Hyperpolarized ¹³C Magnetic Resonance Spectroscopy Reveals the Rate-Limiting Role of the Blood–Brain Barrier in the Cerebral Uptake and Metabolism of l‑Lactate in Vivo

The dynamics of l-lactate transport across the blood–brain barrier (BBB) and its cerebral metabolism are still subject to debate. We studied lactate uptake and intracellular metabolism in the mouse brain using hyperpolarized ¹³C magnetic resonance spectroscopy (MRS). Following the intravenous injection of hyperpolarized [1-¹³C]­lactate, we observed that the distribution of the ¹³C label between lactate and pyruvate, which has been shown to be representative of their pool size ratio, is different in NMRI and C57BL/6 mice, the latter exhibiting a higher level of cerebral lactate dehydrogenase A (Ldha) expression. On the basis of this observation, and an additional set of experiments showing that the cerebral conversion of [1-¹³C]­lactate to [1-¹³C]­pyruvate increases after exposing the brain to ultrasound irradiation that reversibly opens the BBB, we concluded that lactate transport is rate-limited by the BBB, with a 30% increase in lactate uptake after its disruption. It was also deduced from these results that hyperpolarized ¹³C MRS can be used to detect a variation in cerebral lactate uptake of <40 nmol in a healthy brain during an in vivo experiment lasting only 75 s, opening new opportunities to study the role of lactate in brain metabolism.