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Extended proteomes of brain organ from individual neonatal rats for understanding hypoxia–ischemia-related brain Injury and drug action.

ABSTRACT: Next-generation shotgun proteomics of brain organ from individual neonatal rats suffering hypoxia-ischemia related brain injury in order to assess their response to a novel pharmaceutical drug.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Jean ARMENGAUD

LAB HEAD: Jean Armengaud

PROVIDER: PXD050059 | Pride | 2025-10-13

REPOSITORIES: Pride

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			Action	DRS
	E00839_MS21-047_Sham_F7_L_1.mgf	Mgf
	E00839_MS21-047_Sham_F7_L_1.raw	Raw
	E00840_MS21-047_Sham_F9_L_3.mgf	Mgf
	E00840_MS21-047_Sham_F9_L_3.raw	Raw
	E00841_MS21-047_Sham_F10_L_4.mgf	Mgf

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Publications

Novel purine derivatives mitigate hypoxia ischemia related brain injury through agrin, zyxin and synaptotagmin proteins.

Mabondzo Aloïse A Disdier Clémence C Bouzid Amal A Larbi Khadidja Side KS Tsintzou Amalia A Maïza Auriane A Kim Boram B Costa Narciso N Harati Rania R Nguyen Anvi Laetitia AL Pruvost Alain A Galons Hervé H Oumata Nassima N Armengaud Jean J Knijnenburg Marlou M Verma Gaurav G Hagberg Henrik H Gressens Pierre P Chen Xiaodi F XF Hamoudi Rifat A RA Stonestreet Barbara S BS

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20250617 5

Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in newborns resulting in motor and cognitive impairment. Therapeutic hypothermia is the only treatment approved for HIE. Consequently, there is a critical requirement for additional treatments for hypoxic-ischemic (HI) brain injury because hypothermia is only partially protective. Pharmacological therapeutics are as yet not available to treat HIE. Therefore, we developed a novel trisubstituted purine-derivative dru ...[more]

PMID: 40533307

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Age dependent effects of hypoxia-ischemia in neonatal mice brain

Project description:Goal was to determine differences in response to hypoxa-ischemia in the mouse brain at development stages representative of human preterm or term neonates, and to detect putative interference with spontaneous development from 2 to 15 days post-natal. Hypoxia-ischemia was realized in 5-day old and 10 day-old mice by unilateral permanent carotid ligature followed by 40 min oxygen restriction (8%). Ipsilateral hemisphere were collected at 3h, 6h 12h or 24h after hypoxia and pools of sex-equilibrated 4-6 brains were used for total RNA extraction at each time point. Co-hybridization of ishemic mRNA (labelled Cy5) and control tissues (labelled Cy3) were performed on Agilent (design 026655) micro-arrays in three independent experiments. In order to evaluate hypoxia ischemia interference during development, we evaluated spontaneous expression at P5 and P10 (Cy3) and extented the observations in a separate set of tissues extracted at P2 and P15.

2020-11-13 | GSE144456 | GEO

Age dependent effects of hypoxia-ischemia in neonatal mice brain

Project description:Age dependent effects of hypoxia-ischemia in neonatal mice brain

| PRJNA603699 | ENA

Proteome analysis of neonatal mouse brain and brain capillaries

Project description:The functions and protein expressions of the blood-brain barrier are changed during brain development after birth. The purpose of the present study was to develop a method to isolate brain capillaries from a single frozen neonatal mouse brain and elucidate the enrichment of brain capillaries by quantitative proteomic analysis. The brain capillary fraction was prepared by the optimized method from a single frozen mouse neonatal brain (postnatal day 7). The brain capillary fractions and brain lysates were digested by trypsin and analyzed by DIA.

2023-07-12 | PXD039296 | JPOST Repository

Understanding Pain: From Cells to Brain to Individual Perceptions

Project description: Not available

| S-EPMC8933029 | biostudies-literature

Single Dose Caffeine Protects the Neonatal Mouse Brain against Hypoxia Ischemia.

Project description:In this randomized blinded study, we investigated caffeine 5 mg/kg treatment given directly after neonatal brain hypoxia ischemia. Brain morphology, behavior and key brain infiltrating immune populations were examined. Caffeine treatment significantly improves outcome when compared to phosphate buffered saline. Flow cytometric analysis of immune responses revealed no persistent immunological alterations. Given its safety caffeine emerges as a candidate for neuroprotective intervention after neonatal brain injury.

| S-EPMC5271335 | biostudies-literature

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice.

Project description:BackgroundNeuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear.MethodsTamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ (microglia-depleted model) and Cx3cr1CreER/+Rosa26DTA/- (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13.ResultsAt P10, tamoxifen administration induced > 99% microglial depletion in DTA+ mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA- mice, male DTA+ mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA- mice, male DTA+ mice had a significantly higher density of TUNEL+ cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA- mice, female DTA+ mice showed a significantly greater number of TUNEL+ cells in the hippocampus and thalamus. Compared to DTA- mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA+ mice under both normal conditions and after HI (more pronounced).ConclusionWe established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males.

| S-EPMC7149909 | biostudies-literature

Effect of Trp53 gene deficiency on brain injury after neonatal hypoxia-ischemia.

Project description:Hypoxia-ischemia (HI) can result in permanent life-long injuries such as motor and cognitive deficits. In response to cellular stressors such as hypoxia, tumor suppressor protein p53 is activated, potently initiating apoptosis and promoting Bax-dependent mitochondrial outer membrane permeabilization. The aim of this study was to investigate the effect of Trp53 genetic inhibition on injury development in the immature brain following HI. HI (50 min or 60 min) was induced at postnatal day 9 (PND9) in Trp53 heterozygote (het) and wild type (WT) mice. Utilizing Cre-LoxP technology, CaMK2α-Cre mice were bred with Trp53-Lox mice, resulting in knockdown of Trp53 in CaMK2α neurons. HI was induced at PND12 (50 min) and PND28 (40 min). Extent of brain injury was assessed 7 days following HI. Following 50 min HI at PND9, Trp53 het mice showed protection in the posterior hippocampus and thalamus. No difference was seen between WT or Trp53 het mice following a severe, 60 min HI. Cre-Lox mice that were subjected to HI at PND12 showed no difference in injury, however we determined that neuronal specific CaMK2α-Cre recombinase activity was strongly expressed by PND28. Concomitantly, Trp53 was reduced at 6 weeks of age in KO-Lox Trp53 mice. Cre-Lox mice subjected to HI at PND28 showed no significant difference in brain injury. These data suggest that p53 has a limited contribution to the development of injury in the immature/juvenile brain following HI. Further studies are required to determine the effect of p53 on downstream targets.

| S-EPMC5355327 | biostudies-literature

Proteomic Analysis of Mouse Cortex Postsynaptic Density following Neonatal Brain Hypoxia-Ischemia.

Project description:Proteomics of the synapses and postsynaptic densities (PSDs) have provided a deep understanding of protein composition and signal networks in the adult brain, which underlie neuronal plasticity and neurodegenerative or psychiatric disorders. However, there is a paucity of knowledge about the architecture and organization of PSDs in the immature brain, and how it is modified by brain injury in an early developing stage. Mass spectrometry (MS)-based proteomic analysis was performed on PSDs prepared from cortices of postnatal day 9 naïve mice or pups which had suffered hypoxic-ischemic (HI) brain injury. 512 proteins of different functional groups were identified from PSDs collected 1 h after HI injury, among which 60 have not been reported previously. Seven newly identified proteins involved in neural development were highlighted. HI injury increased the yield of PSDs at early time points upon reperfusion, and multiple proteins were recruited into PSDs following the insult. Quantitative analysis was performed using spectral counting, and proteins whose relative expression was more than 50% up- or downregulated compared to the sham animals 1 h after HI insult were reported. Validation with Western blotting demonstrated changes in expression and phosphorylation of the N-methyl-D-aspartate receptor, activation of a series of postsynaptic protein kinases and dysregulation of scaffold and adaptor proteins in response to neonatal HI insult. This work, along with other recent studies of synaptic protein profiling in the immature brain, builds a foundation for future investigation on the molecular mechanisms underlying developing plasticity. Furthermore, it provides insights into the biochemical changes of PSDs following early brain hypoxia-ischemia, which is helpful for understanding not only the injury mechanisms, but also the process of repair or replenishment of neuronal circuits during recovery from brain damage.

| S-EPMC5519436 | biostudies-literature

Intestinal microbiota modulates neuroinflammatory response and brain injury after neonatal hypoxia-ischemia.

Project description:Premature infants lack a normal intestinal microbial community and also at risk of perinatal hypoxic-ischemic (HI) brain injury, which is considered to be one of the major factors for motor, sensory, and cognitive deficits. We hypothesized that neonatal gut microbiota composition modulated the immune reaction and severity of neonatal H-I brain injury. Neonatal C57BL/6J mouse pups were exposed to H-I protocol consisting of permanent left carotid artery ligation, followed by 8% hypoxia for 60 min. Microbial manipulation groups included 1) antibiotic treatment, E18 (maternal) to P5; 2) antibiotic treatment E18 to P5 + E. coli gavage; 3) antibiotic treatment E18 to P5 + B. infantis gavage; and 4) saline to pups with dams getting fresh water. The extent of brain injury and recovery was measured on MRI. Edematous injury volume was significantly higher in E. coli group than that in B. infantis group and in fresh water group. Gene expression in brains of pro-inflammatory cytokines (IL1β, IL6, IL2, TNF-α and toll-like receptors 2-6) were elevated to a greater extent in the E. coli group at P10, no injury, and at P13, 72 hours after H-I relative to sham control and B. infantis groups. Significant effects of microbiome and brain injury and interaction of these factors were found in abundance of major phyla. The neuroinflammatory response and brain injury after neonatal hypoxia-ischemia are affected by intestinal microbiota, providing opportunities for therapeutic intervention through targeting the early colonization and development of the gut microbiota.

| S-EPMC10978030 | biostudies-literature

Bcl-x pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia.

Project description:The bcl-x gene appears to play a critical role in regulating apoptosis in the developing and mature CNS and following CNS injury. Two isoforms of Bcl-x are produced as a result of alternative pre-mRNA splicing: Bcl-x(L) (the long form) is anti-apoptotic, while Bcl-x(S) (short form) is pro-apoptotic. Despite the antagonistic activities of these two isoforms, little is known about how regulation of alternative splicing of bcl-x may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered Bcl-x splicing in neural cells, decreasing Bcl-x(L) while increasing Bcl-x(S). Specific knockdown of Bcl-x(S) attenuated apoptosis. To further define regulatory elements that influenced Bcl-x splicing, a Bcl-x minigene was constructed. Deletional analysis revealed several consensus sequences within intron 2 that altered splicing. We found that the splicing factor, CUG-binding-protein-1 (CUGBP1), bound to a consensus sequence close to the Bcl-x(L) 5' splice site, altering the Bcl-x(L)/Bcl-x(S) ratio and influencing cell death. In vivo, neonatal hypoxia-ischemia reciprocally altered Bcl-x pre-mRNA splicing, similar to the in vitro studies. Manipulation of the splice isoforms using viral gene transfer of Bcl-x(S) shRNA into the hippocampus of rats before neonatal hypoxia-ischemia decreased vulnerability to injury. Moreover, alterations in nuclear CUGBP1 preceded Bcl-x splicing changes. These results suggest that alternative pre-mRNA splicing may be an important regulatory mechanism for cell death after acute neurological injury and may potentially provide novel targets for intervention.

| S-EPMC3482490 | biostudies-literature