Therapeutic hypothermia and hypoxia–ischemia in the term-equivalent neonatal rat: characterization of a translational preclinical model

Patel, Shyama D.; Pierce, Leslie; Ciardiello, Amber; Hutton, Alexandra; Paskewitz, Samuel; Aronowitz, Eric; Voss, Henning U.; Moore, Holly; Vannucci, Susan J.

doi:10.1038/pr.2015.100

Cited by 74 publications

(86 citation statements)

References 40 publications

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“…For example, the rotarod test failed to reveal significant differences between the control and the newborn rat model of HI at any time point until 5 weeks of age [42]. Lack of significant improvement in the novel objection test might be due to relatively less severe infarcts in our P13 rat model in comparison with infarcts that occurred in the P7 rats following the same Rice-Vannucci procedure [26,43,44]. In a study using term-equivalent rat pups subjected to unilateral HI injury and hypothermic intervention, differences in the discrimination index were shown only in the group that had severe damage but not in the group that had moderate damage [44].…”

Section: Discussionmentioning

confidence: 82%

“…Lack of significant improvement in the novel objection test might be due to relatively less severe infarcts in our P13 rat model in comparison with infarcts that occurred in the P7 rats following the same Rice-Vannucci procedure [26,43,44]. In a study using term-equivalent rat pups subjected to unilateral HI injury and hypothermic intervention, differences in the discrimination index were shown only in the group that had severe damage but not in the group that had moderate damage [44]. Secondly, the higher blood BHB levels in the BHB-treated rats do not necessarily reflect a higher cerebral BHB level, and, indeed, we did not directly measure the BHB concentration in the brain tissue or cerebrospinal fluid.…”

Section: Discussionmentioning

confidence: 87%

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Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy

Lee

Woo

et al. 2018

Dev Neurosci

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β-Hydroxybutyrate (BHB) is a representative ketone body that may play a role in the mitigation of neonatal hypoxic-ischemic encephalopathy by altering energy metabolism. This study aimed to investigate the neuroprotective efficacy of exogenous BHB administration in a suckling rat model after hypoxia-ischemia (HI). Thirteen-day-old (P13) rat pups were subjected to 120 min of hypoxia according to the Rice-Vannucci model. BHB (5.0 mmol/kg, HI-BHB) or vehicle (0.9% saline, HI-Veh) was administered 0, 2, 4, and 6 h after HI induction. Pathologic injury scores and the number of TUNEL-positive cells were evaluated on P15. Residual hemispheric volume was measured with T2-weighted MRI (on P27) and functional tests, such as the negative geotaxis test, rope suspension test, rotarod test, novel object recognition test, and cylinder test, were performed. Systemic ketosis (approx. 2.0–3.0 mM/L) was well tolerated by the rat pups with no difference in the mortality rate between both groups. Compared with the HI-Veh group, the HI-BHB group demonstrated significantly lower pathological scores as well as fewer TUNEL-positive cells. The intact residual hemispheric and hippocampal volumes were greater in the HI-BHB group than the HI-Veh group. However, the results of functional tests did not differ between both groups. Postischemic BHB administration reduced brain injury in suckling rats after HI. The safe clinical application of our animal model to human infants with HI requires further investigation.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 87%

Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy

Lee

Woo

et al. 2018

Dev Neurosci

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“…As recently reviewed, neonatal rats are closest to term equivalent at P10-P14 [17] . The responses to HI at P10 have been carefully characterized [29] . Even at P10-P14, healthy neonatal rodents often show significant spontaneous central hypothermia in the typical laboratory nesting environment [20] , and therefore they still require continuous core temperature monitoring and control.…”

Section: Discussionmentioning

confidence: 99%

In the Era of Therapeutic Hypothermia, How Well Do Studies of Perinatal Neuroprotection Control Temperature?

et al. 2016

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In the era of therapeutic hypothermia, reliable preclinical studies are integral to successfully identify neuroprotective strategies to further improve outcomes of encephalopathy at term. We reviewed preclinical neuroprotection studies reported between January 2014 and June 2016 to assess the use of effective temperature monitoring and control. As a secondary measure, we examined whether studies addressed other methodological issues such as stage of brain development, sex differences, the timing of the treatment relative to the insult, and the histological and functional endpoints used after hypoxia-ischemia. The extent and duration of temperature monitoring was highly inconsistent. Only a minority of papers monitored core (19/61; 31%) or brain temperature (3/61; 5%). Most (40/45) of the neuroprotectants either were likely to affect thermoregulation or their impact is unknown. In 85% of papers neonatal rodents were used (67% at P7); 51% of papers did not report the sex of the animals or tested the effect of potential neuroprotectants on just one sex. In 76% of studies, treatment was before or immediately after the insult (within the first 2 h), and few studies assessed long-term histological and behavioral outcomes. In conclusion, many recent preclinical neonatal studies cannot exclude the possibility that apparent neuroprotection might be related to drug-induced hypothermia or to other methodological choices. Close monitoring and control of brain temperature during, as well as for many days after, experimental hypoxia-ischemia are now critical to reliably develop new ways to improve neurodevelopmental outcomes after perinatal hypoxic-ischemic encephalopathy.

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“…A well-established rat model of term neonatal HIE (Vannucci model), [32][33][34][35] combining a left common carotid artery ligation and a 2-hour exposure to 8% oxygen, was used with 10-day-old rat pups as previously described, 3 because this model mimics the patterns of brain injury observed in human term asphyxiated newborns [32][33][34][35] and produces concomitant retinal injury. 3 Rats undergoing both the ligation and hypoxia were considered the HI group.…”

Section: Induction Of Term Neonatal Hiementioning

confidence: 99%

Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia

Jung

Johnstone

Khoja

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to investigate the effects of sildenafil on retinal injury following neonatal hypoxia-ischemia (HI) at term-equivalent age in rat pups.METHODS. Hypoxia-ischemia was induced in male Long-Evans rat pups at postnatal day 10 (P10) by a left common carotid ligation followed by a 2-hour exposure to 8% oxygen. Shamoperated rats served as the control group. Both groups were administered vehicle or 2, 10, or 50 mg/kg sildenafil, twice daily for 7 consecutive days. Retinal function was assessed by flash electroretinograms (ERGs) at P29, and retinal structure was assessed by retinal histology at P30.RESULTS. Hypoxia-ischemia caused significant functional (i.e., attenuation of the ERG a-wave and b-wave amplitudes and photopic negative response) and structural (i.e., thinning of the total retina, especially the inner retinal layers) retinal damage in the left eyes (i.e., ipsilateral to the carotid ligation). Treatment with the different doses of sildenafil led to a dose-dependent increase in the amplitudes of the ERG a-and b-waves and of the photopic negative response in HI animals, with higher doses associated with greater effect sizes. Similarly, a dose response was observed in terms of improvements in the retinal layer thicknesses.CONCLUSIONS. Hypoxia-ischemia at term-equivalent age induced functional and structural damage mainly to the inner retina. Treatment with sildenafil provided a dose-dependent recovery of retinal function and structure.

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Therapeutic hypothermia and hypoxia–ischemia in the term-equivalent neonatal rat: characterization of a translational preclinical model

Cited by 74 publications

References 40 publications

Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy

Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy

In the Era of Therapeutic Hypothermia, How Well Do Studies of Perinatal Neuroprotection Control Temperature?

Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia

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