A Critical Review of Models of Perinatal Infection

Dean, Justin M.; Shi, Zhijun; Fleiss, Bobbi; Gunn, Katherine C.; Groenendaal, Floris; Bel, Frank van; Derrick, Matthew; Juul, Sandra E.; Tan, Sidhartha; Gressèns, Pierre; Mallard, Carina; Gunn, Alistair J.

doi:10.1159/000370309

Cited by 37 publications

(38 citation statements)

References 136 publications

(152 reference statements)

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“…Studies on LPS-sensitised HI injury have demonstrated microglia to be both more numerous and in a more activated state around the site of the lesion [18,45,46] . The sensitising effect of LPS on the immature brain has been attributed to the number of activated microglia.…”

Section: Discussionmentioning

confidence: 99%

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

et al. 2017

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Perinatal infection increases the vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury. Hypothermia treatment (HT) does not provide neuroprotection after pre-insult inflammatory sensitisation by lipopolysaccharide (LPS), a gram-negative bacterial wall constituent. However, early-onset sepsis in term babies is caused by gram-positive species in more than 90% of cases, and neuro-inflammatory responses triggered through the gram-negative route (Toll-like receptor 4, TLR-4) are different from those induced through the gram-positive route via TLR-2. Whether gram-positive septicaemia sensitises the neonatal brain to hypoxia and inhibits the neuroprotective effect of HT is unknown. Seven-day-old Wistar rats (n = 178) were subjected to intraperitoneal injections of PAM₃CSK₄ (1 mg/kg, a synthetic TLR-2 agonist) or vehicle (0.9% NaCl). After an 8-h delay, the left carotid artery was ligated followed by 50 min of hypoxia (8% O₂) at a rectal temperature of 36°C. Pups received a 5-h treatment of normothermia (NT, 37°C) or HT (32°C) immediately after the insult. Brains were harvested after 7 days' survival for hemispheric and hippocampal area loss analyses and immunolabelling of microglia (Iba1) and hippocampal neurons (NeuN). Normothermic PAM₃CSK₄-injected animals showed significantly more brain injury than vehicle animals (p = 0.014). Compared to NT, HT significantly reduced injury in the PAM₃CSK₄-injected animals, with reduced area loss (p < 0.001), reduced microglial activation (p = 0.006), and increased neuronal rescue in the CA1 region (p < 0.001). Experimental induction of a sepsis-like condition through the gram-positive pathway sensitises the brain to HI injury. HT was highly neuroprotective after the PAM₃CSK₄-triggered injury, suggesting HT may be neuroprotective in the presence of a gram-positive infection. These results are in strong contrast to LPS studies where HT is not neuroprotective.

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Section: Discussionmentioning

confidence: 99%

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

et al. 2017

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“…Neonatal hypoxia ischaemia has been modeled extensively in mice and rats (reviewed in Hagberg et al, 2002; van der Worp et al, 2007; Yager and Ashwal, 2009; Dean et al, 2015), with a minority of researchers also studying larger animals such as pigs, sheep (reviewed in Roohey et al, 1997; Dean et al, 2015) or primates (Fahn et al, 1979; Volpe, 2012). Models intending to replicate the clinical symptoms of neonatal human HI can be roughly divided into the four categories discussed below.…”

Section: Evaluation Of Available Animal Models Of Neonatal Hypoxia Ismentioning

confidence: 99%

“…(B) The general method with specifications taken from the pool of papers summarized in Supplementary Table 1. (C) The range of inflammatory models reviewed in Dean et al (2015).…”

Section: Evaluation Of Available Animal Models Of Neonatal Hypoxia Ismentioning

confidence: 99%

“…One is its prevalence, allowing direct comparisons with many other published papers (Vannucci et al, 1993, 2005; Yager and Ashwal, 2009; Dean et al, 2015). Another is that the contralateral hemisphere, exposed to hypoxia in the absence of ischemia, appears normal (Yager et al, 1991, 1992, 1996; Vannucci and Yager, 1992), providing a control hemisphere within the experimental brain.…”

Section: Evaluation Of Available Animal Models Of Neonatal Hypoxia Ismentioning

confidence: 99%

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Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

Millar

Shi

Hoerder‐Suabedissen

et al. 2017

Front. Cell. Neurosci.

288

272

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Neonatal hypoxia-ischaemia (HI) is the most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment. Improved intensive care technology has increased survival without preventing neurological disorder, increasing morbidity throughout the adult population. Early preventative or neuroprotective interventions have the potential to rescue brain development in neonates, yet only one therapeutic intervention is currently licensed for use in developed countries. Recent investigations of the transient cortical layer known as subplate, especially regarding subplate’s secretory role, opens up a novel set of potential molecular modulators of neonatal HI injury. This review examines the biological mechanisms of human neonatal HI, discusses evidence for the relevance of subplate-secreted molecules to this condition, and evaluates available animal models. Neuroserpin, a neuronally released neuroprotective factor, is discussed as a case study for developing new potential pharmacological interventions for use post-ischaemic injury.

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“…It is now recognized that the etiology of preterm brain injury is likely multifactorial. While HI is likely to be important, there is now compelling evidence that exposure to infection and secondary inflammation, both before and after birth, is highly associated with preterm brain injury and deficits in neuronal architecture and function in later life [2,3,4,5,6,7,8,9]. …”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

Dhillon

Gunn

Jung³

et al. 2015

Dev Neurosci

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Acute exposure to subclinical infection modulates subsequent hypoxia-ischemia (HI) injury in a time-dependent manner, likely by cross-talk through Toll-like receptors (TLRs), but the specific pathways are unclear in the preterm-equivalent brain. In the present study, we tested the hypothesis that repeated low-dose exposure to lipopolysaccharide (LPS) before acute ischemia would be associated with induction of specific TLRs that are potentially neuroprotective. Fetal sheep at 0.65 gestation (term is ∼145 days) received intravenous boluses of low-dose LPS for 5 days (day 1, 50 ng/kg; days 2-5, 100 ng/kg) or the same volume of saline. Either 4 or 24 h after the last bolus of LPS, complete carotid occlusion was induced for 22 min. Five days after LPS, brains were collected. Pretreatment with LPS for 5 days decreased cellular apoptosis, microglial activation and reactive astrogliosis in response to HI injury induced 24 but not 4 h after the last dose of LPS. This was associated with upregulation of TLR4, TLR7 and IFN-β mRNA, and increased fetal plasma IFN-β concentrations. The association of reduced white matter apoptosis and astrogliosis after repeated low-dose LPS finishing 24 h but not 4 h before cerebral ischemia, with central and peripheral induction of IFN-β, suggests the possibility that IFN-β may be an important mediator of endogenous neuroprotection in the developing brain.

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A Critical Review of Models of Perinatal Infection

Cited by 37 publications

References 136 publications

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

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