LDH and PDH Activities in the Ischemic Brain and the Effect of Reperfusion-An Ex Vivo MR Study in Rat Brain Slices Using Hyperpolarized [1-13C]Pyruvate.

Gal Sapir,Naama Lev-Cohain,Rachel Katz-Brull,Moshe J Gomori,David Shaul,Jacob Sosna

doi:10.3390/metabo11040210

Gal Sapir, Naama Lev-Cohain + Show 4 more

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https://doi.org/10.3390/metabo11040210

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Journal: Metabolites	Publication Date: Mar 30, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: Hebrew University of Jerusalem

Abstract

Ischemic stroke is a leading cause for neurologic disability worldwide, for which reperfusion is the only available treatment. Neuroimaging in stroke guides treatment, and therefore determines the clinical outcome. However, there are currently no imaging biomarkers for the status of the ischemic brain tissue. Such biomarkers could potentially be useful for guiding treatment in patients presenting with ischemic stroke. Hyperpolarized 13C MR of [1-13C]pyruvate is a clinically translatable method used to characterize tissue metabolism non-invasively in a relevant timescale. The aim of this study was to utilize hyperpolarized [1-13C]pyruvate to investigate the metabolic consequences of an ischemic insult immediately during reperfusion and upon recovery of the brain tissue. The rates of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) were quantified by monitoring the rates of [1-13C]lactate and [13C]bicarbonate production from hyperpolarized [1-13C]pyruvate. 31P NMR of the perfused brain slices showed that this system is suitable for studying ischemia and recovery following reperfusion. This was indicated by the levels of the high-energy phosphates (tissue viability) and the chemical shift of the inorganic phosphate signal (tissue pH). Acidification, which was observed during the ischemic insult, has returned to baseline level following reperfusion. The LDH/PDH activity ratio increased following ischemia, from 47.0 ± 12.7 in the control group (n = 6) to 217.4 ± 121.3 in the ischemia-reperfusion group (n = 6). Following the recovery period (ca. 1.5 h), this value had returned to its pre-ischemia (baseline) level, suggesting the LDH/PDH enzyme activity ratio may be used as a potential indicator for the status of the ischemic and recovering brain.

Highlights

Stroke is a leading cause for both death and acquired neurologic disability worldwide [1,2] and the global burden of the disease is increasing
The overarching goal of this study was to evaluate the dynamic changes in lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) activities following ischemia and reperfusion, using in parallel 31P NMR indicators to validate the ischemic status of the tissue
Typical 31P spectra from both the control and the ischemia-reperfusion groups are shown in Figure 1b,c, respectively

Summary

Introduction

Stroke is a leading cause for both death and acquired neurologic disability worldwide [1,2] and the global burden of the disease is increasing. In the US alone the annual incidence of stroke is about 800,000 cases [3]. The primary goal in the management of acute ischemic stroke is the restoration of tissue blood supply by arterial recanalization. There are currently two treatment options to achieve this goal: fibrinolytic agents (such as alteplase or tenecteplase), and mechanical thrombectomy [4]. The management of acute stroke, i.e., the decision on applying these treatment options, is dictated mainly by imaging findings. This practice was endorsed widely and became official in the 2018 American Heart Association/American Stroke Association society guidelines [5]. To indicate that the therapeutic window for this disorder is wider than once believed, the phrase “imaging is brain” [6] was suggested as an update to the iconic “time is brain” coined more than a quarter century ago [7]

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