Therapeutic hypothermia modulates complement factor C3a and C5a levels in a rat model of hypoxic ischemic encephalopathy

Shah, Tushar A.; Nejad, Jasmine E.; Pallera, Haree K.; Lattanzio, Frank A.; Farhat, Rawad; Kumar, Parvathi S.; Hair, Pamela S.; Bass, W. Thomas; Krishna, Neel K.

doi:10.1038/pr.2016.271

Cited by 24 publications

(31 citation statements)

References 40 publications

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“…The decrease in C5a levels may lead to worsened disease outcome as C5-deficient mice demonstrate impaired bacterial clearance (52) and a study of adult patients with sepsis-induced brain dysfunction revealed a correlation between decreased C5a levels with increased mortality (53). Neonatal rats demonstrate elevated expression of C5a and C5 receptors in the blood and brain following HI, which is reduced with therapeutic hypothermia, suggesting that C5a has an injurious effect in cerebral tissue (18,19). In contrast, even though C5 receptor expression was increased in the liver, we did not find any major changes in the mRNA expression of C5 or C5 receptors in the brain of infected mice prior to HI.…”

Section: Discussionmentioning

confidence: 99%

“…at 24 h [F (1,17) = 36.84, p < 0.0001] and 5 d [F (1,19) = 7.20, p = 0.01]. Compared to their respective saline cohorts, brain CCL2 concentrations in infected mice at 24 h were significantly higher in both males and females (18.2-fold in males, p = 0.007; 16.4-fold in females, p = 0.001) (Figure 6A).…”

Section: S Epidermidis Induced Cytokine and Chemokine Production In mentioning

confidence: 99%

“…C5a signaling through C5a receptors plays an important role in the development of sepsis (17). C5 has also been implicated in cerebral injury (18,19) and C5a is elevated in CSF of preterm infants (20). We therefore also investigated the involvement of C5 signaling following S. epidermidis infection.…”

Section: Introductionmentioning

confidence: 99%

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Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

et al. 2020

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Background: Staphylococcus epidermidis is the most common nosocomial infection and the predominant pathogen in late-onset sepsis in preterm infants. Infection and inflammation are linked to neurological and developmental sequelae and bacterial infections increase the vulnerability of the brain to hypoxia-ischemia (HI). We thus tested the hypothesis that S. epidermidis exacerbates HI neuropathology in neonatal mice.Methods: Male and female C57Bl/6 mice were injected intraperitoneally with sterile saline or 3.5 × 10 7 colony-forming units of S. epidermidis on postnatal day (PND) 4 and then subjected to HI on PND5 (24 h after injection) or PND9 (5 d after injection) by left carotid artery ligation and exposure to 10% O 2 . White and gray matter injury was assessed on PND14-16. In an additional group of animals, the plasma, brain, and liver were collected on PND5 or PND9 after infection to evaluate cytokine and chemokine profiles, C5a levels and C5 signaling.Results: HI induced 24 h after injection of S. epidermidis resulted in greater gray and white matter injury compared to saline injected controls in males, but not in females. Specifically, males demonstrated increased gray matter injury in the cortex and striatum, and white matter loss in the subcortical region, hippocampal fimbria and striatum. In contrast, there was no potentiation of brain injury when HI occurred 5 d after infection in either sex. In the plasma, S. epidermidis-injected mice demonstrated increased levels of pro-and anti-inflammatory cytokines and chemokines and a reduction of C5a at 24 h, but not 5 d after infection. Brain CCL2 levels were increased in both sexes 24 h after infection, but increased only in males at 5 d post infection.Conclusion: Ongoing S. epidermidis infection combined with neonatal HI increases the vulnerability of the developing brain in male but not in female mice. These sex-dependent effects were to a large extent independent of expression of systemic cytokines or brain CCL2 expression. Overall, we provide new insights into how systemic S. epidermidis infection affects the developing brain and show that the time interval between infection and HI is a critical sensitizing factor in males.

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Section: Discussionmentioning

confidence: 99%

Section: S Epidermidis Induced Cytokine and Chemokine Production In mentioning

confidence: 99%

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Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

et al. 2020

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“…The neuroprotection observed in Phase 3 of this study using T2 MRI at 7 days after HI was significantly greater than the initial protection observed at 3 h. This suggests that the additional 3 h of hypothermia after imaging at 3 h may improve neuroprotection, and/or that some of the neuroprotective effects of hypothermia may involve later mechanisms of injury such as inflammation. In neonatal rat HIE models, hypothermia reduces caspase-3 activation, apoptosis, and necrosis examined 24 h after HI ( 45 ), modifies complement factor expression ( 46 ), and reduces IL1β levels ( 47 ). Later effects of hypothermia on cytokine levels and microglial activation have been reported in an adult murine stroke model ( 48 ), and a shift in microglial polarization toward an M2 phenotype at 24 h has been observed after hypothermia in an adult rat TBI model ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Early Detection of Hypothermic Neuroprotection Using T2-Weighted Magnetic Resonance Imaging in a Mouse Model of Hypoxic Ischemic Encephalopathy

et al. 2018

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Perinatal hypoxic-ischemic encephalopathy (HIE) can lead to neurodevelopmental disorders, including cerebral palsy. Standard care for neonatal HIE includes therapeutic hypothermia, which provides partial neuroprotection; magnetic resonance imaging (MRI) is often used to assess injury and predict outcome after HIE. Immature rodent models of HIE are used to evaluate mechanisms of injury and to examine the efficacy and mechanisms of neuroprotective interventions such as hypothermia. In this study, we first confirmed that, in the CD1 mouse model of perinatal HIE used for our research, MRI obtained 3 h after hypoxic ischemia (HI) could reliably assess initial brain injury and predict histopathological outcome. Mice were subjected to HI (unilateral carotid ligation followed by exposure to hypoxia) on postnatal day 7 and were imaged with T2-weighted MRI and diffusion-weighted MRI (DWI), 3 h after HI. Clearly defined regions of increased signal were comparable in T2 MRI and DWI, and we found a strong correlation between T2 MRI injury scores 3 h after HI and histopathological brain injury 7 days after HI, validating this method for evaluating initial injury in this model of HIE. The more efficient, higher resolution T2 MRI was used to score initial brain injury in subsequent studies. In mice treated with hypothermia, we found a significant reduction in T2 MRI injury scores 3 h after HI, compared to normothermic littermates. Early hypothermic neuroprotection was maintained 7 days after HI, in both T2 MRI injury scores and histopathology. In the normothermic group, T2 MRI injury scores 3 h after HI were comparable to those obtained 7 days after HI. However, in the hypothermic group, brain injury was significantly less 7 days after HI than at 3 h. Thus, early neuroprotective effects of hypothermia were enhanced by 7 days, which may reflect the additional 3 h of hypothermia after imaging or effects on later mechanisms of injury, such as delayed cell death and inflammation. Our results demonstrate that hypothermia has early neuroprotective effects in this model. These findings suggest that hypothermia has an impact on early mechanisms of excitotoxic injury and support initiation of hypothermic intervention as soon as possible after diagnosis of HIE.

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“…Neonatal hypoxic-ischemic brain damage (NHIBD) is a severe disease that can cause irreversible neurological sequelae, such as cerebral palsy, mental deficiency, memory impairment and learning disabilities and is often characterized by permanent neurological deficits [1,2]. Currently, there is no effective clinical treatment for NHIBD [3][4][5]. Thus, effective therapeutic agents that inhibit damage cascades activated after NHIBD should be identified.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-9 Mediated the Protective Effect of Ferulic Acid on Hypoxic-Ischemic Brain Injury in Neonatal Rats

Yao

Yang

et al. 2020

Preprint

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Abbreviations: HIBD, hypoxic-ischemic brain damage; HI, hypoxia-ischemia; FA, ferulic acid; SF, sodium ferulic; qRT-PCR, quantitative real-time PCR; AchE, acetylcholinesterase; PSD-95, postsynaptic density protein-95; miR-9, microRNA-9; LNA-miR-9: locked nucleic acid-miR-9; DG, dentate gyrus.Abstract--Neonatal hypoxic-ischemic brain damage (NHIBD) leads to cognitive and memory impairments, and there is no effective clinical treatment. Ferulic acid (FA)is found within members of the genus Angelica, reportedly shows protective effects on neuronal damage; however, the mechanism of the protective effects of FA on rats following NHIBD remains unclear. Using the Morris water maze task, we herein found that the impairment of spatial memory formation in adult rats exposed to NHIBD was significantly reversed by FA treatment and the administration of LNA-miR-9. RT-PCR analyses revealed that miRNA-9 was significantly increased in the hippocampus of neonatal rats and neuronal PC12 cells following NHIBD and that FA and LNA-miR-9 both inhibited the expression of miRNA-9, suggesting that the therapeutic effect of FA was mainly attributed to the inhibition of miRNA-9 expression. Indeed, the silencing of miR-9 by LNA-miR-9 or FA similarly attenuated neuronal damage and cerebral atrophy in the rat hippocampus after NHIBD, which was consistent with the restored expression levels of brain-derived neurotrophic factor (BDNF). Therefore, FA treatment may protect against neuronal death through the inhibition of miRNA-9 induction in the rat hippocampus following hypoxic-ischemic damage.

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Therapeutic hypothermia modulates complement factor C3a and C5a levels in a rat model of hypoxic ischemic encephalopathy

Abstract: HT is associated with significant alteration of complement effectors and their cognate receptors. Complement modulation may improve outcomes in neonatal HIE.

Cited by 24 publications

References 40 publications

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

Early Detection of Hypothermic Neuroprotection Using T2-Weighted Magnetic Resonance Imaging in a Mouse Model of Hypoxic Ischemic Encephalopathy

MicroRNA-9 Mediated the Protective Effect of Ferulic Acid on Hypoxic-Ischemic Brain Injury in Neonatal Rats

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