Abstract
Cerebral metabolism, which can be monitored by magnetic resonance spectroscopy (MRS), changes rapidly after brain ischaemic injury. Hyperpolarisation techniques boost 13C MRS sensitivity by several orders of magnitude, thereby enabling in vivo monitoring of biochemical transformations of hyperpolarised (HP) 13C-labelled precursors with a time resolution of seconds. The exogenous administration of the metabolite L-lactate was shown to decrease lesion size and ameliorate neurological outcome in preclinical studies in rodent stroke models, as well as influencing brain metabolism in clinical pilot studies of acute brain injury patients. The aim of this study was to demonstrate the feasibility of measuring HP [1-13C] L-lactate metabolism in real-time in the mouse brain after ischaemic stroke when administered after reperfusion at a therapeutic dose. We showed a rapid, time-after-reperfusion-dependent conversion of [1-13C] L-lactate to [1-13C] pyruvate and [13C] bicarbonate that brings new insights into the neuroprotection mechanism of L-lactate. Moreover, this study paves the way for the use of HP [1-13C] L-lactate as a sensitive molecular-imaging biosensor in ischaemic stroke patients after endovascular clot removal.
Highlights
Cerebral metabolism, which can be monitored by magnetic resonance spectroscopy (MRS), changes rapidly after brain ischaemic injury
The infusion of HP [1-13C] lactate leads to labelling of the pyruvate pool as mediated by lactate dehydrogenase (LDH). [1-13C] pyruvate is further metabolised to produce 13C labelled bicarbonate; due to limited signal-to-noise ratio (SNR) we could only clearly identify the bicarbonate signal in the sum spectra in 9 out of the 15 animals that received HP [1-13C] lactate
We observed larger [1-13C] pyruvate signals in 1 h post-reperfusion injected animals compared to 2 h post-reperfusion and sham (Fig. 2). 37.5 s after the beginning of HP [1-13C] lactate infusion, we barely detected pyruvate signals, and so we calculated pyruvate-to-lactate ratios (PLR) and bicarbonate-to-lactate ratios (BLR) from the spectra acquired during the first 37.5 s of the experiment
Summary
Cerebral metabolism, which can be monitored by magnetic resonance spectroscopy (MRS), changes rapidly after brain ischaemic injury. The aim of this study was to demonstrate the feasibility of measuring HP [1-13C] L-lactate metabolism in real-time in the mouse brain after ischaemic stroke when administered after reperfusion at a therapeutic dose. In addition to timely clot-removal interventions, neuroprotective strategies applied in the acute phase of ischaemic stroke could improve patient outcome by enhancing the recovery of brain cells not yet irreversibly damaged or by promoting the brain’s endogenous self-repair mechanisms. The recent development of hyperpolarised (HP) 13C MRS by dissolution dynamic nuclear polarisation (dDNP)[22] enables boosting MR sensitivity and monitoring brain metabolism in vivo in real time in preclinical studies[23,24,25,26,27] and clinical settings[28,29,30]. Lactate is among the many endogenous molecules that can be polarised[32,33,34,35,36] and given that the plasma concentration of endogenous lactate is rather high, it can be safely administered at the typical millimolar concentrations necessary for both HP 13C MRS measurements[33,34,35,36] and neuroprotection[16]
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