Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes

O’Dea, Mary; Kelly, Lynne; McKenna, Ellen; Strickland, Tammy; Hurley, Tim; Butler, John M.; Vavasseur, Claudine; El-Khuffash, Afif; Miletin, Jan; Fallah, Lida; White, Arthur; Wyse, Jason; Molloy, Eleanor J.

doi:10.3389/fped.2021.734540

Cited by 9 publications

(8 citation statements)

References 56 publications

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“…Understanding the role of cytokines in the evolution of neonatal brain injury, as well as the dynamic nature of cytokine release after a hypoxic-ischemic insult, is a promising avenue for identifying biomarkers of ongoing brain injury in newborns with antenatal/postnatal infection/inflammation following HI, especially those that do not show an improved outcome after TH [84,[104][105][106][107].…”

Section: Discussionmentioning

confidence: 99%

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Bernis

Schleehuber

Zweyer

et al. 2022

Oxidative Medicine and Cellular Longevity

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Hypoxic-ischemic encephalopathy (HIE) mainly affects preterm and term newborns, leading to a high risk of brain damage. Coexisting infection/inflammation and birth asphyxia are key factors associated with intracerebral increase of proinflammatory cytokines linked to HIE. Microglia are key mediators of inflammation during perinatal brain injury, characterized by their phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with pro- and anti-inflammatory cytokines as well as the nucleotide-binding domain, leucine-rich repeat protein (NLRP-3) inflammasome from microglia cells. For this purpose, we used our established neonatal rat model of inflammation-sensitized hypoxic-ischemic (HI) brain injury in seven-day-old rats. We assessed gene expression profiles of 11 cytokines and for NLRP-3 using real-time PCR from sorted CD11b/c microglia of brain samples at different time points (3.5 h after LPS injection and 0, 5, 24, 48, and 72 hours post HI) following different treatments: vehicle, E. coli lipopolysaccharide (LPS), vehicle/HI, and LPS/HI. Our results showed that microglia are early key mediators of the inflammatory response and exacerbate the inflammatory response following HI, polarizing into a predominant proinflammatory M1 phenotype in the early hours post HI. The brains only exposed to HI showed a delay in the expression of proinflammatory cytokines. We also demonstrated that NLRP-3 plays a role in the inflammatory resolution with a high expression after HI insult. The combination of both, a preinfection/inflammation condition and hypoxia-ischemia, resulted in a higher proinflammatory cytokine storm, highlighting the significant contribution of acute inflammation sensitizing prior to a hypoxic insult on the severity of perinatal brain damage.

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Section: Discussionmentioning

confidence: 99%

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Bernis

Schleehuber

Zweyer

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Indeed, O'Dea et al reported relative immune hyporesponsiveness to endotoxin challenge among infants with NE with elevated cytokine levels. 68 Additional therapies targeting immunomodulation such as azithromycin 69,70 may complement the neuroprotective effect of melatonin.…”

Section: Discussionmentioning

confidence: 99%

“…These excessively high cytokine levels, leading to overwhelming immune hyperactivation, may impair the ability of melatonin to modulate the immune response. Indeed, O'Dea et al reported relative immune hypo‐responsiveness to endotoxin challenge among infants with NE with elevated cytokine levels 68 . Additional therapies targeting immunomodulation such as azithromycin 69,70 may complement the neuroprotective effect of melatonin.…”

Section: Discussionmentioning

confidence: 99%

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Pang,

Meehan,

Maple

et al. 2024

Journal of Pineal Research

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There is a need to develop therapies for neonatal encephalopathy (NE) in low‐ and middle‐income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation‐amplified hypoxia–ischaemia (IA‐HI) in the newborn piglet. The IA‐HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N‐acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA‐HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA‐HI, piglets were randomised to HI‐saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15–30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI‐saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [−0.366, −0.028], Pr(sup) 98.8%) in basal‐ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [−0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI‐saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI‐saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL‐positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early‐phase clinical trials. Melatonin is protective following IA‐HI where HT is not effective. These data guide the design of future dose‐escalation studies in the next phase of the translational pipeline.

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“…Serum Epo levels are significantly elevated in both term and preterm infants with adverse neurodevelopmental outcomes and remain dysregulated in later childhood post-NE. 3,[90][91][92][93] Recombinant Epo may upregulate Epo receptors in animal models of neonatal HI and Epo levels for tissue protection may be up to 1000-fold higher than required for erythropoiesis. 94 Numerous studies of Epo neuroprotection performed in rodents, sheep, and nonhuman primates have provided consistent evidence that exogenous Epo results in both histologic and functional benefit, with most benefit seen in multiple, high-dose treatment regimens.…”

Section: Seizure Managementmentioning

confidence: 99%

Section: Erythropoietin In Term Infantsmentioning

confidence: 99%

Neuroprotective therapies in the NICU in term infants: present and future

Molloy

El‐Dib²,

Juul³

et al. 2022

Pediatr Res

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Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30–50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. Impact The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30–50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

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Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes

Cited by 9 publications

References 56 publications

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Neuroprotective therapies in the NICU in term infants: present and future

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