scholarly journals Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy

2021 ◽  
Vol 15 ◽  
Author(s):  
Tushar A. Shah ◽  
Haree K. Pallera ◽  
Cortney L. Kaszowski ◽  
William Thomas Bass ◽  
Frank A. Lattanzio
Keyword(s):  
Therapeutic Hypothermia ◽  
Developing Brain ◽  
Hypoxic Ischemic Encephalopathy ◽  
Treatment Groups ◽  
Classical Complement Pathway ◽  
Rat Pups ◽  
Downstream Effectors ◽  
Immunofluorescence Labeling ◽  
The Impact ◽  
Ischemic Encephalopathy

ObjectiveComplement activation is instrumental in the pathogenesis of Hypoxic-ischemic encephalopathy (HIE), a significant cause of neonatal mortality and disability worldwide. Therapeutic hypothermia (HT), the only available treatment for HIE, only modestly improves outcomes. Complement modulation as a therapeutic adjunct to HT has been considered, but is challenging due to the wide-ranging role of the complement system in neuroinflammation, homeostasis and neurogenesis in the developing brain. We sought to identify potential therapeutic targets by measuring the impact of treatment with HT on complement effector expression in neurons and glia in neonatal HIE, with particular emphasis on the interactions between microglia and C1q.MethodsThe Vannucci model was used to induce HIE in term-equivalent rat pups. At P10-12, pups were randomly assigned to three different treatment groups: Sham (control), normothermia (NT), and hypothermia (HT) treatment. Local and systemic complement expression and neuronal apoptosis were measured by ELISA, TUNEL and immunofluorescence labeling, and differences compared between groups.ResultsTreatment with HT is associated with decreased systemic and microglial expression of C1q, decreased systemic C5a levels, and decreased microglial and neuronal deposition of C3 and C9. The effect of HT on cytokines was variable with decreased expression of pro and anti-inflammatory effectors. HT treatment was associated with decreased C1q binding on cells undergoing apoptosis.ConclusionOur data demonstrate the extreme complexity of the immune response in neonatal HIE. We propose modulation of downstream effectors C3a and C5a as a therapeutic adjunct to HT to enhance neuroprotection in the developing brain.

scholarly journals Treating Seizures after Hypoxic-Ischemic Encephalopathy—Current Controversies and Future Directions

2021 ◽  
Vol 22 (13) ◽  
pp. 7121
Author(s):  
Kelly Q. Zhou ◽  
Alice McDouall ◽  
Paul P. Drury ◽  
Christopher A. Lear ◽  
Kenta H. T. Cho ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
Newborn Infants ◽  
Developing Brain ◽  
Hypoxic Ischemic Encephalopathy ◽  
Neurodevelopmental Outcomes ◽  
High Quality ◽  
Future Directions ◽  
Phenobarbital Administration ◽  
The Impact ◽  
Ischemic Encephalopathy

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.

scholarly journals Inhaled H2 or CO2 Do Not Augment the Neuroprotective Effect of Therapeutic Hypothermia in a Severe Neonatal Hypoxic-Ischemic Encephalopathy Piglet Model

2020 ◽  
Vol 21 (18) ◽  
pp. 6801
Author(s):  
Viktória Kovács ◽  
Gábor Remzső ◽  
Valéria Tóth-Szűki ◽  
Viktória Varga ◽  
János Németh ◽  
...  
Keyword(s):  
Caudate Nucleus ◽  
Therapeutic Hypothermia ◽  
Neuroprotective Effect ◽  
Fold Increase ◽  
Hypoxic Ischemic Encephalopathy ◽  
Mrna Levels ◽  
Treatment Groups ◽  
Apoptosis Inducing Factor ◽  
Co2 Treatment ◽  
Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is still a major cause of neonatal death and disability as therapeutic hypothermia (TH) alone cannot afford sufficient neuroprotection. The present study investigated whether ventilation with molecular hydrogen (2.1% H2) or graded restoration of normocapnia with CO2 for 4 h after asphyxia would augment the neuroprotective effect of TH in a subacute (48 h) HIE piglet model. Piglets were randomized to untreated naïve, control-normothermia, asphyxia-normothermia (20-min 4%O2–20%CO2 ventilation; Tcore = 38.5 °C), asphyxia-hypothermia (A-HT, Tcore = 33.5 °C, 2–36 h post-asphyxia), A-HT + H2, or A-HT + CO2 treatment groups. Asphyxia elicited severe hypoxia (pO2 = 19 ± 5 mmHg) and mixed acidosis (pH = 6.79 ± 0.10). HIE development was confirmed by altered cerebral electrical activity and neuropathology. TH was significantly neuroprotective in the caudate nucleus but demonstrated virtually no such effect in the hippocampus. The mRNA levels of apoptosis-inducing factor and caspase-3 showed a ~10-fold increase in the A-HT group compared to naïve animals in the hippocampus but not in the caudate nucleus coinciding with the region-specific neuroprotective effect of TH. H2 or CO2 did not augment TH-induced neuroprotection in any brain areas; rather, CO2 even abolished the neuroprotective effect of TH in the caudate nucleus. In conclusion, the present findings do not support the use of these medical gases to supplement TH in HIE management.

Visual outcomes in children with neonatal hypoxic ischemic encephalopathy treated with therapeutic hypothermia

2021 ◽  
Author(s):  
Jerry Hsu ◽  
Noreen Shaikh ◽  
Hantamalala Ralay Ranaivo ◽  
Andrea C. Pardo ◽  
Rebecca B. Mets-Halgrimson
Keyword(s):  
Therapeutic Hypothermia ◽  
Hypoxic Ischemic Encephalopathy ◽  
Visual Outcomes ◽  
Ischemic Encephalopathy

scholarly journals Mammillary body atrophy and other MRI correlates of school-age outcome following neonatal hypoxic-ischemic encephalopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kim V. Annink ◽  
Linda S. de Vries ◽  
Floris Groenendaal ◽  
Rian M. J. C. Eijsermans ◽  
Manouk Mocking ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
Memory Function ◽  
Neurodevelopmental Outcome ◽  
Standard Of Care ◽  
Hypoxic Ischemic Encephalopathy ◽  
School Age ◽  
Brain Volumes ◽  
Mammillary Bodies ◽  
Memory Problems ◽  
Ischemic Encephalopathy

AbstractThe mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.

scholarly journals Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia

2017 ◽  
Vol 176 (10) ◽  
pp. 1295-1303 ◽  
Author(s):  
Hemananda Muniraman ◽  
Danielle Gardner ◽  
Jane Skinner ◽  
Anna Paweletz ◽  
Anitha Vayalakkad ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
Hepatic Injury ◽  
Hypoxic Ischemic Encephalopathy ◽  
And Function ◽  
Ischemic Encephalopathy

Blanket temperature during therapeutic hypothermia and outcomes in hypoxic ischemic encephalopathy

2022 ◽  
Author(s):  
John Flibotte ◽  
Abbot R. Laptook ◽  
Seetha Shankaran ◽  
Scott A. McDonald ◽  
Mariana C. Baserga ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
Hypoxic Ischemic Encephalopathy ◽  
Ischemic Encephalopathy
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