The metabolic representation of ischemia in rat brain slices: A hyperpolarized 13 C magnetic resonance study

Abstract

The ischemic penumbra in stroke is not clearly defined by today's available imaging tools. This study aimed to develop a model system and noninvasive biomarkers of ischemic brain tissue for an examination that might potentially be performed in humans, very quickly, in the course of stroke triage. Perfused rat brain slices were used as a model system and ³¹ P spectroscopy verified that the slices were able to recover from an ischemic insult of about 3.5 min of perfusion arrest. This was indicated as a return to physiological pH and adenosine triphosphate levels. Instantaneous changes in lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) activities were monitored and quantified by the metabolic conversions of hyperpolarized [1-¹³ C]pyruvate to [1-¹³ C]lactate and [¹³ C]bicarbonate, respectively, using ¹³ C spectroscopy. In a control group (n = 8), hyperpolarized [1-¹³ C]pyruvate was administered during continuous perfusion of the slices. In the ischemia group (n = 5), the perfusion was arrested 30 s prior to administration of hyperpolarized [1-¹³ C]pyruvate and perfusion was not resumed throughout the measurement time (approximately 3.5 min). Following about 110 s of the ischemic insult, LDH activity increased by 80.4 ± 13.5% and PDH activity decreased by 47.8 ± 25.3%. In the control group, the mean LDH/PDH ratio was 16.6 ± 3.3, and in the ischemia group, the LDH/PDH ratio reached an average value of 38.7 ± 16.9. The results suggest that monitoring the activity of LDH and PDH, and their relative activities, using hyperpolarized [1-¹³ C]pyruvate, could serve as an imaging biomarker to characterize the changes in the ischemic penumbra.

Keywords: ATP; [1-13C]pyruvate; hyperpolarized carbon-13; ischemia; lactate dehydrogenase; magnetic resonance spectroscopy; pH; pyruvate dehydrogenase.