Inhibition of endogenous blood glutamate oxaloacetate transaminase enhances the ischemic damage

Dopico-López, Antonio; Pérez‐Mato, María; Silva‐Candal, Andrés da; Iglesias‐Rey, Ramón; Rabinkov, Aharon; Bugallo-Casal, Ana; Sobrino, Tomás; Mirelman, David; Castillo, José; Campos, Francisco

doi:10.1016/j.trsl.2020.10.004

Cited by 11 publications

(9 citation statements)

References 26 publications

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“…The efflux of glutamate with pyruvate or OxAc is blocked by adding exogenous glutamate, demonstrating the dependence of the scavenging method on lowering blood glutamate [ 37 , 103 ]. GOT and GPT likely enhance the efflux of glutamate from the brain and blocking the function of GOT and GPT exacerbated the behavioral and morphological deficits following ischemia [ 107 ].…”

Section: New Treatment Strategies For Neuropsychiatric Consequences O...mentioning

confidence: 99%

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

Gruenbaum

Zlotnik

Fleidervish

et al. 2022

IJMS

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Traumatic brain injury (TBI) is associated with significant cognitive and psychiatric conditions. Neuropsychiatric symptoms can persist for years following brain injury, causing major disruptions in patients’ lives. In this review, we examine the role of glutamate as an aftereffect of TBI that contributes to the development of neuropsychiatric conditions. We hypothesize that TBI causes long-term blood–brain barrier (BBB) dysfunction lasting many years and even decades. We propose that dysfunction in the BBB is the central factor that modulates increased glutamate after TBI and ultimately leads to neurodegenerative processes and subsequent manifestation of neuropsychiatric conditions. Here, we have identified factors that determine the upper and lower levels of glutamate concentration in the brain after TBI. Furthermore, we consider treatments of disruptions to BBB integrity, including repairing the BBB and controlling excess glutamate, as potential therapeutic modalities for the treatment of acute and chronic neuropsychiatric conditions and symptoms. By specifically focusing on the BBB, we hypothesize that restoring BBB integrity will alleviate neurotoxicity and related neurological sequelae.

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Section: New Treatment Strategies For Neuropsychiatric Consequences O...mentioning

confidence: 99%

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

Gruenbaum

Zlotnik

Fleidervish

et al. 2022

IJMS

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“…Remarkably, the protective effects of hrGOT were maintained even when the treatment was given 1 h postreperfusion . Also, the inhibition of GOT with anti-GOT antibodies in an ischemic animal model caused higher brain glutamate concentrations, and this response was associated with larger ischemic lesion . Thus, reducing blood GOT activity leads to more severe ischemic damage and poorer outcome, which supports the protective role of GOT against ischemic insults.…”

Section: Peripheral Glutamate Scavenging Using Enzymes: a New Opportu...mentioning

confidence: 64%

“…38 Also, the inhibition of GOT with anti-GOT antibodies in an ischemic animal model caused higher brain glutamate concentrations, and this response was associated with larger ischemic lesion. 39 Thus, reducing blood GOT activity leads to more severe ischemic damage and poorer outcome, which supports the protective role of GOT against ischemic insults. Furthermore, it has been hypothesized that the elimination of glutamate takes place only from regions where it is pathologically higher.…”

Section: Peripheral Glutamate Scavenging Using Enzymes: a New Opportu...mentioning

confidence: 74%

New Perspectives for Developing Therapeutic Bioconjugates of Metabolite-Depleting Enzymes: Lessons Learned Combating Glutamate Excitotoxicity

et al. 2022

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“…Thereafter, the presented infarct volume was calculated as follows: (infarct volume [mm 3 /MD]/ipsilateral hemispheric area [mm 3 ]) × 100. These procedures have been used repeatedly in the literature to measure and evaluate stroke outcome in experimental models [15, 17, 18]…”

Section: Methodsmentioning

confidence: 99%

Relevance of Sham Control Group in Preclinical Animal Studies of Cerebral Ischemia

Candamo-Lourido,

López-Arias,

López-Amoedo

et al. 2023

Preprint

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BackgroundIn experimental animal studies, control sham groups are essential to reduce the influence of the surgical intervention on the analysis. The intraluminal filament procedure is one of the most common models of middle cerebral artery occlusion (MCAO) used in the study of cerebral ischemia. However, in these studies, the sham group has not usually been included in the experimental design because of the assumption that the surgical procedure required to access the middle cerebral artery does not affect brain tissue, or that the results obtained from this group are not relevant.ObjectivesIn this study, we aimed to evaluate the relevance of the sham group by analyzing and comparing the brain protein profile of a sham and an ischemic group subjected to the surgical intraluminal filament occlusion of the middle cerebral artery.Material and MethodsThree randomized experimental groups were tested: control group (healthy animals), sham group, and ischemic group. Twenty-four hours after the interventional procedure, the brain tissue was evaluated by magnetic resonance imaging (MRI). After animal perfusion, the brain is removed for proteomic analysis by liquid chromatography-mass spectrometry (LC-MS/MS) using both a qualitative analysis by data-dependent acquisition (DDA) mode and a quantitative analysis, using a sequential window acquisition of all theoretical mass spectra (SWATH-MS) method on a hybrid quadrupole time-of-flight mass spectrometer.ResultsMRI results showed that only animals subjected to cerebral ischemia had ischemic injury. In the sham group 137 dysregulated proteins were detected compared to the 65 in the ischemic group. Moreover, a comparative study of both protein profiles showed the existence of a pool of 17 that appeared dysregulated in both sham and ischemic animals. These results indicate that the surgical procedure required for intraluminal occlusion of the MCA induce changes on brain protein expression that are not associated with the ischemic lesion.ConclusionThis study highlights the importance of including a sham group in the experimental model design to guarantee that the therapeutic target under study is not affected by the surgical intervention.

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Inhibition of endogenous blood glutamate oxaloacetate transaminase enhances the ischemic damage

Cited by 11 publications

References 26 publications

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

New Perspectives for Developing Therapeutic Bioconjugates of Metabolite-Depleting Enzymes: Lessons Learned Combating Glutamate Excitotoxicity

Relevance of Sham Control Group in Preclinical Animal Studies of Cerebral Ischemia

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