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A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy
Published on: May 16, 2015
Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic
Ryan M McAdams1, Bobbi Fleiss, Christopher Traudt
1Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA, USA.
Insights
Therapeutic hypothermia plus erythropoietin (TH + Epo) showed long-term safety in a primate model of hypoxic-ischemic encephalopathy (HIE). This treatment reduced brain pathology in animals that developed cerebral palsy (CP).
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Pediatric Neurology
Background:
- Cerebral palsy (CP) is a common childhood motor disability.
- Hypoxic-ischemic encephalopathy (HIE) is a significant contributor to CP.
- Limited long-term neuropathological data exists for the HIE-CP association.
Purpose of the Study:
- To investigate the long-term neuropathological effects of HIE in a nonhuman primate model.
- To evaluate the safety and efficacy of therapeutic hypothermia (TH) and erythropoietin (Epo) in mitigating HIE-induced brain injury.
- To correlate neuropathological findings with the development and severity of CP.
Main Methods:
- Thirty-four term macaques underwent cesarean delivery, with 25 experiencing umbilical cord occlusion (UCO) to induce perinatal asphyxia.
- UCO animals were randomized to saline, TH, or TH + Epo treatment.
- Serial developmental assessments, MRI with diffusion tensor imaging (DTI), necropsy, and histological/immunohistochemical analyses were performed at 9 months.
Main Results:
- All UCO animals met criteria for moderate-to-severe HIE.
- TH + Epo treatment resulted in no deaths, moderate-to-severe CP, or long-term neuropathological toxicity.
- CP animals exhibited white-matter abnormalities (decreased fractional anisotropy), cortical neuron loss, increased brainstem glial scarring, and cerebellar changes compared to controls.
Conclusions:
- TH + Epo demonstrates long-term safety and reduces brain pathology in an HIE primate model.
- CP development in this model correlates with white-matter tract abnormalities, gray/white matter histopathology, and brainstem injury.
- This HIE model is suitable for further research into the brainstem injury-CP relationship.
Background:
Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited.
Methodology:
Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed.
Results:
All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP.
Conclusions/Significance:
In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.
