Injury of the Developing Cerebellum: A Brief Review of the Effects of Endotoxin and Asphyxial Challenges in the Late Gestation Sheep Fetus

Hutton, Lisa Cathleen; Yan, Edwin BingBing; Yawno, Tamara; Castillo‐Melendez, Margie; Hirst, Jonathan J.; Walker, David

doi:10.1007/s12311-014-0602-3

Cited by 18 publications

(19 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The gene expression of MMP-2 and MMP-9, as well as the protein levels of active MMP-2 and MMP-9, was associated with increased activity in the liver and lungs, whereas no such association was found in the striatum. Due to the important role of Purkinje cells in the developing brain [ 29 ], we speculate that the analysis of gelatinolytic activity in these cells could serve as an important tool in evaluating the various effects of neuroprotective substances after hypoxia in different models. The observation that pigs treated with NACA had a tendency to lower levels of gelatinolytic activity, compared with the vehicle-treated group may indicate that NACA reduces inflammation in the cerebellum.…”

Section: Discussionmentioning

confidence: 99%

Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide

et al. 2018

View full text Add to dashboard Cite

Background After perinatal asphyxia, the cerebellum presents more damage than previously suggested. Objectives To explore if the antioxidant N-acetylcysteine amide (NACA) could reduce cerebellar injury after hypoxia-reoxygenation in a neonatal pig model. Methods Twenty-four newborn pigs in two intervention groups were exposed to 8% oxygen and hypercapnia, until base excess fell to −20 mmol/l or the mean arterial blood pressure declined to <20 mmHg. After hypoxia, they received either NACA (NACA group, n = 12) or saline (vehicle-treated group, n = 12). One sham-operated group (n = 5) served as a control and was not subjected to hypoxia. Observation time after the end of hypoxia was 9.5 hours. Results The intranuclear proteolytic activity in Purkinje cells of asphyxiated vehicle-treated pigs was significantly higher than that in sham controls (p = 0.03). Treatment with NACA was associated with a trend to decreased intranuclear proteolytic activity (p = 0.08), There were significantly less mutations in the mtDNA of the NACA group compared with the vehicle-treated group, 2.0 × 10−4 (±2.0 × 10−4) versus 4.8 × 10−5(±3.6 × 10−4, p < 0.05). Conclusion We found a trend to lower proteolytic activity in the core of Purkinje cells and significantly reduced mutation rate of mtDNA in the NACA group, which may indicate a positive effect of NACA after neonatal hypoxia. Measuring the proteolytic activity in the nucleus of Purkinje cells could be used to assess the effect of different neuroprotective substances after perinatal asphyxia.

show abstract

Section: Discussionmentioning

confidence: 99%

Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Although the cerebellum is not classically considered a site of brain injury in premature infants, more recent findings indicate that cerebellar underdevelopment may be common in preterm infants [37]. A strong relationship between decreased cerebellar volumes with presence of PVL has been reported [38], suggesting a common insult, such as inflammation, which is known to cause injury to the developing cerebellum [39, 40]. Another site with upregulation of pro-inflammatory cytokines after IA LPS was the thalamus, where we observed a twofold increase in CCL2 and COX-2 mRNA and a trend towards increased IL-1β mRNA.…”

Section: Discussionmentioning

confidence: 99%

Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques

Schmidt

Senthamaraikannan

Chougnet

et al. 2016

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundChorioamnionitis is associated with an increased risk of brain injury in preterm neonates. Inflammatory changes in brain could underlie this injury. Here, we evaluated whether neuroinflammation is induced by chorioamnionitis in a clinically relevant model.MethodsRhesus macaque fetuses were exposed to either intra-amniotic (IA) saline, or IA lipopolysaccharide (LPS) (1 mg) 16 or 48 h prior to delivery at 130 days (85 % of gestation) (n = 4–5 animals/group). We measured cytokines in the cerebrospinal fluid (CSF), froze samples from the left brain for molecular analysis, and immersion fixed the right brain hemisphere for immunohistology. We analyzed the messenger RNA (mRNA) levels of the pro-inflammatory cytokines IL-1β, CCL2, TNF-α, IL-6, IL-8, IL-10, and COX-2 in the periventricular white matter (PVWM), cortex, thalamus, hippocampus, and cerebellum by RT-qPCR. Brain injury was assessed by immunohistology for myelin basic protein (MBP), IBA1 (microglial marker), GFAP (astrocyte marker), OLIG2 (oligodendrocyte marker), NeuN (neuronal marker), CD3 (T cells), and CD14 (monocytes). Microglial proliferation was assessed by co-immunostaining for IBA1 and Ki67. Data were analyzed by ANOVA with Tukey’s post-test.ResultsIA LPS increased mRNA expression of pro-inflammatory cytokines in the PVWM, thalamus, and cerebellum, increased IL-6 concentration in the CSF, and increased apoptosis in the periventricular area after 16 h. Microglial proliferation in the white matter was increased 48 h after IA LPS.ConclusionsLPS-induced chorioamnionitis caused neuroinflammation, microglial proliferation, and periventricular apoptosis in a clinically relevant model of chorioamnionitis in fetal rhesus macaques. These findings identify specific responses in the fetal brain and support the hypothesis that neuroinflammatory changes may mediate the adverse neurodevelopmental outcomes associated with chorioamnionitis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0706-4) contains supplementary material, which is available to authorized users.

show abstract

“…In piglets, models of perinatal hypoxia demonstrate cerebellar injury [22–24]. In fetal sheep, Purkinje cell death and reduced cerebellar strata occur following hypoxia/asphyxia insults [25]. In mice, reduced cerebellar volumes occurred at postnatal day 18 (p18) in male mice with HIE that were treated with therapeutic hypothermia on p10 [26].…”

Section: Discussionmentioning

confidence: 99%

Diffusion Tensor Imaging Detects Occult Cerebellar Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy

Lemmon¹,

Wagner

Bosemani

et al. 2017

Dev Neurosci

View full text Add to dashboard Cite

Background: Despite the benefits of whole-body hypothermia therapy, many infants with hypoxic-ischemic encephalopathy (HIE) die or have significant long-term neurodevelopmental impairment. Prospectively identifying neonates at risk of poor outcome is essential but not straightforward. The cerebellum is not classically considered to be a brain region vulnerable to hypoxic-ischemic insults; recent literature suggests, however, that the cerebellum may be involved in neonatal HIE. In this study, we aimed to assess the microstructural integrity of cerebellar and linked supratentorial structures in neonates with HIE compared to neurologically healthy neonatal controls. Methods: In this prospective cohort study, we performed a quantitative diffusion tensor imaging (DTI) analysis of the structural pathways of connectivity, which may be affected in neonatal cerebellar injury by measuring fractional anisotropy (FA) and mean diffusivity (MD) within the superior, middle, and inferior cerebellar peduncles, dentate nuclei, and thalami. All magnetic resonance imaging (MRI) studies were grouped into 4 categories of severity based on a qualitative evaluation of conventional and advanced MRI sequences. Multivariable linear regression analysis of cerebellar scalars of patients and controls was performed, controlling for gestational age, age at the time of MRI, and HIE severity. Spearman rank correlation was performed to correlate DTI scalars of the cerebellum and thalami. Results: Fifty-seven (23 females, 40%) neonates with HIE and 12 (6 females, 50%) neonatal controls were included. There were 8 patients (14%) in HIE severity groups 3 and 4 (injury of the basal ganglia/thalamus and/or cortex). Based on a qualitative analysis of conventional and DTI images, no patients had evidence of cerebellar injury. No significant differences between patients and controls were found in the FA and MD scalars. However, FA values of the middle cerebellar peduncles (0.294 vs. 0.380, p < 0.001) and MD values of the superior cerebellar peduncles (0.920 vs. 1.007 × 10^-3 mm/s², p = 0.001) were significantly lower in patients with evidence of moderate or severe injury on MRI (categories 3 and 4) than in controls. In patients, cerebellar DTI scalars correlated positively with DTI scalars within the thalami. Conclusion: Our results suggest that infants with moderate-to-severe HIE may have occult injury of cerebellar white-matter tracts, which is not detectable by the qualitative analysis of neuroimaging data alone. Cerebellar DTI scalars correlate with thalamic measures, highlighting that cerebellar injury is unlikely to occur in isolation and may reflect the severity of HIE. The impact of concomitant cerebellar injury in HIE on long-term neurodevelopmental outcome warrants further study.

show abstract

Injury of the Developing Cerebellum: A Brief Review of the Effects of Endotoxin and Asphyxial Challenges in the Late Gestation Sheep Fetus

Cited by 18 publications

References 76 publications

Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide

Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide

Intra-amniotic LPS causes acute neuroinflammation in preterm rhesus macaques

Diffusion Tensor Imaging Detects Occult Cerebellar Injury in Severe Neonatal Hypoxic-Ischemic Encephalopathy

Contact Info

Product

Resources

About