Limitations of Mild, Moderate, and Profound Hypothermia in Protecting Developing Hippocampal Neurons After Simulated Ischemia

Gregersen, Maren; Lee, Deok Hee; Gabatto, Pablo; Bickler, Philip E.

doi:10.1089/ther.2013.0017

Cited by 9 publications

(4 citation statements)

References 54 publications

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“…In our experimental settings, we cooled culture slices at 33 ° C, a condition considered to be moderate hypothermia in animal models and humans [24]. Lower temperatures were not adopted because they could be detrimental to developing hippocampal neurons [25], increasing the possibility of hypothermia-induced side effects. We found that cooling hippocampal slices at 33 ° C immediately after OGD for 24 h had a maximal protective effect, in line with previous findings [10].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

et al. 2018

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Background: Hypoxic-ischemic encephalopathy is a major cause of neonatal morbidity. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Thus, adjunctive therapies, such as melatonin, are needed to provide additional neuroprotection. Objectives: The aim of this study was to determine a range of melatonin concentrations that could result in neuroprotective synergy with hypothermia. Methods: Hypoxia-ischemia was simulated by transient oxygen-glucose deprivation (OGD) in organotypic hippocampal slice cultures derived from neonatal rats. Cell damage was quantified by propidium iodide (PI) labeling. Results: Melatonin reduced OGD- induced cell death in a concentration-dependent manner (1–100 μM) with an EC₅₀ of about 25 μM. Hypothermia attenuated cell death in a time-dependent manner, with a nearly full protection upon 24-h exposure (78%) and partial protection (40%) upon 6-h exposure. When submaximal effective concentrations of melatonin (25 or 50 μM, resulting in 54 and 64% protection) were combined with 6 h of hypothermia, nearly full protection (73 and 78%, respectively; p < 0.05 and p < 0.01) was observed. Conclusion: Melatonin acts in synergy with hypothermia in attenuating OGD-induced damage in organotypic hippocampal cultures. This reductionist approach allows the determination of a range of concentrations of melatonin capable of enhancing hypothermic neuroprotection. This information, coupled with pharmacokinetic data, will help to define the therapeutic dosage of melatonin in vivo and, ultimately, in patients.

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Section: Discussionmentioning

confidence: 99%

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

et al. 2018

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“…61 Using animal and in vitro models, mild to moderate therapeutic hypothermia has been shown to reduce hippocampal cell death following an hypoxic or ischaemic insult. 62 However, while patients with perinatal asphyxia experience an acute phase of hypoxia 63 , more prolonged exposure to hypoxia may exist in the patient groups described in this review. Furthermore, hypothermia likely does not protect the hippocampus against the other types of harmful conditions associated with critical illness.…”

Section: Neuroprotectionmentioning

confidence: 95%

Memory deficits following neonatal critical illness: a common neurodevelopmental pathway

Schiller

IJsselstijn

Hoskote

et al. 2018

The Lancet Child & Adolescent Health

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Over the past decade, evidence has emerged that children growing up after neonatal critical illness, irrespective of underlying diagnosis, are at risk of memory impairment and academic problems. These difficulties are manifest even when intelligence is within the normal range. In this Review, we propose a common neurodevelopmental pathway following neonatal critical illness by showing that survivors of preterm birth, congenital heart disease, and severe respiratory failure share an increased risk of long-term memory deficits and associated hippocampal alterations. Rather than a consequence of underlying diagnosis, we suggest that this shared vulnerability is probably related to common conditions associated with neonatal critical illness, including hypoxia, neuroinflammation, stress, exposure to anaesthetics, or a complex interplay of these factors at different postconceptional ages. Future work should be aimed at improvement of early identification of patients at risk and evaluation of intervention modalities, such as exercise or cognitive training.

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“…Some authors (McManus et al, ; Rytter et al, ) found that postischemic hypothermia was inefficient to protect against ischemia contrary to intraischemic hypothermia, whereas other authors (Lawrence et al, ) demonstrated neuroprotection with delayed initiation of prolonged hypothermia. More recently, Gregersen et al () compared the protective effect of hypothermia of different degrees and durations. They showed that the most efficient protocol was a 4‐ to 6‐h mild hypothermia starting immediately after OGD while delayed (4 h) or longer hypothermia (24 h) had no effect.…”

Section: Introductionmentioning

confidence: 99%

Regional and time-dependent neuroprotective effect of hypothermia following oxygen-glucose deprivation

et al. 2014

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The neuroprotective effect of hypothermia has been demonstrated in in vivo and in vitro models of cerebral ischemia. In regard to the hippocampus, previous studies have mainly focused on CA1 pyramidal neurons, which are very vulnerable to ischemia. But the dentate gyrus (DG), in which neuronal proliferation occurs, can also be damaged by ischemia. In this study, we explored the neuroprotective effect of postischemic hypothermia in different areas of the hippocampus after mild or severe ischemia. Organotypic hippocampal slice cultures were prepared from 6- to 8-day-old rats and maintained for 12 days. Cultures were exposed to 25 or 35 min of oxygen and glucose deprivation (OGD). Neuronal damage was quantified after 6, 24, 48, and 72 h by propidium iodide fluorescence. Mild hypothermia (33°C) was induced 1 h after the end of OGD and was maintained for a period of 24 h. Short OGD produced delayed neuronal damage in the CA1 area and in the DG and to a lesser extend in the CA3 area. Damage in CA1 pyramidal cells was totally prevented by hypothermia whereas neuroprotection was limited in the DG. Thirty-five-minute OGD induced more rapid and more severe cell death in the three regions. In this case, hypothermia induced 1 h after OGD was unable to protect CA1 pyramidal cells whereas hypothermia induced during OGD was able to prevent cell loss. This study provides evidence that neuroprotection by hypothermia is limited to specific areas and depends on the severity of the ischemia.

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Limitations of Mild, Moderate, and Profound Hypothermia in Protecting Developing Hippocampal Neurons After Simulated Ischemia

Cited by 9 publications

References 54 publications

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

Memory deficits following neonatal critical illness: a common neurodevelopmental pathway

Regional and time-dependent neuroprotective effect of hypothermia following oxygen-glucose deprivation

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