Suppression of spreading depolarization and stabilization of dendritic spines by GLYX-13, an NMDA receptor glycine-site functional partial agonist

Zhang, Xiao lei; Shuttleworth, C. William; Moskal, Joseph R.; Stanton, Patric K.

doi:10.1016/j.expneurol.2015.07.025

Cited by 12 publications

(5 citation statements)

References 60 publications

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“…B. diazoefficiens USDA 110 was cultured on Yeast Extract Mannitol (YEM) agar (Sherwood, 1972 ) at 28°C for 12 day. DNA was extracted from these cells using MoBio UltraClean DNA extraction kit (MoBio, USA).…”

Section: Methodsmentioning

confidence: 99%

Integrating DNA Methylation and Gene Expression Data in the Development of the Soybean-Bradyrhizobium N2-Fixing Symbiosis

et al. 2016

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Very little is known about the role of epigenetics in the differentiation of a bacterium from the free-living to the symbiotic state. Here genome-wide analysis of DNA methylation changes between these states is described using the model of symbiosis between soybean and its root nodule-forming, nitrogen-fixing symbiont, Bradyrhizobium diazoefficiens. PacBio resequencing of the B. diazoefficiens genome from both states revealed 43,061 sites recognized by five motifs with the potential to be methylated genome-wide. Of those sites, 3276 changed methylation states in 2921 genes or 35.5% of all genes in the genome. Over 10% of the methylation changes occurred within the symbiosis island that comprises 7.4% of the genome. The CCTTGAG motif was methylated only during symbiosis with 1361 adenosines methylated among the 1700 possible sites. Another 89 genes within the symbiotic island and 768 genes throughout the genome were found to have methylation and significant expression changes during symbiotic development. Of those, nine known symbiosis genes involved in all phases of symbiotic development including early infection events, nodule development, and nitrogenase production. These associations between methylation and expression changes in many B. diazoefficiens genes suggest an important role of the epigenome in bacterial differentiation to the symbiotic state.

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Section: Methodsmentioning

confidence: 99%

Integrating DNA Methylation and Gene Expression Data in the Development of the Soybean-Bradyrhizobium N2-Fixing Symbiosis

et al. 2016

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“…After placement of electrodes into the slice (See Electrophysiology methods) slices were allowed 20 minutes for equilibration. As described below (Results), modified aCSF with elevated K + (8mM) was used for most experiments, in order to increase ability of single slices to support repetitive SDs and enable rigorous testing of drug effects (Funke et al, 2009, Zhang et al, 2015). SDs were evoked by pressure microinjection (40ms, 30 psi; Picospritzer; Parker Hannifin, OH, USA) of KCl (1M) via a glass micropipette ~3 MΩ) placed in hippocampal CA1 stratum radiatum.…”

Section: Methodsmentioning

confidence: 99%

Ketamine reduces deleterious consequences of spreading depolarizations

Reinhart

Shuttleworth

2018

Experimental Neurology

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Recent work has implicated spreading depolarization (SD) as a key contributor the progression of acute brain injuries, however development of interventions selectively targeting SD has lagged behind. Initial clinical intervention efforts have focused on observations that relatively high doses of the sedative agent ketamine can completely suppress SD. However, blocking propagation of SD could theoretically prevent beneficial effects of SD in surrounding brain regions. Selective targeting of deleterious consequences of SD (rather than abolition) could be a useful adjunct approach, and be achieved with lower ketamine concentrations. We utilized a brain slice model to test whether deleterious consequences of SD could be prevented by ketamine, using concentrations that did not prevent the initiation and propagation of SD. Studies were conducted using murine brain slices, with focal KCl as an SD stimulus. Consequences of SD were assessed with electrophysiological and imaging measures of ionic and synaptic recovery. Under control conditions, ketamine (up to 30 μM) did not prevent SD, but significantly reduced neuronal Ca loading and the duration of associated extracellular potential shifts. Recovery of postsynaptic potentials after SD was also significantly accelerated. When SD was evoked on a background of mild metabolic compromise, neuronal recovery was substantially impaired. Under compromised conditions, the same concentrations of ketamine reduced ionic and metabolic loading during SD, sufficient to preserve functional recovery after repetitive SDs. These results suggest that lower concentrations of ketamine could be utilized to prevent damaging consequences of SD, while not blocking them outright and thereby preserving potentially protective effects of SD.

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“…Glyx-13 has been observed to increase the refractory period of hippocampal rat SD, to limit the propagation of SD, and to reduce the amplitude of the negative field potential shift and restored the dendritic spines. 148 Since Glyx-13 is not an NMDA receptor antagonist, but rather an allosteric modulator, therapeutic application could be facilitated because the side-effects of NMDA receptor channel blockers would be avoided.…”

Section: Substancesmentioning

confidence: 99%

Systematic review of the pharmacological agents that have been tested against spreading depolarizations

Klass

Sánchez-Porras

Santos

2018

J Cereb Blood Flow Metab

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Spreading depolarization (SD) occurs alongside brain injuries and it can lead to neuronal damage. Therefore, pharmacological modulation of SD can constitute a therapeutic approach to reduce its detrimental effects and to improve the clinical outcome of patients. The major objective of this article was to produce a systematic review of all the drugs that have been tested against SD. Of the substances that have been examined, most have been shown to modulate certain SD characteristics. Only a few have succeeded in significantly inhibiting SD. We present a variety of strategies that have been proposed to overcome the notorious harmfulness and pharmacoresistance of SD. Information on clinically used anesthetic, sedative, hypnotic agents, anti-migraine drugs, anticonvulsants and various other substances have been compiled and reviewed with respect to the efficacy against SD, in order to answer the question of whether a drug at safe doses could be of therapeutic use against SD in humans.

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Suppression of spreading depolarization and stabilization of dendritic spines by GLYX-13, an NMDA receptor glycine-site functional partial agonist

Cited by 12 publications

References 60 publications

Integrating DNA Methylation and Gene Expression Data in the Development of the Soybean-Bradyrhizobium N2-Fixing Symbiosis

Integrating DNA Methylation and Gene Expression Data in the Development of the Soybean-Bradyrhizobium N2-Fixing Symbiosis

Ketamine reduces deleterious consequences of spreading depolarizations

Systematic review of the pharmacological agents that have been tested against spreading depolarizations

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