Neuroprotective role of lactate in rat neonatal hypoxia-ischemia

Abstract

Hypoxic-ischemic (HI) encephalopathy remains a major cause of perinatal mortality and chronic disability in newborns worldwide (1–6 for 1000 births). The only current clinical treatment is hypothermia, which is efficient for less than 60% of babies. Mainly considered as a waste product in the past, lactate, in addition to glucose, is increasingly admitted as a supplementary fuel for neurons and, more recently, as a signaling molecule in the brain. Our aim was to investigate the neuroprotective effect of lactate in a neonatal (seven day old) rat model of hypoxia-ischemia. Pups received intra-peritoneal injection(s) of lactate (40 μmol). Size and apparent diffusion coefficients of brain lesions were assessed by magnetic resonance diffusion-weighted imaging. Oxiblot analyses and long-term behavioral studies were also conducted. A single lactate injection induced a 30% reduction in brain lesion volume, indicating a rapid and efficient neuroprotective effect. When oxamate, a lactate dehydrogenase inhibitor, was co-injected with lactate, the neuroprotection was completely abolished, highlighting the role of lactate metabolism in this protection. After three lactate injections (one per day), pups presented the smallest brain lesion volume and a complete recovery of neurological reflexes, sensorimotor capacities and long-term memory, demonstrating that lactate administration is a promising therapy for neonatal HI insult.

Proton Magnetic Resonance Spectroscopy Lactate/N-Acetylaspartate Within 48 h Predicts Cell Death Following Varied Neuroprotective Interventions in a Piglet Model of Hypoxia–Ischemia With and Without Inflammation-Sensitization

“…In adults with traumatic brain injury, administration of 13 C-labeled lactate via the microdialysis catheter and simultaneous collection of the microdialysates, with 13 C NMR analysis, revealed 13 C labeling in glutamine, consistent with lactate metabolism in the TCA cycle ( 31 , 35 ). Interestingly, Roumes et al ( 36 ) recently demonstrated the neuroprotective effect of exogenous lactate administration in a neonatal HI rat model. Rice-Vannucci P7 rats that received intraperitoneal injection of lactate following unilateral carotid ligation exhibited a significant reduction in the volume of high-signal intensity brain lesions on DWI and reduced severity of cytotoxic edema as demonstrated by higher apparent diffusion coefficient (ADC) values compared to animals that received 0.9% sodium chloride.…”

Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia

“…Indeed, the lactate level rises after a hypoxic-ischemic episode 22,23 . It is likely that administration of lactate could further leverage the effect of HCAR1: two recent studies showed that mouse pups injected with lactate before, or in the hours or days following HI had improved recovery 7,8 . The authors suggested that the protective effect of lactate was mainly due to lactate being used as a metabolite to make ATP 7,8 .…”

“…It is likely that administration of lactate could further leverage the effect of HCAR1: two recent studies showed that mouse pups injected with lactate before, or in the hours or days following HI had improved recovery 7,8 . The authors suggested that the protective effect of lactate was mainly due to lactate being used as a metabolite to make ATP 7,8 . However, our data suggest that recovery after lactate injection is partly mediated by HCAR1, which promotes a stronger transcriptional response to HI and thereby facilitates neurogenesis and tissue regeneration after injury.…”

“…Recent studies in mice have shown improved recovery after neonatal HI by administration of lactate 7,8 , but the underlying mechanisms for this beneficial effect are unclear. It is unknown whether lactate improves recovery by giving metabolic support to the cells or by signalling via the Hydroxycarboxylic acid receptor 1 (HCAR1), or both.…”

Effet neuroprotecteur du lactate dans l’hypoxie-ischémie cérébrale néonatale

“…donc du potentiel d'oxydo-réduction de la cellule, qui contrôle de nombreuses réactions enzymatiques. L'administration de lactate est déjà testée en clinique comme thérapie après un traumatisme crânien chez l'adulte [19] [18]. Un suivi longitudinal de ces animaux, à la fois par IRM, pour déterminer la…”