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Abstract
Therapeutic hypothermia is standard of care for infants with hypoxic ischemic encephalopathy. Murine models of hypoxic-ischemic injury exist; however, a well-established mouse model of therapeutic hypothermia following hypoxic-ischemic injury is lacking. The goal of this study was to develop a full-term-equivalent murine model of therapeutic hypothermia after hypoxia-ischemia and examine magnetic resonance imaging, behavior, and histology in a region and sex specific manner. Hypoxic-ischemic injury was induced at postnatal day 10 in C57BL6 mice using a modified Vannucci model. Mice were randomized to control, hypothermia (31˚C for 4h), or normothermia (36˚C) following hypoxic-ischemic injury and stratified by sex. T2-weighted magnetic resonance imaging was obtained at postnatal day 18 and 30 and regional and total cerebral and cerebellar volumes measured. Behavioral assessments were performed on postnatal day 14, 21, and 28. On postnatal day 18, normothermic mice had smaller cerebral volumes (p < 0.001 vs. controls and p = 0.009 vs. hypothermia), while at postnatal day 30 both injured groups had smaller volumes than controls. When stratified by sex, only normothermia treated male mice had smaller cerebral volumes (p = 0.001 vs. control; p = 0.008 vs. hypothermia) at postnatal day 18, which persisted at postnatal day 30 (p = 0.001 vs. control). Female mice had similar cerebral volumes between groups at both day 18 and 30. Cerebellar volumes of hypothermia treated male mice differed from control at day 18, but not at 30. Four hours of therapeutic hypothermia in this murine hypoxic-ischemic injury model provides sustained neuroprotection in the cerebrum of male mice. Due to variable degree of injury in female mice, response to therapeutic hypothermia is difficult to discern. Deficits in female behavior tests are not fully explained by imaging measures and likely represent injury not detectable by volume measurements alone.
Highlights
Therapeutic hypothermia (TH) is standard-of-care treatment for neonates with hypoxic ischemic (HI) encephalopathy [1, 2], a condition that affects 1.5 per 1000 newborns annually in developed nations [3]
Four hours of hypothermia following HI injury in this murine p10 model provided neuroprotection one week post-HI; neuroprotection did not persist twenty days post-HI in the group as a whole
When results were stratified for sex, neuroprotection was evident on both Magnetic resonance imaging (MRI) and behavioral testing in male mice out to p30
Summary
Therapeutic hypothermia (TH) is standard-of-care treatment for neonates with hypoxic ischemic (HI) encephalopathy [1, 2], a condition that affects 1.5 per 1000 newborns annually in developed nations [3]. TH is only partially neuroprotective, decreasing death and neurodevelopmental disability by one third [4,5,6]. Despite TH use in standard care of infants with HIE, there is no standardized mouse model of HI and TH with which to test new adjuvant therapies. Regional variability of HI injury has been well characterized in animal models [7,8,9,10]. There is no agreement on whether there is regional selectivity in the neuroprotection provided by TH after HI injury
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