Venue: BBS
Ifrah Omar Ibrahim
RMSB – Team Metapat
https://www.rmsb.u-bordeaux.fr/fr/la-recherche/equipe-metapat/
Supervisor: Anne-Karine Bouzier-Sore
Title
Lactate and Hypothermia: A Dual Approach for Neuroprotectionin Neonatal Hypoxia-Ischemia
Abstract
Since the introduction of the astrocyte-neuron lactate shuttle (ANLS) concept by Pellerin and Magistretti in 1994, it has been proposed that lactate produced by astrocytes via glycolysis is transferred to neurons as a preferred energy substrate. More recently, the critical role of ANLS in brain activation and its associated functions has been demonstrated in vivo. Given that lactate is essential for neuronal activity, the question arises: could it also be neuroprotective in conditions characterized by cerebral energy deficits? To address this question, we used a neonatal hypoxia-ischemia (NHI) model, a leading cause of mortality and subsequent disabilities in infants. NHI results in brain lesions due to a significant reduction in oxygen (O2) and glucose supply. Currently, the only clinical treatment is moderate therapeutic hypothermia (TH), which helps limit the neurological damage caused by NHI. However, nearly half of the affected newborns do not respond favorably to this treatment.
Research conducted by our team using an NHI rat model demonstrated that lactate administration has neuroprotective effects. The aim of my thesis was to determine whether lactate administration is compatible with HT following an NHI event and to compare the effects of combining these two therapies with HT alone. To achieve this goal, my thesis was structured around three main objectives:
- Development of a hypothermia protocol in an NHI rat model: This was done to identify optimal treatment conditions. Three hypothermia durations (2 h, 3 h, and 5 h) post-NHI were compared through longitudinal monitoring of brain damage using MRI (Bruker 4.7T) and various behavioral tests. Histological and immunohistochemical analysis were also conducted to provide complementary insights.
- Evaluation of the therapeutic potential of lactate combined with hypothermia: The neuroprotective effects of this combination were compared to TH alone. The optimal window for lactate administration was also established. The molecular mechanisms underlying these neuroprotective effects were investigated using Western blot analysis. Additionally, the impact of lactate on neuroinflammation was examined by evaluating its role in modulating microglial phenotypes.
- Assessment of the safety of lactate administration on neonatal blood parameters: This was conducted through a retrospective study of preterm infants who received sodium L-lactate infusions.
Our findings clearly indicated that 2 hours of TH were sufficient to reduce brain lesion volumes and achieve optimal performance in behavioral tests. Moreover, lactate administration combined with TH proved to be more neuroprotective than TH alone. Finally, in the retrospective study, sodium L-lactate infusion in preterm infants did not increase lactatemia or disturb other blood parameters.
In conclusion, lactate administration is neuroprotective in the context of NHI, even when combined with TH, and is safe for preterm infants, even when lactatemia is already elevated. These results suggest promising potential for clinical pediatric applications.
Key words : Brain metabolism, lactate, neonatal hypoxia-ischemia, MRI, behavior, hypothermia.
Jury
- Mme. Anne-Karine BOUZIER-SORE, Directrice de Recherche CNRS / Université de Bordeaux – Directrice de thèse
- Mme. Rosa Chiara PAOLICELLI, Professeure associée / Université de Lausanne – Rapporteure
- Laurent SUISSA, Professeur des Universités – Praticien Hospitalier / Université d’Aix-Marseille – Rapporteur
- Rémy GUILLEVIN, Professeur des Universités – Praticien Hospitalier / Université de Poitiers – Examinateur
- Mme. Émilie PACARY, Chargée de Recherche Inserm / Université de Bordeaux – Examinatrice
- Sylvain MIRAUX, Directeur de Recherche CNRS / Univeristé de Bordeaux – Invité
- Luc PELLERIN, Professeur des Universités – Praticien Hospitalier / Université de Poitiers – Invité
- Mme. Hélène ROUMES, Chargée de Recherche CNRS / Université de Bordeaux – Invitée