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Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy.

ABSTRACT: This study was undertaken to determine whether maternal intrauterine endotoxin administration leads to neurobehavioral deficits in newborn rabbits.Pregnant New Zealand white rabbits were injected with 1 mL saline solution (n = 8) or 20 microg/kg of lipopolysaccharide in saline solution (n = 8) into the uterine wall on day 28/31 of gestation. On postnatal day 1, kits (saline solution [n = 30] and lipolysaccharide in saline solution [n = 18] from 4 consecutive litters) underwent neurobehavioral testing. Neonatal brains were stained for microglial cells and myelin.Kits in the lipopolysaccharide in saline solution group were hypertonic and demonstrated significant impairment in posture, righting reflex, locomotion, and feeding, along with neuroinflammation indicated by activated microglia and hypomyelination in the periventricular regions. A greater mortality was noted in the lipopolysaccharide in saline solution group (16 stillbirths from 3 litters vs 3 from 1 litter).Maternal intrauterine endotoxin administration leads to white matter injury and motor deficits in the newborn rabbit, resulting in a phenotype that resembles those found in periventricular leukomalacia and cerebral palsy.

SUBMITTER: Saadani-Makki F

PROVIDER: S-EPMC2913549 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy.

Saadani-Makki Fadoua F Kannan Sujatha S Lu Xin X Janisse James J Dawe Elizabeth E Edwin Samuel S Romero Roberto R Chugani Diane D

American journal of obstetrics and gynecology 20081009 6

<h4>Objective</h4>This study was undertaken to determine whether maternal intrauterine endotoxin administration leads to neurobehavioral deficits in newborn rabbits.<h4>Study design</h4>Pregnant New Zealand white rabbits were injected with 1 mL saline solution (n = 8) or 20 microg/kg of lipopolysaccharide in saline solution (n = 8) into the uterine wall on day 28/31 of gestation. On postnatal day 1, kits (saline solution [n = 30] and lipolysaccharide in saline solution [n = 18] from 4 consecutiv ...[more]

PMID: 18845289

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Project description:ImportanceAir pollution is associated with structural brain changes, disruption of neurogenesis, and neurodevelopmental disorders. The association between prenatal exposure to ambient air pollution and risk of cerebral palsy (CP), which is the most common motor disability in childhood, has not been thoroughly investigated.ObjectiveTo evaluate the associations between prenatal residential exposure to ambient air pollution and risk of CP among children born at term gestation in a population cohort in Ontario, Canada.Design, setting, and participantsPopulation-based cohort study in Ontario, Canada using linked, province-wide health administrative databases. Participants were singleton full term births (≥37 gestational weeks) born in Ontario hospitals between April 1, 2002, and March 31, 2017. Data were analyzed from January to December 2022.ExposuresWeekly average concentrations of ambient fine particulate matter with a diameter 2.5 μm (PM2.5) or smaller, nitrogen dioxide (NO2), and ozone (O3) during pregnancy assigned by maternal residence reported at delivery from satellite-based estimates and ground-level monitoring data.Main outcome and measuresCP cases were ascertained by a single inpatient hospitalization diagnosis or at least 2 outpatient diagnoses for children from birth to age 18 years.ResultsThe present study included 1 587 935 mother-child pairs who reached term gestation, among whom 3170 (0.2%) children were diagnosed with CP. The study population had a mean (SD) maternal age of 30.1 (5.6) years and 811 745 infants (51.1%) were male. A per IQR increase (2.7 μg/m3) in prenatal ambient PM2.5 concentration was associated with a cumulative hazard ratio (CHR) of 1.12 (95% CI, 1.03-1.21) for CP. The CHR in male infants (1.14; 95% CI, 1.02-1.26) was higher compared with the CHR in female infants (1.08; 95% CI, 0.96-1.22). No specific window of susceptibility was found for prenatal PM2.5 exposure and CP in the study population. No associations or windows of susceptibility were found for prenatal NO2 or O3 exposure and CP risk.Conclusions and relevanceIn this large cohort study of singleton full term births in Canada, prenatal ambient PM2.5 exposure was associated with an increased risk of CP in offspring. Further studies are needed to explore this association and its potential biological pathways, which could advance the identification of environmental risk factors of CP in early life.

Project description:BackgroundMaternal infection is a risk factor for periventricular leukomalacia and cerebral palsy (CP) in neonates. We have previously demonstrated hypomyelination and motor deficits in newborn rabbits, as seen in patients with cerebral palsy, following maternal intrauterine endotoxin administration. This was associated with increased microglial activation, primarily involving the periventricular region (PVR). In this study we hypothesized that maternal intrauterine inflammation leads to a pro-inflammatory environment in the PVR that is associated with microglial activation in the first 2 postnatal weeks.MethodsTimed pregnant New Zealand white rabbits underwent laparotomy on gestational day 28 (G28). They were randomly divided to receive lipopolysaccharide (LPS; 20μg/kg in 1mL saline) (Endotoxin group) or saline (1mL) (control saline, CS group), administrated along the wall of the uterus. The PVR from the CS and Endotoxin kits were harvested at G29 (1day post-injury), postnatal day1 (PND1, 3day post-injury) and PND5 (7days post-injury) for real-time PCR, ELISA and immunohistochemistry. Kits from CS and Endotoxin groups underwent longitudinal MicroPET imaging, with [11C]PK11195, a tracer for microglial activation.ResultsWe found that intrauterine endotoxin exposure resulted in pro-inflammatory microglial activation in the PVR of rabbits in the first postnatal week. This was evidenced by increased TSPO (translocator protein) expression co-localized with microglia/macrophages in the PVR, and changes in the microglial morphology (ameboid soma and retracted processes). In addition, CD11b level significantly increased with a concomitant decline in the CD45 level in the PVR at G29 and PND1. There was a significant elevation of pro-inflammatory cytokines and iNOS, and decreased anti-inflammatory markers in the Endotoxin kits at G29, PND1 and PND5. Increased [11C]PK11195 binding to the TSPO measured in vivo by PET imaging in the brain of Endotoxin kits was present up to PND14-17.ConclusionsOur results indicate that a robust pro-inflammatory microglial phenotype/brain milieu commenced within 24h after LPS exposure and persisted through PND5 and in vivo TSPO binding was found at PND14-17. This suggests that there may be a window of opportunity to treat after birth. Therapies aimed at inducing an anti-inflammatory phenotype in microglia might promote recovery in maternal inflammation induced neonatal brain injury.

Project description:AimTo synthetize studies assessing somatosensory deficits and alterations in cerebral responses evoked by somatosensory stimulation in individuals with cerebral palsy (CP) compared to typically developing individuals.MethodA scoping review of the literature was performed in the MEDLINE, Embase, PsycInfo, CINAHL, Evidence-Based Medicine Reviews, and Web of Science databases (last search carried out on 6th and 7th August 2020) with a combination of keywords related to CP and somatosensory functions. Somatosensory deficits were measured with clinical tests and alterations in cerebral responses were measured with functional magnetic resonance imaging, electroencephalography, and magnetoencephalography.ResultsForty-eight articles were included. Overall, 1463 participants with CP (mean [SD] age 13y 1mo [4y 11mo], range 1-55y; 416 males, 319 females, sex not identified for the remaining participants) and 1478 controls (mean [SD] age 13y 1mo [5y 8mo], range 1-42y; 362 males, 334 females, sex not identified for the remaining participants) were included in the scoping review. For tactile function, most studies reported registration (8 out of 13) or perception (21 out of 21) deficits in participants with CP. For proprioception, most studies also reported registration (6 out of 8) or perception (10 out of 15) deficits. Pain function has not been studied as much, but most studies reported registration (2 out of 3) or perception (3 out of 3) alterations. Neuroimaging findings (18 studies) showed alterations in the somatotopy, morphology, latency, or amplitude of cortical responses evoked by somatosensory stimuli.InterpretationDespite the heterogeneity in the methods employed, most studies reported somatosensory deficits. The focus has been mainly on tactile and proprioceptive function, whereas pain has received little attention. Future research should rigorously define the methods employed and include a sample that is more representative of the population with CP. What this paper adds Most of the papers reviewed found tactile registration and perception deficits in the upper limbs. Proprioceptive deficits were generally observed in cerebral palsy but results were heterogeneous. Pain has received little attention compared to tactile and proprioceptive functions. Neuroimaging studies supported behavioral observations. Alterations were observed for both the most and least affected limb.

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Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy.

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Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy.

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