The effect of pyruvate on the development and progression of post-stroke depression: A new therapeutic approach

Frank, Dmitry; Kuts, Ruslan; Tsenter, Philip; Gruenbaum, Benjamin F.; Grinshpun, Yulia; Zvenigorodsky, Vladislav; Shelef, Ilan; Natanel, Dmitry; Brotfain, Evgeni; Zlotnik, Alexander; Boyko, Matthew

doi:10.1016/j.neuropharm.2019.05.035

Cited by 35 publications

(39 citation statements)

References 58 publications

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“…This decrease in blood levels causes glutamate to shift down its concentration gradient from the brain to the blood resulting in lower brain glutamate levels. Animal studies have shown potential benefits in the treatment of post-stroke depression (62). Genetics studies also suggest links between genes associated with glutamatergic transmission and depression (63,64).…”

Section: Role Of Glutamate In Anxiety-related Disordersmentioning

confidence: 99%

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology

et al. 2020

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Serotonin reuptake inhibitors and benzodiazepines are evidence-based pharmacological treatments for Anxiety Disorders targeting serotonin and GABAergic systems, respectively. Although clearly effective, these medications fail to improve anxiety symptoms in a significant proportion of patients. New insights into the glutamate system have directed attention toward drugs that modulate glutamate as potential alternative treatments for anxiety disorders. Here we summarize the current understanding of the potential role of glutamate neurotransmission in anxiety disorders and highlight specific glutamate receptors that are potential targets for novel anxiety disorder treatments. We also review clinical trials of medications targeting the glutamate system in DSM-5 anxiety disorders. Understanding the role of the glutamate system in the pathophysiology of anxiety disorder may aid in developing novel pharmacological agents that are effective in treating anxiety disorders.

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Section: Role Of Glutamate In Anxiety-related Disordersmentioning

confidence: 99%

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology

et al. 2020

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“…MRI also avoids euthanasia, which is ethically preferred. MRI is further useful for behavioral studies in post-stroke rats, and we have used this technique in our own laboratory in the past for these experiments (Frank et al, 2019). However, in practice histological methods are much more commonly used and remain the gold standard for assessing brain injury after stroke (Liu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…In order to compare the original histologic to MRI imaging techniques, we analyzed data obtained from our previous work (Boyko et al, 2019b; Frank et al, 2019). The experimental procedure was carried out on a 3T MRI clinical scanner (Ingenia, Philips Medical Systems, Best, Netherlands), fitted out with a gradient system of 45 mT/m at 225 μs ramp time, using a commercial eight-channel receive-only wrist coil.…”

Section: Methodsmentioning

confidence: 99%

“…An expert blinded to the experimental procedure carried out image analysis using a Philips software package and an ImageJ software, performed calculations, and analyzed results. The Philips software package (Ingenia, Philips Medical Systems, Best, Netherlands) was used to individual ROI’s for assessment BBB breakdown and to produce a map for the brain images generate quantitative ADC maps, in mm 2 /s, which were subsequently analyzed using the Image J software 1.50i version 1 , described previously (Boyko et al, 2019b; Frank et al, 2019). The viability thresholds used for the identification of every pixel showing irregular ADC features on the slide were 0.53 × 10 –3 mm 2 /s for ADC (Bardutzky et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

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A Novel Method for Assessing Cerebral Edema, Infarcted Zone and Blood-Brain Barrier Breakdown in a Single Post-stroke Rodent Brain

et al. 2019

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Stroke is a major cause of global morbidity and mortality. Middle cerebral artery occlusion (MCAO) has historically been the most common animal model of simulating ischemic stroke. The extent of neurological injury after MCAO is typically measured by cerebral edema, infarct zone, and blood-brain barrier (BBB) permeability. A significant limitation of these methods is that separate sets of brains must be used for each measurement. Here we examine an alternative method of measuring cerebral edema, infarct zone and BBB permeability following MCAO in the same set of brain samples. Ninety-six rats were randomly divided into three experimental groups. Group 1 (n = 27) was used for the evaluation of infarct zone and brain edema in rats post-MCAO (n = 17) vs. sham-operated controls (n = 10). Group 2 (n = 27) was used for the evaluation of BBB breakdown in rats post-MCAO (n = 15) vs. sham-operated controls (n = 10). In Group 3 (n = 42), all three parameters were measured in the same set of brain slices in rats post-MCAO (n = 26) vs. sham-operated controls (n = 16). The effect of Evans blue on the accuracy of measuring infarct zone by 2,3,5-triphenyltetrazolium chloride (TTC) staining was determined by measuring infarct zone with and without an applied blue filter. The effects of various concentrations of TTC (0, 0.05, 0.35, 0.5, 1, and 2%) on the accuracy of measuring BBB permeability was also assessed. There was an increase in infarct volume (p < 0.01), brain edema (p < 0.01) and BBB breakdown (p < 0.01) in rats following MCAO compared to sham-operated controls, whether measured separately or together in the same set of brain samples. Evans blue had an effect on measuring infarct volume that was minimized by the application of a blue filter on scanned brain slices. There was no difference in the Evans blue extravasation index for the brain tissue samples without TTC compared to brain tissue samples incubated in TTC. Our results demonstrate that measuring cerebral edema, infarct zone and BBB permeability following MCAO can accurately be measured in the same set of brain samples.

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“…Recent support for the role of BGS as a therapeutic modality in PSD was demonstrated in a rodent model showing that administration of pyruvate lowered glutamate levels, and improved neurological outcome and post-stroke depressive behavior. 57 In this study, 80 rats were randomly separated into one of three groups: middle cerebral artery occlusion (MCAO) plus pyruvate treatment, MCAO and treatment with placebo, and a control group. The rats in the first group showed significant reduction of lesion volume, brain edema and blood–brain barrier breakdown compared with rats who had MCAO with placebo, and displayed fewer depressive-like behaviors.…”

Section: Bgs With Oxaloacetate and Pyruvate As An Alternative Methodsmentioning

confidence: 99%

Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-stroke depression

Gruenbaum

Kutz

Zlotnik

et al. 2020

Therapeutic Advances in Psychopharmacology

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Post-stroke depression (PSD) is a major complication of stroke that significantly impacts functional recovery and quality of life. While the exact mechanism of PSD is unknown, recent attention has focused on the association of the glutamatergic system in its etiology and treatment. Minimizing secondary brain damage and neuropsychiatric consequences associated with excess glutamate concentrations is a vital part of stroke management. The blood glutamate scavengers, oxaloacetate and pyruvate, degrade glutamate in the blood to its inactive metabolite, 2-ketoglutarate, by the coenzymes glutamate–oxaloacetate transaminase (GOT) and glutamate–pyruvate transaminase (GPT), respectively. This reduction in blood glutamate concentrations leads to a subsequent shift of glutamate down its concentration gradient from the blood to the brain, thereby decreasing brain glutamate levels. Although there are not yet any human trials that support blood glutamate scavengers for clinical use, there is increasing evidence from animal research of their efficacy as a promising new therapeutic approach for PSD. In this review, we present recent evidence in the literature of the potential therapeutic benefits of blood glutamate scavengers for reducing PSD and other related neuropsychiatric conditions. The evidence reviewed here should be useful in guiding future clinical trials.

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The effect of pyruvate on the development and progression of post-stroke depression: A new therapeutic approach

Cited by 35 publications

References 58 publications

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology

A Novel Method for Assessing Cerebral Edema, Infarcted Zone and Blood-Brain Barrier Breakdown in a Single Post-stroke Rodent Brain

Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-stroke depression

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