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Glutamate Transporters and Brain Injury

Tate Gisslen, Garima Singh, Michael K Georgieff
BACKGROUND: Inflammation is a major cause of preterm birth and often results in a fetal inflammatory response syndrome (FIRS). Preterm infants with FIRS have a higher childhood incidence of neurodevelopmental disability than preterm infants without FIRS. The mechanisms connecting FIRS to neurodevelopmental disability in formerly preterm infants are not fully understood, but the effect on premature gray matter may have an important role. METHODS: Fetal rats were exposed to intra-amniotic (i...
February 11, 2019: Pediatric Research
Shotaro Michinaga, Yutaka Koyama
The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage...
January 29, 2019: International Journal of Molecular Sciences
Mustafa Q Hameed, Tsung-Hsun Hsieh, Leon Morales-Quezada, Henry H C Lee, Ugur Damar, Paul C MacMullin, Takao K Hensch, Alexander Rotenberg
Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings...
December 22, 2018: Cerebral Cortex
Péter Hertelendy, Dániel P Varga, Ákos Menyhárt, Ferenc Bari, Eszter Farkas
Secondary injury following acute brain insults significantly contributes to poorer neurological outcome. The spontaneous, recurrent occurrence of spreading depolarization events (SD) has been recognized as a potent secondary injury mechanism in subarachnoid hemorrhage, malignant ischemic stroke and traumatic brain injury. In addition, SD is the underlying mechanism of the aura symptoms of migraineurs. The susceptibility of the nervous tissue to SD is subject to the metabolic status of the tissue, the ionic composition of the extracellular space, and the functional status of ion pumps, voltage-gated and other cation channels, glutamate receptors and excitatory amino acid transporters...
October 15, 2018: Neurochemistry International
Dainan Zhang, Meng Xiao, Long Wang, Wang Jia
Excessive glutamate release has been implicated as a major contributor to multiple post-traumatic brain injury (TBI) deficits, including neurodegeneration and cognitive impairment. Prior to the presence of behavior change, synaptic plasticity is rapidly and potently disrupted by TBI, which is believed to be relevant to inappropriately increased extracellular glutamate concentration and glutamatergic receptor activation. Acutely promoting brain glutamate clearance with a blood-based scavenging system, glutamate oxaloacetate transaminase (GOT), prevents the delayed inhibition of LTP post-TBI...
September 25, 2018: Neurotoxicity Research
Sebastian Rühling, Franziska Kramer, Selina Schmutz, Sandra Amor, Zhan Jiangshan, Christoph Schmitz, Markus Kipp, Tanja Hochstrasser
Axonal damage is a major factor contributing to disease progression in multiple sclerosis (MS) patients. On the histological level, acute axonal injury is most frequently analyzed by anti-amyloid precursor protein immunohistochemistry. To what extent this method truly detects axonal injury, and whether other proteins and organelles are as well subjected to axonal transport deficits in demyelinated tissues is not known. The aim of this study was to correlate ultrastructural morphology with the immunohistochemical appearance of acute axonal injury in a model of toxin-induced oligodendrocyte degeneration...
September 21, 2018: Molecular Neurobiology
Tengfei Zhao, Yibiao Jing, Xiaopeng Zhou, Jingkai Wang, Xianpeng Huang, Liansheng Gao, Yongjian Zhu, Linlin Wang, Zhongru Gou, Chengzhen Liang, Kan Xu, Fangcai Li, Qixin Chen
OBJECTIVES: Biomaterials are used to aid in the regeneration of damaged tissue and in promotion of axonal guidance following spinal cord injury (SCI). In the present study, electrospun composite poly(hydroxybutyrate-cohydroxyvalerate) (PHBV), poly(lactic acid) (PLA), and collagen (Col) nanofibrous scaffolds were applied to determine their roles in neural regeneration and recovery in a rat model of SCI. METHODS: The morphological and chemical properties of the electrospun scaffolds were investigated...
November 1, 2018: Journal of Biomedical Nanotechnology
Xian Wang, Xiaofeng Shen, Yingli Xu, Shiqin Xu, Fan Xia, Bei Zhu, Yusheng Liu, Wei Wang, Haibo Wu, Fuzhou Wang
Neuropathic pain is a common chronic pain condition with mechanisms far clearly been elucidated. Mounting preclinical and clinical studies have shown neuropathic pain is highly associated with histone acetylation modification, which follows expression regulation of various pain-related molecules such as mGluR1/5, glutamate aspartate transporter, glutamate transporter-1, GAD65, Nav 1.8, Kv4.3, μ-opioid receptor, brain-derived neurotrophic factor, and certain chemokines. As two types of pivotal enzymes involved in histone acetylation, histone deacetylases induce histone deacetylation to silence gene expression; in contrast, histone acetyl transferases facilitate histone acetylation to potentiate gene transcription...
January 2018: Molecular Pain
Kyle H Flippo, Aswini Gnanasekaran, Guy A Perkins, Ahmad Ajmal, Ronald A Merrill, Audrey S Dickey, Susan S Taylor, G Stanley McKnight, Anil K Chauhan, Yuriy M Usachev, Stefan Strack
Mitochondrial fission and fusion impact numerous cellular functions and neurons are particularly sensitive to perturbations in mitochondrial dynamics. Here we describe that male mice lacking the mitochondrial A-kinase anchoring protein 1 (AKAP1) exhibit increased sensitivity in the transient middle cerebral artery occlusion model of focal ischemia. At the ultrastructural level, AKAP1-/- mice have smaller mitochondria and increased contacts between mitochondria and the endoplasmic reticulum in the brain. Mechanistically, deletion of AKAP1 dysregulates complex II of the electron transport chain, increases superoxide production, and impairs Ca2+ homeostasis in neurons subjected to excitotoxic glutamate...
September 19, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jonathan P Robson, Bettina Wagner, Elisabeth Glitzner, Frank L Heppner, Thomas Steinkellner, Deeba Khan, Claudia Petritsch, Daniela D Pollak, Harald H Sitte, Maria Sibilia
Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR-/- mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFR-deficient neural stem cells are impaired in their self-renewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFRΔbrain ) show low penetrance of cortical degeneration compared to EGFR-/- mice despite genetic recombination of the conditional allele...
September 2018: FEBS Journal
Raj G Kumar, Kristen B Breslin, Anne C Ritter, Yvette P Conley, Amy K Wagner
Excitotoxicity contributes to epileptogenesis after severe traumatic brain injury (sTBI). Demographic and clinical risk factors for post-traumatic seizures (PTS) have been identified, but genetic risk remains largely unknown. Thus, we investigated whether genetic variation in astroglial glutamate transporter genes is associated with accelerated epileptogenesis and PTS risk after sTBI. Adults (n = 267) 18-75 years old were assessed over a three-year period post-TBI. Single nucleotide polymorphisms (SNPs) throughout the SLC1A2 and SLC1A3 genes were assayed...
September 4, 2018: Journal of Neurotrauma
Donají Chi-Castañeda, Arturo Ortega
L-glutamate is the major excitatory amino acid in the mammalian central nervous system (CNS). This neurotransmitter is essential for higher brain functions such as learning, cognition and memory. A tight regulation of extra-synaptic glutamate levels is needed to prevent a neurotoxic insult. Glutamate removal from the synaptic cleft is carried out by a family of sodium-dependent high-affinity transporters, collectively known as excitatory amino acid transporters. Dysfunction of glutamate transporters is generally involved in acute neuronal injury and neurodegenerative diseases, so characterizing and understanding the mechanisms that lead to the development of these disorders is an important goal in the design of novel treatments for the neurodegenerative diseases...
2018: Frontiers in Endocrinology
Silvia Piccirillo, Pasqualina Castaldo, Maria Loredana Macrì, Salvatore Amoroso, Simona Magi
In brain ischemia, reduction in oxygen and substrates affects mitochondrial respiratory chain and aerobic metabolism, culminating in ATP production impairment, ionic imbalance, and cell death. The restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury, giving rise to ischemia/reperfusion (I/R) injury. In this setting, the imbalance of brain bioenergetics induces important metabolic adaptations, including utilization of alternative energy sources, such as glutamate...
June 28, 2018: Cell Death & Disease
Elisabeth Hansson
Nociceptive and neuropathic pain signals are known to result from noxious stimuli, which are converted into electrical impulses within tissue nociceptors. There is a complex equilibrium of pain-signalling and pain-relieving pathways connecting PNS and CNS. Drugs against long-term pain are today directed against increased neuronal excitability, mostly with less success. An injury often starts with acute physiological pain, which becomes inflammatory, nociceptive, or neuropathic, and may be transferred into long-term pain...
April 1, 2010: Scandinavian Journal of Pain
Federica Ferrari, Antonella Gorini, Siegfried Hoyer, Roberto Federico Villa
Glutamate is involved in cerebral ischemic injury, but its role has not been completely clarified and studies are required to understand how to minimize its detrimental effects, contemporarily boosting the positive ones. In fact, glutamate is not only a neurotransmitter, but primarily a key metabolite for brain bioenergetics. Thus, we investigated the relationships between glutamate and brain energy metabolism in an in vivo model of complete cerebral ischemia of 15 min and during post-ischemic recovery after 1, 24, 48, 72, and 96 h in 1-year-old adult and 2-year-old aged rats...
August 2018: Journal of Neurochemistry
Zhuoyang Zhao, Yuichi Hiraoka, Hiroshi Ogawa, Kohichi Tanaka
Glutamate is a major excitatory neurotransmitter and plays an important role in neuropathic pain, which is frequently caused by nerve damage. According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region...
September 2018: Glia
Katarzyna Kamińska, Karolina Noworyta-Sokołowska, Anna Górska, Joanna Rzemieniec, Agnieszka Wnuk, Adam Wojtas, Grzegorz Kreiner, Małgorzata Kajta, Krystyna Gołembiowska
According to the European Drug Report (2016), the use of synthetic cathinones, such as mephedrone, among young people has rapidly increased in the last years. Studies in humans indicate that psychostimulant drug use in adolescence increases risk of drug abuse in adulthood. Mephedrone by its interaction with transporters for dopamine (DAT) and serotonin (SERT) stimulates their release to the synaptic cleft. In animal studies, high repeated doses of mephedrone given to adolescent but not adult mice or rats induced toxic changes in 5-hydroxytryptamine (5-HT) neurons...
October 2018: Neurotoxicity Research
A Justin, S Divakar, M Ramanathan
In the present study, we investigated the effects of angiotensin (Ang II) receptor blockers in cerebral ischemia by administration of telmisartan (AT1 blocker) and/or PD123319 (AT2 blocker) in global ischemic mice model. The neuroprotective effect of AT antagonists was evaluated through monitoring muscle co-ordination and cerebral blood perfusion in ischemic mice. Gene expression studies (NF-κB, GSK-3β, EAAT-2, AT1 & AT2 receptors) and staining of brain regions with cresyl violet, GFAP, synaptophysin and NSE methods were carried out in to understand the molecular mechanisms...
June 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Marina Zaric, Dunja Drakulic, Ivana Gusevac Stojanovic, Natasa Mitrovic, Ivana Grkovic, Jelena Martinovic
Excessive glutamate efflux and N-methyl-D-aspartate receptor (NMDAR) over-activation represent well-known hallmarks of cerebral ischemia/reperfusion (I/R) injury, still, expression of proteins involved in this aspect of I/R pathophysiology show inconsistent data. Neurosteroid dehydroepiandrosterone (DHEA) has been proposed as potent NMDAR modulator, but its influence on I/R-induced changes up to date remains questionable. Therefore, I/R-governed alteration of vesicular glutamate transporter 1 (vGluT1), synaptic NMDAR subunit composition, postsynaptic density protein 95 (PSD-95) and neuronal morphology alone or following DHEA treatment were examined...
June 1, 2018: Brain Research
Ignacio Ibáñez, David Bartolomé-Martín, Dolores Piniella, Cecilio Giménez, Francisco Zafra
GLT-1 is the main glutamate transporter in the brain and its trafficking controls its availability at the cell surface, thereby shaping glutamatergic neurotransmission under physiological and pathological conditions. Extracellular glutamate is known to trigger ubiquitin-dependent GLT-1 internalization from the surface of the cell to the intracellular compartment, yet here we show that internalization also requires the participation of calcium ions. Consistent with previous studies, the addition of glutamate (1 mM) to mixed primary cultures (containing neurons and astrocytes) promotes GLT-1 internalization, an effect that was suppressed in the absence of extracellular Ca2+ ...
March 21, 2018: Neurochemistry International
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