Combined lactate and hypothermia therapy enhances neuroprotection following neonatal hypoxic-ischemic brain injury
Abstract
Background and Purpose: Neonatal hypoxia-ischemia (NHI) is a leading cause of mortality and long-term neurodevelopmental disability. Therapeutic hypothermia (TH) is currently the only established treatment for NHI; however, its efficacy remains limited, underscoring the need for adjunctive neuroprotective strategies. Lactate is now regarded as a major metabolic substrate of the brain and has previously been shown to exert neuroprotective effects following experimental NHI. We investigated whether lactate enhances hypothermia-induced neuroprotection and evaluated the optimal timing of administration and potential underlying mechanisms. Methods: Postnatal day 7 Wistar rats were subjected to NHI using the Rice-Vannucci model and treated with TH alone (2h at 32°C), sodium L-lactate alone, or combined L-lactate–TH. Animals underwent longitudinal magnetic resonance imaging (MRI) and behavioral assessments, complemented by histological, immunohistochemical, and Western blot analyses, including assessment of protein lactylation. The effect of sodium L-lactate administration timing relative to TH was also evaluated. Results: Lactate significantly enhanced the neuroprotective effects of TH, particularly when administered before hypothermia, resulting in greater lesion recovery, reduced neuroinflammation and apoptotic cell death, preserved neuronal integrity, and improved long-term motor and cognitive outcomes. Combined treatment preserved neuronal lactate transporter, prevented NHI-induced astrocytic glutamate transporter upregulation, modulated lactylation markers, supporting coordinated metabolic and epigenetic adaptations following NHI. Conclusions: Early lactate administration enhances the neuroprotective efficacy of TH following NHI. These findings identify lactate as a promising adjunct to TH and support its translational potential as a metabolic strategy to improve outcomes following NHI brain injury.
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BibTeX
@misc{ibrahim2026combined,
title = {{Combined lactate and hypothermia therapy enhances neuroprotection following neonatal hypoxic-ischemic brain injury}},
author = {Ifrah Omar Ibrahim and Sébastien Giraud and Estelle Lemarié and Anne-Karine Bouzier-Sore and Marie-Christine Beauvieux and Stéphane Sanchez and Marc Biran and Aurélien Trottier and Karine Viaud and Jean-François Chateil and Jean Delmas and Luc Pellerin and Hélène Roumes},
howpublished = {HAL},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754268},
url = {https://hal.science/hal-05795436v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Combined lactate and hypothermia therapy enhances neuroprotection following neonatal hypoxic-ischemic brain injury
AU - Ifrah Omar Ibrahim
AU - Sébastien Giraud
AU - Estelle Lemarié
AU - Anne-Karine Bouzier-Sore
AU - Marie-Christine Beauvieux
AU - Stéphane Sanchez
AU - Marc Biran
AU - Aurélien Trottier
AU - Karine Viaud
AU - Jean-François Chateil
AU - Jean Delmas
AU - Luc Pellerin
AU - Hélène Roumes
PY - 2026
DA - 2026/09/24
PB - HAL
DO - 10.64898/2026.09.24.754268
UR - https://hal.science/hal-05795436v1
AB - Background and Purpose: Neonatal hypoxia-ischemia (NHI) is a leading cause of mortality and long-term neurodevelopmental disability. Therapeutic hypothermia (TH) is currently the only established treatment for NHI; however, its efficacy remains limited, underscoring the need for adjunctive neuroprotective strategies. Lactate is now regarded as a major metabolic substrate of the brain and has previously been shown to exert neuroprotective effects following experimental NHI. We investigated whether lactate enhances hypothermia-induced neuroprotection and evaluated the optimal timing of administration and potential underlying mechanisms. Methods: Postnatal day 7 Wistar rats were subjected to NHI using the Rice-Vannucci model and treated with TH alone (2h at 32°C), sodium L-lactate alone, or combined L-lactate–TH. Animals underwent longitudinal magnetic resonance imaging (MRI) and behavioral assessments, complemented by histological, immunohistochemical, and Western blot analyses, including assessment of protein lactylation. The effect of sodium L-lactate administration timing relative to TH was also evaluated. Results: Lactate significantly enhanced the neuroprotective effects of TH, particularly when administered before hypothermia, resulting in greater lesion recovery, reduced neuroinflammation and apoptotic cell death, preserved neuronal integrity, and improved long-term motor and cognitive outcomes. Combined treatment preserved neuronal lactate transporter, prevented NHI-induced astrocytic glutamate transporter upregulation, modulated lactylation markers, supporting coordinated metabolic and epigenetic adaptations following NHI. Conclusions: Early lactate administration enhances the neuroprotective efficacy of TH following NHI. These findings identify lactate as a promising adjunct to TH and support its translational potential as a metabolic strategy to improve outcomes following NHI brain injury.
ER -