Intracerebral transformation of pyruvate to lactate is deleterious for the neurological function after an experimental cardiac arrest in rabbits

Abstract

Cardiac arrest is a very severe public health issue associated with dramatic neurological injury after the return of spontaneous circulation. During ischemia, neurons can use lactate as an alternative source of energy by oxidazing it into pyruvate via the lactate dehydrogenase (LDH). In the context of cardiac arrest, the neurological consequences of this phenomenon are however unknown. Our aim is to decipher the role of the cerebral lactate consumption on neurological injury after a cardiac arrest. Rabbits were resuscitated after 10 min of ventricular fibrillation and randomly received an intravenous infusion of lactate or pyruvate (10 mg/kg/min, Lact and Pyr groups, n = 6 for each), or oxamate, an inhibitor of LDH (37.5 mg/kg/min, Oxa group, n = 6). In a first set of experiment, we measured the arteriojugular concentrations differences in lactate oxygen and glucose, as well as cerebral extracellular concentration in lactate, pyruvate and glucose via microdialysis catheter during 4 h after cardiac arrest. Secondarly, we evaluated the neurological recovery of additional rabbits during 48 h after cardiac arrest. In both procedures, neuronal death and astrogliosis were assessed histologically. In control animals, cardiac arrest led to an intense metabolic crisis characterised by high cerebral consumptions in oxygen, glucose and lactate. Lactate administration slightly increased neurological dysfunction and neuronal death in comparison to control. Pyruvate administration led to a significant increase in the extracellular concentration in lactate 30 min after ROSC (8.4 ± 0.5 vs. 6.8 ± 1.1 fold change from baseline in Pyr and control groups respectively), which was associated with an aggravation of the neurological dysfunction, the number of degenerative neurons and astrogliosis. Inhibition of LDH by oxamate administration mitigated dramatically this metabolic crisis and was associated with improvement of neurological function and a decrease of neuronal death and astrogliosis compared to control group (15 ± 6 vs. 60 ± 9% of neurological dysfunction in Oxa and control groups, respectively). Our results state that cerebral oxidation of lactate into pyruvate seems to be related to neurological injury after cardiac arrest.