scholarly journals Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy

2017 ◽  
Vol 39 (1-4) ◽  
pp. 124-140 ◽  
Author(s):  
Ryan M. McAdams ◽  
Bobbi Fleiss ◽  
Christopher Traudt ◽  
Leslie Schwendimann ◽  
Jessica M. Snyder ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
White Matter ◽  
Cesarean Section ◽  
Nonhuman Primate ◽  
Cortical Neurons ◽  
Macaca Nemestrina ◽  
Hypoxic Ischemic Encephalopathy ◽  
Brainstem Injury ◽  
Ischemic Encephalopathy

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.

scholarly journals Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates

2017 ◽  
Vol 39 (1-4) ◽  
pp. 107-123 ◽  
Author(s):  
Ryan M. McAdams ◽  
Ronald J. McPherson ◽  
Raj P. Kapur ◽  
Sandra E. Juul
Keyword(s):  
Brain Injury ◽  
Cesarean Section ◽  
Brain Stem ◽  
In Utero ◽  
Negative Regulator ◽  
Macaca Nemestrina ◽  
Hypoxic Ischemic Encephalopathy ◽  
Microscopy Imaging ◽  
Human Neonates ◽  
Ischemic Encephalopathy

Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O2 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated ultrastructural white matter abnormalities, characterized by perinuclear vacuolation and axonal dilation, in 3 of 4 animals. Immunolabeling of Nogo-A, a negative regulator of neuronal growth, was not increased in the injured brains compared to 2 control animals. Using GC × GC-TOFMS, we identified metabolites previously recognized as potential biomarkers of perinatal asphyxia. The basal ganglia-thalamus-brain stem injury produced by UCO is consistent with the deep nuclear/brainstem injury pattern seen in human neonates after severe, abrupt hypoxic-ischemic insults. The UCO model permits timely detection of biomarkers associated with specific patterns of neonatal brain injury, and it may ultimately be useful for validating therapeutic strategies to treat neonatal HIE.

scholarly journals Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin

2021 ◽  
pp. 0271678X2199143
Author(s):  
Thomas R Wood ◽  
Phuong T Vu ◽  
Bryan A Comstock ◽  
Janessa B Law ◽  
Dennis E Mayock ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
Injury Severity ◽  
Response To Therapy ◽  
Macaca Nemestrina ◽  
Hypoxic Ischemic Encephalopathy ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Long Term Outcome ◽  
Severity Of Injury ◽  
Ischemic Encephalopathy

Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine Macaca nemestrina were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h–6h, and significantly lower MCP-4 and MDC at 24 h–72h, respectively. IL-12p40 was lower at 24 h–72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.

scholarly journals Can diffusion tensor imaging predict cerebral palsy in term neonates with hypoxic ischemic encephalopathy?

2019 ◽  
Vol 50 (1) ◽  
Author(s):  
Ahmed A. ElBeheiry ◽  
Mohamed A. Elgamal ◽  
Ashraf N. Ettaby ◽  
Tarek E. Omar ◽  
Adham O. Badeib
Keyword(s):  
Cerebral Palsy ◽  
Diffusion Tensor Imaging ◽  
White Matter ◽  
Diffusion Tensor ◽  
Hypoxic Ischemic Encephalopathy ◽  
Early Prediction ◽  
Imaging Features ◽  
Term Neonates ◽  
Conventional Mri ◽  
Ischemic Encephalopathy

Abstract Background Hypoxic ischemic encephalopathy (HIE) is a principal cause of pediatric mortality and morbidity, with possible neurologic sequel, such as cerebral palsy. Thus, it is of outmost importance to assess, shortly after birth, the prognosis of neonates with HIE. The purpose of this study was to assess the role of diffusion tensor imaging (DTI) in early prediction of cerebral palsy in term neonates with HIE. The study was carried out initially on 35 full-term neonates admitted to the neonatal intensive care unit (NICU) with manifestations of HIE. Imaging was done at the age of 10.32 ± 1.78 days including conventional MRI and DTI (for detection of white matter injury). Thirty-three infants out of the initially examined 35 were finally evaluated at the age of 1 year with the Bayley Scales of Infant and Toddler Development 3rd edition for development of cerebral palsy. Another MRI brain study was done at 1 year of age to evaluate the final brain imaging features and assess white matter integrity. Results Seventeen infants (17/33) were clinically normal while 16 (16/33) acquired cerebral palsy (CP) by the end of the first year. Initial conventional MRI showed false-negative results in 7 patients. Diffusion tensor imaging showed significantly different reduction in fractional anisotropy within the examined brain regions of interest (ROIs) between CP and normal outcome infants mostly at the posterior limb of the internal capsule, centrum semiovale, and corpus callosum with significant cutoff values of ≤ 0.435, ≤ 0.235, and ≤ 0.45, respectively. Conclusions Diffusion tensor imaging is a valuable tool for early prediction of CP in HIE neonates.

scholarly journals The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy

2021 ◽  
Vol 22 (9) ◽  
pp. 4822
Author(s):  
Viktória Kovács ◽  
Gábor Remzső ◽  
Tímea Körmöczi ◽  
Róbert Berkecz ◽  
Valéria Tóth-Szűki ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Kynurenic Acid ◽  
Neuronal Damage ◽  
Brain Regions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Hippocampal Field ◽  
Power Spectral ◽  
Density Values ◽  
Ischemic Encephalopathy

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.

scholarly journals Protective Effects ofN-Acetyl-L-Cysteine in Human Oligodendrocyte Progenitor Cells and Restoration of Motor Function in Neonatal Rats with Hypoxic-Ischemic Encephalopathy

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Dongsun Park ◽  
Kyungha Shin ◽  
Ehn-Kyoung Choi ◽  
Youngjin Choi ◽  
Ja-Young Jang ◽  
...  
Keyword(s):  
White Matter ◽  
Progenitor Cells ◽  
Hypoxic Ischemic Encephalopathy ◽  
Oligodendrocyte Progenitor Cells ◽  
Protective Effects ◽  
Neonatal Rats ◽  
Motor Functions ◽  
Ischemic Encephalopathy

Objective. Since oligodendrocyte progenitor cells (OPCs) are the target cells of neonatal hypoxic-ischemic encephalopathy (HIE), the present study was aimed at investigating the protective effects ofN-acetyl-L-cysteine (NAC), a well-known antioxidant and precursor of glutathione, in OPCs as well as in neonatal rats.Methods. Inin vitrostudy, protective effects of NAC on KCN cytotoxicity in F3.Olig2 OPCs were investigated via MTT assay and apoptotic signal analysis. Inin vivostudy, NAC was administered to rats with HIE induced by hypoxia-ischemia surgery at postnatal day 7, and their motor functions and white matter demyelination were analyzed.Results. NAC decreased KCN cytotoxicity in F3.Olig2 cells and especially suppressed apoptosis by regulating Bcl2 and p-ERK. Administration of NAC recovered motor functions such as the using ratio of forelimb contralateral to the injured brain, locomotor activity, and rotarod performance of neonatal HIE animals. It was also confirmed that NAC attenuated demyelination in the corpus callosum, a white matter region vulnerable to HIE.Conclusion. The results indicate that NAC exerts neuroprotective effectsin vitroandin vivoby preserving OPCs, via regulation of antiapoptotic signaling, and that F3.Olig2 human OPCs could be a good tool for screening of candidates for demyelinating diseases.

scholarly journals Neurodevelopmental outcome of babies with hypoxic ischemic encephalopathy

2017 ◽  
Vol 5 (7) ◽  
pp. 3197
Author(s):  
Sirajuddin Nazeer ◽  
Senthilkumar K. ◽  
Thangavel A. ◽  
Uma Maheswari M.
Keyword(s):  
Neurological Outcome ◽  
Neurodevelopmental Outcome ◽  
Hypoxic Ischemic Encephalopathy ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Mri Brain ◽  
Early Markers ◽  
Cdc Grading ◽  
Ischemic Encephalopathy

Background: The aim of the study was to find out the neurodevelopmental outcome of babies with hypoxic ischemic encephalopathy at 6 months of age and to predict early markers of abnormal neurological outcome in those babies.Methods: 50 babies admitted with hypoxic ischemic encephalopathy were enrolled in this prospective study and followed up at 3 and 6 months of age at Mahatma Gandhi Memorial Government Hospital, Trichy. The neurological outcome of the babies was assessed by CDC grading of motor milestones, Trivandrum development screening chart, Amiel Tison angles head circumference and weight measured. USG cranium was done for all the babies and MRI brain was done in babies with abnormal neuro sonogram and abnormal outcome. Vision and hearing were tested clinically.Results: The incidence of abnormal neurological outcome was 14%. The early markers predicting abnormal neurological sequele are identified.Conclusions: Early identification of abnormal neuro behaviour helps in starting early intervention to improve the long term outcome.

Variants of the OLIG2 Gene are Associated with Cerebral Palsy in Chinese Han Infants with Hypoxic–Ischemic Encephalopathy

2018 ◽  
Vol 21 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Liya Sun ◽  
Lei Xia ◽  
Mingtai Wang ◽  
Dengna Zhu ◽  
Yangong Wang ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Hypoxic Ischemic Encephalopathy ◽  
Chinese Han ◽  
Ischemic Encephalopathy

scholarly journals Prognostic role of acute kidney injury on long-term outcome in infants with hypoxic-ischemic encephalopathy

2019 ◽  
Vol 35 (3) ◽  
pp. 477-483 ◽  
Author(s):  
Francesco Cavallin ◽  
Giulia Rubin ◽  
Enrico Vidal ◽  
Elisa Cainelli ◽  
Luca Bonadies ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Hypoxic Ischemic Encephalopathy ◽  
Prognostic Role ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Ischemic Encephalopathy
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