Pharmacological modulation of the lactate fuelling of neuron by astrocytes after an experimental cardiac arrest in rabbits

Abstract

Rapid induction of therapeutic hypothermia is known to prevent neurological sequelae after cardiac arrest. Its mechanism of action could involve a preservation of astrocytes function, which are known to fuel neuron with lactate in stress conditions. We investigated whether a specific stimulation of astrocyte metabolism by pyruvate administration could induce lactate release and exacerbate the neuronal death as compared to direct stimulation of neurons by lactate administration. Eighteen rabbits were anesthetized and instrumented for cerebral microdialysis and evaluation of cerebral consumption of O 2 , lactate and glucose. After 10 min of ventricular fibrillation and resuscitation, animals received an intravenous infusion of saline (control group, n = 6), sodium lactate (5 mg/kg/min, Lac group, n = 6) or pyruvate (5 mg/kg/min, Py group, n = 6). Neuronal death was quantified by fluorojade C staining after 240 min of follow-up. After cardiac arrest, cerebral concentration of lactates and glucose increased in all groups, with a concomitant decreased oxygen consumption and increased lactate and glucose consumption. In the Py group, pyruvate was reduced in lactate as suggested by a significant increase in cerebral lactate concentration in Py group vs others (8.0 ± 0.8, 3.5 ± 0.5 vs 4.4 ± 1.2 μmol/L in Py, Lac and Control groups at 30 min post-cardiac arrest, respectively). This led to a greater neuronal death (25 ± 6, 34 ± 6 vs 50 ± 6 dead neurons per field, in Control, Lac and Py groups, respectively), suggesting that astrocyte fuelling with pyruvate is worse than direct neuronal fuelling with lactate. Neuron fuelling with lactate after cardiac arrest is deleterious for neurons. Specific stimulation of astrocytes by pyruvate administration enhances lactate production and worsen the neurological death.