Early Detection of Hypothermic Neuroprotection Using T2-Weighted Magnetic Resonance Imaging in a Mouse Model of Hypoxic Ischemic Encephalopathy.

Sydney E Doman,Maxine S Garcia,Sujatha Kannan,Christina L Nemeth,Mary Ann Wilson,Akanksha Girish,Michael V Johnston,Gabrielle T Drummond,Jiangyang Zhang,Patrice Carr,Ali Fatemi

doi:10.3389/fneur.2018.00304

Abstract

Perinatal hypoxic-ischemic encephalopathy (HIE) can lead to neurodevelopmental disorders, including cerebral palsy. Standard care for neonatal HIE includes therapeutic hypothermia, which provides partial neuroprotection; magnetic resonance imaging (MRI) is often used to assess injury and predict outcome after HIE. Immature rodent models of HIE are used to evaluate mechanisms of injury and to examine the efficacy and mechanisms of neuroprotective interventions such as hypothermia. In this study, we first confirmed that, in the CD1 mouse model of perinatal HIE used for our research, MRI obtained 3 h after hypoxic ischemia (HI) could reliably assess initial brain injury and predict histopathological outcome. Mice were subjected to HI (unilateral carotid ligation followed by exposure to hypoxia) on postnatal day 7 and were imaged with T2-weighted MRI and diffusion-weighted MRI (DWI), 3 h after HI. Clearly defined regions of increased signal were comparable in T2 MRI and DWI, and we found a strong correlation between T2 MRI injury scores 3 h after HI and histopathological brain injury 7 days after HI, validating this method for evaluating initial injury in this model of HIE. The more efficient, higher resolution T2 MRI was used to score initial brain injury in subsequent studies. In mice treated with hypothermia, we found a significant reduction in T2 MRI injury scores 3 h after HI, compared to normothermic littermates. Early hypothermic neuroprotection was maintained 7 days after HI, in both T2 MRI injury scores and histopathology. In the normothermic group, T2 MRI injury scores 3 h after HI were comparable to those obtained 7 days after HI. However, in the hypothermic group, brain injury was significantly less 7 days after HI than at 3 h. Thus, early neuroprotective effects of hypothermia were enhanced by 7 days, which may reflect the additional 3 h of hypothermia after imaging or effects on later mechanisms of injury, such as delayed cell death and inflammation. Our results demonstrate that hypothermia has early neuroprotective effects in this model. These findings suggest that hypothermia has an impact on early mechanisms of excitotoxic injury and support initiation of hypothermic intervention as soon as possible after diagnosis of HIE.

Highlights

Perinatal hypoxic-ischemic encephalopathy (HIE) is a childbirth complication most commonly induced by intrauterine asphyxia [1]
The injury was comparable using these methods, but T2 magnetic resonance imaging (MRI) provided a more detailed assessment of the extent and regional distribution of injury, with less time required for imaging, at higher resolution, than that required for diffusion-weighted MRI (DWI). (A lower resolution for DWI was necessitated by overall imaging/anesthesia time constraints and a voxel size permitting adequate diffusion signals.) The higher resolution T2 MRI were obtained using much shorter imaging times that limited the amount of additional anesthesia and minimized potential interference with thermal control
A secondary goal was to optimize imaging for efficient assessment of initial injury in 10–20 subjects within an imaging session, while limiting the amount of additional anesthesia and potential interference with thermal control. We found that both imaging methods detected brain injury with similar extent and distribution

Summary

Introduction

Perinatal hypoxic-ischemic encephalopathy (HIE) is a childbirth complication most commonly induced by intrauterine asphyxia [1]. Neonatal HIE can lead to a wide spectrum of neurodevelopmental disorders, most notably cerebral palsy (CP) [2]. While CP is a non-progressive disorder, HIE injury is a dynamic process. Injury begins when cerebral blood flow and oxygen delivery to the brain are impaired, resulting in primary energy failure [3,4,5]. Secondary energy failure occurs 6–48 h later, from a combination of oxidative stress, excitotoxicity, and inflammation [6, 7]. The window between primary and secondary energy failure provides a critical period for intervention to mitigate or altogether prevent the effects of secondary energy failure [8]. Classification of HIE severity may allow more appropriate intervention, such as identification of patients who would benefit from more aggressive or pharmaceutical treatment [9]

Methods

Results

Conclusion