Kv7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The Kv7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining...
October 2015: Journal of Cerebral Blood Flow and Metabolism
Raffaela Cipriani, Juan Carlos Chara, Alfredo Rodríguez-Antigüedad, Carlos Matute
BACKGROUND: FTY720 (fingolimod, Gilenya™), a structural analog of sphingosine-1-phosphate (S1P), is the first oral drug approved for treatment the relapsing-remitting form of multiple sclerosis (MS), and its efficacy has been related to induced lymphopenia and consequent immunosuppression via modulation of S1P1 receptors (S1P1R). However, due to its lipophilic nature, FTY720 crosses the blood brain barrier (BBB) and could act directly on neural cells. In this study, we investigated the effectiveness of FTY720 as a neuroprotective agent using in vitro and in vivo models of excitotoxic neuronal death and examined if FTY720 exerts a direct action on neurons, or/and an indirect modulation of inflammation-mediated neurodegeneration as a possible mechanism of neuroprotection...
2015: Journal of Neuroinflammation
R Ya Gordon, L V Shubina, M V Kapralova, E B Pershina, S S Khutzian, V I Arhipov
Comparison between results of different ways of application of excitotoxin (kainic acid, KA), intrahippocampal (0.2 μg/μl) and intraventricular (0.6 μg/μl), was carried out in the course of investigations of the prolonged action of KA on the morphological state of various fields in dorsal hippocampus. Light microscopy with Cresyl Violet staining and fluorescent microscopy with staining by fluoro-jade B were used in our researches. The results revealed that KA, being injected intrahippocampally at a dose, which does not result in animal epileptization, caused obvious degenerative phenomena in hippocampus...
2014: Tsitologiia
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