Seizure Susceptibility Correlates with Brain Injury in Male Mice Treated with Hypothermia after Neonatal Hypoxia-Ischemia

2018 ◽  
Vol 40 (5-6) ◽  
pp. 576-585 ◽  
Author(s):  
Melanie A. McNally ◽  
Raul Chavez-Valdez ◽  
Ryan J. Felling ◽  
Debra L. Flock ◽  
Frances J. Northington ◽  
...  
Keyword(s):  
Brain Injury ◽  
Seizure Susceptibility ◽  
Neonatal Seizures ◽  
Sex Dimorphism ◽  
Significant Morbidity ◽  
Neonatal Brain ◽  
Cortical Injury ◽  
Hypoxia Ischemia ◽  
Underlying Mechanisms ◽  
Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy is a common neonatal brain injury associated with significant morbidity and mortality despite the administration of therapeutic hypothermia (TH). Neonatal seizures and subsequent chronic epilepsy are frequent in this patient population and current treatments are partially effective. We used a neonatal murine hypoxia-ischemia (HI) model to test whether the severity of hippocampal and cortical injury predicts seizure susceptibility 8 days after HI and whether TH mitigates this susceptibility. HI at postnatal day 10 (P10) caused hippocampal injury not mitigated by TH in male or female pups. TH did not confer protection against flurothyl seizure susceptibility at P18 in this model. Hippocampal (R2 = 0.33, p = 0.001) and cortical (R2 = 0.33, p = 0.003) injury directly correlated with seizure susceptibility in male but not female pups. Thus, there are sex-specific consequences of neonatal HI on flurothyl seizure susceptibility in a murine neonatal HI model. Further studies are necessary to elucidate the underlying mechanisms of sex dimorphism in seizure susceptibility after neonatal HI.

scholarly journals Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model

2020 ◽  
Author(s):  
Brennan J. Sullivan ◽  
Pavel A. Kipnis ◽  
Brandon M. Carter ◽  
Shilpa D. Kadam
Keyword(s):  
Mouse Model ◽  
Neonatal Seizure ◽  
Seizure Susceptibility ◽  
Neonatal Seizures ◽  
First Line ◽  
Chloride Homeostasis ◽  
Epilepsy Models ◽  
And Function ◽  
Ischemic Encephalopathy

AbstractNeonatal seizures pose a clinical challenge for their early detection, acute management, and mitigation of long-term comorbidities. A major cause of neonatal seizures is hypoxic-ischemic encephalopathy that results in seizures that are frequently refractory to the first-line anti-seizure medication phenobarbital (PB). One proposed mechanism for PB-inefficacy during neonatal seizures is the reduced expression and function of the neuron-specific K+/Cl− cotransporter 2 (KCC2), the main neuronal Cl− extruder that maintains chloride homeostasis and influences the efficacy of GABAergic inhibition. To determine if PB-refractoriness after ischemic neonatal seizures is dependent upon KCC2 hypofunction and can be rescued by KCC2 functional enhancement, we investigated the recently developed KCC2 functional enhancer CLP290 in a CD-1 mouse model of refractory ischemic neonatal seizures quantified with vEEG. We report that acute CLP290 intervention can rescue PB-resistance, KCC2 expression, and the development of epileptogenesis after ischemic neonatal seizures. KCC2 phosphorylation sites have a strong influence over KCC2 activity and seizure susceptibility in adult experimental epilepsy models. Therefore, we investigated seizure susceptibility in two different knock-in mice in which either phosphorylation of S940 or T906/T1007 was prevented. We report that KCC2 phosphorylation regulates both neonatal seizure susceptibility and CLP290-mediated KCC2 functional enhancement. Our results validate KCC2 as a clinically relevant target for refractory neonatal seizures and provide insights for future KCC2 drug development.

scholarly journals Circulating Tight-Junction Proteins Are Potential Biomarkers for Blood-Brain Barrier Function in a Model of Neonatal Hypoxic/Ischemic Brain Injury

2020 ◽  
Author(s):  
Axel Erik Andersson ◽  
Carina Mallard ◽  
Carl Joakim Ek
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Brain Injuries ◽  
Brain Barrier ◽  
Neonatal Brain ◽  
Ischemic Brain ◽  
Blood Brain ◽  
Hypoxia Ischemia ◽  
The Brain ◽  
Junction Proteins

Abstract BackgroundNeonatal hypoxia-ischemia often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal brain pathologies but there is a lack of diagnostic tools to evaluate the brain vascular health of neonates in a clinical setting. Measurement of blood-brain barrier tight-junction proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury.MethodsThe levels of TJ-proteins (occluding, claudin-5, and zonula occludens-1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood-brain barrier function were measured in a clinically relevant hypoxia/ischemia model in neonatal rats.ResultsTemporally acute elevated levels of occludin and claudin-5 could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood-brain barrier-permeability at 6 and 24h after hypoxia/ischemia.ConclusionsLevels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood-brain barrier-impairment and have promise as early biomarkers for cerebral vascular health and as a tool for risk assessment of neonatal brain injuries.

Long non-coding RNA Snhg3 protects against hypoxia/ischemia-induced neonatal brain injury

2020 ◽  
Vol 112 ◽  
pp. 104343 ◽  
Author(s):  
Qing Yang ◽  
Ming-Fu Wu ◽  
Li-Hua Zhu ◽  
Li-Xing Qiao ◽  
Rui-Bin Zhao ◽  
...  
Keyword(s):  
Brain Injury ◽  
Neonatal Brain ◽  
Neonatal Brain Injury ◽  
Non Coding Rna ◽  
Hypoxia Ischemia ◽  
Long Non Coding Rna

GAS5 silencing protects against hypoxia/ischemia-induced neonatal brain injury

2018 ◽  
Vol 497 (1) ◽  
pp. 285-291 ◽  
Author(s):  
Rui-bin Zhao ◽  
Li-hua Zhu ◽  
Jia-Ping Shu ◽  
Li-Xing Qiao ◽  
Zheng-Kun Xia
Keyword(s):  
Brain Injury ◽  
Neonatal Brain ◽  
Neonatal Brain Injury ◽  
Hypoxia Ischemia

scholarly journals Unbiased Quantification of Subplate Neuron Loss following Neonatal Hypoxia-Ischemia in a Rat Model

2017 ◽  
Vol 39 (1-4) ◽  
pp. 171-181 ◽  
Author(s):  
Alexandra Mikhailova ◽  
Naveena Sunkara ◽  
Patrick S. McQuillen
Keyword(s):  
Brain Injury ◽  
Lower Layer ◽  
Cell Number ◽  
Cortical Layer ◽  
Rodent Model ◽  
Cortical Layers ◽  
Cortical Injury ◽  
Neonatal Hypoxia ◽  
Subplate Neurons ◽  
Hypoxia Ischemia

Background: Cellular targets of neonatal hypoxia-ischemia (HI) include both oligodendrocyte and neuronal lineages with differences in the patterns of vulnerable cells depending upon the developmental stage at which the injury occurs. Injury to the developing white matter is a characteristic feature of human preterm brain injury. Data are accumulating, however, for neuronal injury in the developing cerebral cortex. In the most widely used rodent model of preterm HI brain injury, conflicting data have been reported regarding the sensitivity of subplate neurons to early neonatal HI, with some reports of selective vulnerability and others that find no increased loss of subplate neurons in comparison with other cortical layers. Methods used to identify subplate neurons and quantify their numbers vary across studies. Objective: To use recently developed cortical layer-specific markers quantified with definitive stereologic methods to determine the magnitude and specificity of subplate neuron cell loss following neonatal HI in a rodent model. Methods: Postnatal day 2 (P2) rats underwent right common carotid artery coagulation followed by 2-3 h of hypoxia (5.6% oxygen). Categorically moderately injured brains were stained with subplate and cortical layer III-V markers (Complexin3 and Foxp1, respectively) at P8 and P21 (Foxp1 only). An Optical Fractionator was used to quantify subplate and middle/lower cortical neuronal numbers and these were compared across groups (naive control, hypoxia hemisphere, and HI hemisphere). Results: Following HI at P2 in rats, the total Complexin3-expressing subplate neuron number decreases significantly in the HI hemisphere compared with naive controls or hypoxia alone (HI vs. control 26,747 ± 7,952 vs. 35,468 ± 8,029, p = 0.04; HI vs. hypoxia, 26,747 ± 7,952 vs. 40,439 ± 7,363, p = 0.003). In contrast, the total Foxp1-expressing layer III-V cell number did not differ across the 3 conditions at P8 (HI vs. control 1,195,085 ± 436,609 vs. 1,234,640 ± 178,540, p = 0.19; HI vs. hypoxia, 1,195,085 ± 436,609 vs. 1,289,195 ± 468,941, p = 0.35) and at P21 (HI vs. control 1,265,190 ± 48,089 vs. 1,195,632 ± 26,912, p = 0.19; HI vs. hypoxia, 1,265,190 ± 48,089 vs. 1,309,563 ± 41,669, p = 0.49). Conclusions: There is significant biological variability inherent in both the subplate neuron cell number and the pattern and severity of cortical injury following HI at P2 in rats. Despite this variability, the subplate neuron cell number is lower following P2 HI in animals with mild or moderate cortical injury, whereas the middle-to-lower-layer cortical neuronal number is unchanged. In more severe cases, neurons are lost from the lower cortical layers, suggesting a relative vulnerability of subplate neurons.

scholarly journals Circulating tight-junction proteins are potential biomarkers for blood–brain barrier function in a model of neonatal hypoxic/ischemic brain injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
E. Axel Andersson ◽  
Carina Mallard ◽  
C. Joakim Ek
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Brain Injuries ◽  
Vascular Dysfunction ◽  
Brain Barrier ◽  
Neonatal Brain ◽  
Ischemic Brain ◽  
Blood Brain ◽  
Hypoxia Ischemia ◽  
The Brain

Abstract Background Neonatal encephalopathy often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal neurological disorders but there is a lack of diagnostic tools to evaluate the brain vascular dysfunction of neonates in the clinical setting. Measurement of blood–brain barrier tight-junction (TJ) proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury. Methods The levels of TJ-proteins (occluding, claudin-5, and zonula occludens protein 1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood–brain barrier function via 14C-sucrose (342 Da) and Evans blue extravasation were measured in a hypoxia/ischemia brain-injury model in neonatal rats. Results Time-dependent changes of occludin and claudin-5 levels could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24 h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood–brain barrier-permeability at 6 and 24 h after hypoxia/ischemia. Conclusions Levels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood–brain barrier-impairment and have promise as early biomarkers for cerebral vascular dysfunction and as a tool for risk assessment of neonatal brain injuries.

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