Neuroprotective Effects of the Glutamate Transporter Activator (<i>R</i>)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

Fontana, Andréia Cristina Karklin; Fox, Douglas Paul; Zoubroulis, Argie; Mortensen, Ole V.; Raghupathi, Ramesh

doi:10.1089/neu.2015.4079

Cited by 31 publications

(30 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous work has shown that the levels and/or function of EAAT2 (rodent analog, GLT-1), the most abundantly expressed glutamate transporter in hippocampal astrocytes (Maragakis and Rothstein, 2006) are reduced in conjunction with A␤ pathology and/or glial activation (Masliah et al, 1996;Abdul et al, 2009;Simpson et al, 2010;Tian et al, 2010;Scimemi et al, 2013;Hefendehl et al, 2016). AAV-mediated delivery of VIVIT to 5xFAD mice reduced both A␤ plaque load in CA1 (Fig.…”

Section: Aav-gfa2-vivit Reduces A␤ Pathology and Increases Glt-1 Exprmentioning

confidence: 89%

“…High-speed measures of fluctuating L-glutamate levels in intact mice were performed using ceramicbased microelectrode arrays (MEAs) as previously described (Hascup et al, 2007(Hascup et al, , 2011Miller et al, 2015). The W4 type MEAs (see Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Similar to other neurodegenerative diseases, AD is accompanied by profound glial activation (Bouvier and Murai, 2015;Heneka et al, 2015). Though most conspicuous around amyloid-␤ (A␤) deposits at late disease stages, activated glial cells (i.e., microglia and astrocytes) also appear at the outset of clinical symptoms (Carter et al, 2012;Schöll et al, 2015;Yokokura et al, 2016), suggesting that glial modulation strategies could slow the progression of AD.…”

Section: Introductionmentioning

confidence: 98%

“…Network hyperexcitability is commonly observed in AD brain and AD mouse models (Palop et al, 2007;Busche et al, 2008;Minkeviciene et al, 2009;Noebels, 2011;Putcha et al, 2011;Bakker et al, 2012;Grienberger et al, 2012;Bomben et al, 2014;Kellner et al, 2014;Šišková et al, 2014;Vossel et al, 2016;Fontana et al, 2017) where it is thought to contribute to excitotoxic damage and cognitive loss. Diminished expression and/or functional impairment of astrocyte glutamate transporters is similarly associated with AD and AD-related pathology (Masliah et al, 1996(Masliah et al, , 2000Mookherjee et al, 2011;Schallier et al, 2011;Scimemi et al, 2013;Meeker et al, 2015;Audrain et al, 2016;Hefendehl et al, 2016;Xu et al, 2016), suggesting that impaired glutamate regulation is a key phenotypic trait of activated astrocytes and a primary mechanism for AD-related neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

“…CN is rapidly activated/inactivated by fluctuating Ca 2ϩ levels within healthy cells but can become proteolyzed and irreversibly activated following neural damage Huang et al, 2005;Liu et al, 2005;Shioda et al, 2006;Mohmmad Abdul et al, 2011). Proteolysis of CN is especially pronounced in astrocytes associated with A␤ pathology (Pleiss et al, 2016), leading to the hyperactivation of key substrates, such as the nuclear factor of activated T cells (NFATs; Mohmmad .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice

Sompol¹,

Furman²,

Pleiss³

et al. 2017

J. Neurosci.

View full text Add to dashboard Cite

Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer's disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin (CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno-associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured in vivo with microelectrode arrays and ex vivo brain slices, using whole-cell voltage clamp. VIVIT treatment in 5xFAD mice led to increased expression of the astrocytic glutamate transporter GLT-1 and to attenuated changes in dendrite morphology, synaptic strength, and NMDAR-dependent responses. The results reveal astrocytic CN/NFAT4 as a key pathologic mechanism for driving glutamate dysregulation and neuronal hyperactivity during AD.

show abstract

Section: Aav-gfa2-vivit Reduces A␤ Pathology and Increases Glt-1 Exprmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice

Sompol¹,

Furman²,

Pleiss³

et al. 2017

J. Neurosci.

View full text Add to dashboard Cite

show abstract

Protocols for Measuring Glutamate Uptake: Dose‐Response and Kinetic Assays in In Vitro and Ex Vivo Systems

Fontana

2018

CP Pharmacology

View full text Add to dashboard Cite

This article presents detailed descriptions of procedures and troubleshooting tips for basic in vitro and ex vivo uptake assays for the functional characterization of glutamate transporters and the assessment of the effect of compounds that modulate their activity. Assays are performed in cell lines that transiently or stably express a particular transporter under investigation, in primary cultures of astrocytes, or in ex vivo synaptosomal preparations that endogenously express these transporters. Two main assays are described, including dose-response assays to measure potencies of test compounds for stimulation or inhibition of function (EC or IC values, respectively) and kinetic functional assays to calculate apparent affinity (K ) and maximal velocity (V ) of radiolabeled substrate uptake into the cells. The methods described use glutamate transporters as an example; however, the protocols can be adapted to other neurotransmitter transporters using their respective substrates (e.g., GABA uptake through GATs, serotonin uptake through SERTs, among others). © 2018 by John Wiley & Sons, Inc.

show abstract

Development of a systems‐based in situ multiplex biomarker screening approach for the assessment of immunopathology and neural tissue plasticity in male rats after traumatic brain injury

Bogoslovsky

Bernstock

Bull

et al. 2017

J of Neuroscience Research

View full text Add to dashboard Cite

Traumatic brain injuries (TBI) pose a massive burden of disease and continue to be a leading cause of morbidity and mortality throughout the world. A major obstacle in developing effective treatments is the lack of comprehensive understanding of the underlying mechanisms that mediate tissue damage and recovery after TBI. As such, our work aims to highlight the development of a novel experimental platform capable of fully characterizing the underlying pathobiology that unfolds post-TBI. This platform encompasses an empirically optimized multiplex immunohistochemistry staining and imaging system customized to screen for a myriad of biomarkers required to comprehensively evaluate the extent of neuroinflammation, neural tissue damage and repair in response to TBI. Herein, we demonstrate that our multiplex biomarker screening platform is capable of evaluating changes in both the topographical location and functional states of resident and infiltrating cell types that play a role in neuropathology after controlled cortical impact injury to the brain in male Sprague-Dawley rats. Our results demonstrate that our multiplex biomarker screening platform lays the groundwork for the comprehensive characterization of changes that occur within the brain after TBI. Such work may ultimately lead to the understanding of the governing pathobiology of TBI, thereby fostering the development of novel therapeutic interventions tailored to produce optimal tissue protection, repair and/or regeneration with minimal side effects and may ultimately find utility in wide variety of other neurological injuries, diseases and disorders that share components of TBI pathobiology.

show abstract

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

Cited by 31 publications

References 90 publications

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice

Protocols for Measuring Glutamate Uptake: Dose‐Response and Kinetic Assays in In Vitro and Ex Vivo Systems

Development of a systems‐based in situ multiplex biomarker screening approach for the assessment of immunopathology and neural tissue plasticity in male rats after traumatic brain injury

Contact Info

Product

Resources

About