Evaluating the potential of hyperpolarised [1-13C] L-lactate as a neuroprotectant metabolic biosensor for stroke

Abstract

Cerebral metabolism, which can be monitored by magnetic resonance spectroscopy (MRS), changes rapidly after brain ischaemic injury. Hyperpolarisation techniques boost 13 C MRS sensitivity by several orders of magnitude, thereby enabling in vivo monitoring of biochemical transformations of hyperpolarised (HP) 13 C-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 [1-13 C] 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 [1-13 C] L-lactate to [1-13 c] pyruvate and [ 13 c] bicarbonate that brings new insights into the neuroprotection mechanism of L-lactate. Moreover, this study paves the way for the use of HP [1-13 C] L-lactate as a sensitive molecular-imaging biosensor in ischaemic stroke patients after endovascular clot removal.

A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells

“…This would make sense if we consider that in vitro, iRPE cells are maintained in glucose medium, even if glucose or other substrates were excluded from the iRPE solution before the assay was performed (see Materials and Methods). The use of fluxomics could potentially improve the measure of transepithelial lactate transport [ 37 ].…”

Hyperpolarized 13C Spectroscopy with Simple Slice-and-Frequency-Selective Excitation

“…With dynamic measurements, advanced spectral fitting algorithms can be unreliable, making spectral signal isolation during acquisition more advantageous. Metabolic processes, like conversion of [1- 13 C]lactate to [1- 13 C]pyruvate and [1- 13 C]bicarbonate [ 6 ] or [1- 13 C]glucose to [1- 13 C]glycogen [ 38 ], are thus potential applications for narrow bandwidth methods.…”

“…Pyruvate was dissolved in 3.4 ± 0.3 mL buffered solution that was heated to 180 °C and contained 80 mM TRIS, 0.1 g/l EDTA and 80 mM sodium hydroxide (NaOH), resulting in a 80 mM [1- 13 C]pyruvate solution with mean pH of 7.1 ± 0.2. Lactate [ 6 , 30 , 31 ] was similarly dissolved in 3 mL of 80 mM TRIS/0.1 g/l EDTA/D 2 O/1 M NaOD solution, resulting in a 100 mM [1- 13 C]lactate solution, with mean pH of 7.3 ± 0.2.…”

“…Hyperpolarized 13 C magnetic resonance spectroscopy and spectroscopic imaging are used to characterize metabolism in vivo using a variety of acquisition schemes [ 1 , 2 , 3 ], both in preclinical studies [ 4 , 5 , 6 ] and clinical settings [ 7 , 8 ]. An important application area of spectroscopic imaging with hyperpolarized [1- 13 C]pyruvate is detection of metabolic changes of inflammatory processes caused by infiltrating immune cells such as macrophages.…”

“…Substrates with lower levels of the downstream metabolites are also challenging, like conversion of [1- 13 C]lactate into [1- 13 C]pyruvate and [ 13 C]HCO 3 − [ 6 , 23 ], particularly when chemical shifts of metabolites [ 20 ] are close. For injected [1- 13 C]lactate and downstream [1- 13 C]pyruvate with broad bandwidth excitation, the tails of the injected lactate peak are comparable in magnitude to the pyruvate peak at its central frequency, potentially interfering with pyruvate quantification [ 6 ].…”