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Steven R Vigna
Clostridium difficile toxin A is a colonic inflammatory agent that acts partially by activation of TRPV1 (transient receptor potential vanilloid type 1). Resiniferatoxin (RTX) is an excitotoxin that activates TRPV1 at low concentrations and defunctionalizes TRPV1 at high concentrations. RTX at various doses was injected intraluminally into isolated ileal segments in anesthetized rats. After 3 hours, the treated segments were removed and inflammation was assessed. This acute treatment with RTX resulted in biphasic responses: (1) an increase in inflammation similar to that caused by toxin A and capsaicin at low doses of up to 100 ng RTX and (2) no inflammatory effect of RTX at higher doses (1-100 μg), consistent with a defunctionalizing or neurotoxic effect of RTX at high doses...
2017: Gastroenterology Research and Practice
Amanda Eskelund, Yan Li, David P Budac, Heidi K Müller, Maria Gulinello, Connie Sanchez, Gregers Wegener
The metabolism of tryptophan through kynurenine and serotonin pathways is linked to depression. Here, effects of different drugs with antidepressant properties (vortioxetine, fluoxetine, and ketamine) on various tryptophan metabolites in different brain regions and plasma were examined using tandem mass spectrometry (LC-MS/MS), in Flinders Sensitive Line rats, a genetic rat model of depression, and its controls: Flinders Sensitive Line and Sprague-Dawley rats. Protein levels of kynurenine pathway enzymes were measured in the brains and livers of these rat strains...
July 2017: Journal of Neurochemistry
Lakshmi Swarna Mukhi Pidugu, Heather Neu, Tin Lok Wong, Edwin Pozharski, John L Molloy, Sarah L J Michel, Eric A Toth
3-Hydroxyanthranilate 3,4-dioxygenase (3HAO) is an enzyme in the microglial branch of the kynurenine pathway of tryptophan degradation. 3HAO is a non-heme iron-containing, ring-cleaving extradiol dioxygenase that catalyzes the addition of both atoms of O2 to the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3-HANA) to form quinolinic acid (QUIN). QUIN is a highly potent excitotoxin that has been implicated in a number of neurodegenerative conditions, making 3HAO a target for pharmacological downregulation...
April 1, 2017: Acta Crystallographica. Section D, Structural Biology
Dhwani Kumar, Rachna Manek, Vijaya Raghavan, Kevin K Wang
A number of neuronal and glial proteins were previously found to be released in free-standing soluble form from cultured brain cells into cell-conditioned media. Here, we sought to examine if similar proteins are also contained in neural and astroglial cell-released extracellular microvesicles/exosomes (MV/E). In this study, MV/E were isolated from cell-conditioned media from control and cytotoxin-challenged rat cerebrocortical mixed culture (CTX) and mouse neuroblastoma N2a cells. Cytotoxin challenges included pro-necrosis calcium ionophore A23187, pro-apoptosis staurosporine (STS), and excitotoxin N-methyl-D-aspartate...
March 10, 2017: Molecular Neurobiology
Andreas Baranyi, Omid Amouzadeh-Ghadikolai, Dirk von Lewinski, Robert J Breitenecker, Tatjana Stojakovic, Winfried März, Christoph Robier, Hans-Bernd Rothenhäusler, Harald Mangge, Andreas Meinitzer
Quinolinic acid, a macrophage/microglia-derived excitotoxin fulfills a plethora of functions such as neurotoxin, gliotoxin, and proinflammatory mediator, and it alters the integrity and cohesion of the blood-brain barrier in several pathophysiological states. Beta-trace protein (BTP), a monomeric glycoprotein, is known to indicate cerebrospinal fluid leakage. Thus, the prior aim of this study was to investigate whether BTP might non-invasively indicate quinolinic acid-induced impaired blood-brain barrier integrity...
March 9, 2017: Scientific Reports
Cecilia Rajda, Dániel Pukoli, Zsuzsanna Bende, Zsófia Majláth, László Vécsei
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS. The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances...
February 8, 2017: International Journal of Molecular Sciences
Hyunjung Baek, Chae Seong Lim, Hee Sun Byun, Hyun Sil Cho, Yu Ran Lee, Yong Sup Shin, Hyun-Woo Kim, Byeong Hwa Jeon, Dong Woon Kim, Jinpyo Hong, Gang Min Hur, Jin Bong Park
Apurinic/apyrimidinic endonuclease 1 (APE1), a ubiquitous multipurpose protein, is also known as redox effector factor-1 (Ref-1). It is involved in DNA repair and redox signaling and, in turn, oxidative stress-induced neurodegeneration. Although previous studies have demonstrated that APE1/Ref-1 functions as a negative regulator of inflammatory response via several mechanisms in neuronal cells, little is known about the roles of APE1/Ref-1 in glial cells. In this study, we found that cytoplasmic APE1/Ref-1 expression was upregulated in reactive astrocytes of the kainic acid- or lipopolysaccharide (LPS)-injected hippocampus...
December 16, 2016: Molecular Brain
Matthew V Green, Stanley A Thayer
HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Infected non-neuronal cells release neurotoxic factors such as the viral protein transactivator of transcription (Tat) that potentiate NMDAR function. NMDARs regulate synaptic changes observed after exposure to HIV proteins, which may underlie cognitive impairment in HAND patients. Here, we used patch-clamp recording to measure NMDAR-mediated currents in rat hippocampal cultures after exposure to Tat. Tat (4-16 h) potentiated NMDA-evoked whole-cell current and increased the NMDAR:AMPAR ratio of evoked EPSCs...
December 14, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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...
January 2017: 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
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