Biology subjects

Bouzier-Sore, A.-K.

Publications and source records attributed to Bouzier-Sore, A.-K..

5 recordsLinked to original sources

bioRxiv2026

Combined lactate and hypothermia therapy enhances neuroprotection following neonatal hypoxic-ischemic brain injury

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{degrees}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.

neuroscience↗

bioRxiv2026

Lactate Promotes an Anti-Inflammatory Phenotype in Activated Microglia

Microglial activation is a central component of neuroinflammatory responses in many brain pathologies. Increasing evidence indicates that microglial phenotype is tightly linked to cellular metabolism, with pro-inflammatory activation associated with enhanced glycolytic flux. Lactate, traditionally considered a metabolic substrate, has recently emerged as a signaling molecule capable of modulating immune responses. However, its direct impact on microglial inflammatory activation remains incompletely understood. In the present study, we investigated the effects of lactate on microglial phenotype under inflammatory conditions using primary rat microglial cultures stimulated with lipopolysaccharide (LPS). Microglial activation was assessed through the expression of phenotypic markers, cytokine production, and secreted chemokine profiles. LPS stimulation induced a strong pro-inflammatory response characterized by increased CD86 expression, elevated TNF-alpha secretion, and enhanced release of several pro-inflammatory chemokines. Post-treatment with sodium L-lactate significantly attenuated these inflammatory responses, reducing pro-inflammatory marker expression and cytokine secretion, while restoring the anti-inflammatory marker CD206. To explore the relevance of these findings in a pathological context, the effects of lactate were further examined in a neonatal rat model of hypoxia-ischemia. Sodium L-lactate administration after injury reduced microglial activation and promoted a shift toward an anti-inflammatory phenotype in cortical regions, whereas hippocampal microglia showed a more limited response. Together, these results demonstrate that lactate directly modulates microglial inflammatory activation and cytokine production in vitro and suggest that lactate-mediated metabolic signaling may contribute in vivo to the regulation of neuroinflammatory responses.

neuroscience↗

bioRxiv2026

A Grape Seed Oligomeric Procyanidin Extract Reverses Diet-Induced Obesity Through Gut Microbiota Remodeling and Restoration of GLP-1, Gut-Brain, and Gut-Liver Signaling

BackgroundObesity is a complex multifactorial disease associated with chronic low grade inflammation, gut microbiota dysbiosis, and impaired gut-brain communication. Oligomeric procyanidins from grape seed extracts (GSE) are promising prebiotic candidates, capable of modulating host metabolism through interactions with the gut microbiota. MethodsC57Bl/6J male mice were rendered obese by feeding them a high fat, high sucrose diet and were orally administered GSE at a dose of 1or 2 g/kg/day for 12 weeks. We assessed body weight, adiposity, glucose tolerance, insulin sensitivity, circulating hormones, brain homeostasis markers, colonic and liver gene expression, 16S rRNA gene sequencing of the gut microbiota profiles, and untargeted cecal metabolomics. ResultsGSE reduced body weight gain, visceral adiposity, adipocyte hypertrophy, and improved oral glucose tolerance and insulin sensitivity. It normalized circulating lipid and glucose levels and lowered fasting insulin and leptin while increasing endogenous GLP-1. Hepatic gene expression analysis revealed a dose-dependent restoration of antioxidant defenses (SOD, CAT) and lipogenic transcription factors (SREBP, ChREBP). In the colon, GSE attenuated pro-inflammatory IL6 cytokine expression and strikingly upregulated GLP-1 and GLP-1 receptor expression. Microbiota analysis revealed a profound, dose-dependent remodeling of gut microbiota composition and diversity, with an expansion of health-associated taxa, such as Akkermansia muciniphila. Brain analyses revealed restoration of NAA and BDNF levels together with markers consistent with improved mitochondrial function. Cecal metabolomics revealed normalization of secondary bile acid metabolism, restoration of arginine bioavailability, and reduction in the accumulation of L-DOPA and spermidine. ConclusionsAn oligomeric procyanidin-rich grape seed extract acts as a multitarget prebiotic that alleviates diet-induced obesity and is associated with coordinated restoration of gut microbiota composition, GLP-1 signaling, and gut-brain and gut-liver communication pathways. Convergent dose-dependent effects on Akkermansia muciniphila abundance, GLP-1, NAA, and BDNF identify key mechanisms underlying its metabolic benefits.

microbiology↗

bioRxiv2026

Optimizing therapeutic hypothermia conditions in a translational preclinical model of neonatal hypoxia-ischemia in rats

BackgroundTherapeutic hypothermia is the only clinically approved treatment for neonatal hypoxia-ischemia (NHI), although its efficacy remains partial. In preclinical research, hypothermia is widely used as a reference therapy; however, its protocol is highly variable across studies, limiting robust comparisons with emerging neuroprotective strategies. This study aimed to define an optimal and standardized hypothermia protocol in the Rice-Vannucci model, not to challenge clinical practice, but to establish a reliable benchmark for preclinical therapeutic development. MethodsNHI was induced in postnatal day 7 (P7) rat pups, followed by normothermia or hypothermia for 2, 3, or 5 hours. Short- and long-term outcomes were assessed using lesion volume measurements by MRI, neurological scoring, behavioral tests, and histological analyses. The impact of immediate hypothermia initiation was also examined. ResultsAcross analyses, both 2- and 3-hour hypothermia durations provided greater neuroprotection than 5 hours--including brain lesion volume, motor and cognitive performances, and markers of neuronal preservation and neuroinflammation. However, for several parameters, 2 hours of hypothermia showed superior efficacy compared with 3 hours. Immediate initiation further modestly improved outcomes. ConclusionA 2-hour hypothermia protocol represents the most robust and reproducible preclinical reference, enabling meaningful comparison with novel therapies in the Rice-Vannucci model. IMPACTO_LIBy establishing an optimized hypothermia protocol in the Rice-Vannucci model, this study offers a consistent and robust reference for preclinical evaluation of emerging therapies. C_LIO_LIIt does not question clinical hypothermia protocols, but addresses variability in preclinical literature C_LIO_LIOptimizing the hypothermia reference protocol is mandatory to reliably identify new effective treatments in preclinical studies and to enhance their likelihood of successful and efficient clinical translation C_LI

neuroscience↗

bioRxiv2023

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

Control of brain energy metabolism and regulation of synaptic activity through gliotransmission are two important ways, through which astrocytes contribute to mental functions. However, the potential functional and molecular links between these two astrocyte-dependent processes have been scantly explored. Here we show that a lactate-dependent shift of glycolysis underlies the production of the gliotransmitter D-serine by acute activation of astrocyte type-1 cannabinoid (CB1) receptors, thereby gating synaptic and cognitive processes. Acute cannabinoid application causes a CB1 receptor-dependent rapid and reversible increase of lactate production and release in primary astrocyte cultures. As shown before, mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) were impaired in a novel object recognition (NOR) memory task. This phenotype was rescued not only by the gliotransmitter D-serine, but also by its precursor L-serine. Surprisingly, the administration of lactate and of an agonist of the lactate receptor HCAR1 also reverted the memory impairment of GFAP-CB1-KO mice. This rescue effect was abolished by in vivo blockade of the astrocyte-specific phosphorylated pathway (PP), which diverts glycolysis towards L-serine synthesis, suggesting that lactate signaling might promote the accumulation of this amino acid. Consistent with this idea, lactate and HCAR1 agonism increased the co-agonist occupancy of CA1 post-synaptic hippocampal NMDA receptors. This effect of lactate was abolished by blockade of PP. By establishing a mechanistic link between lactate production and signaling, serine availability, synaptic activity and behavior, these results reveal an unforeseen functional connection between energy metabolism and gliotransmission to control cognitive processes.

neuroscience↗