Rewarming from Therapeutic Hypothermia Induces Cortical Neuron Apoptosis in a Swine Model of Neonatal Hypoxic–Ischemic Encephalopathy

Wang, Bing; Armstrong, James C.; Lee, Jeong Hoo; Bhalala, Utpal; Kulikowicz, Ewa; Zhang, Hui; Reyes, Michael; Moy, Nicole; Spicer, Dawn; Zhu, Junchao; Yang, Zixiao; Koehler, Raymond C.; Martin, Lee J.; Lee, Jennifer K.

doi:10.1038/jcbfm.2014.245

Cited by 59 publications

(102 citation statements)

References 46 publications

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“…Research on hyperthermia is lagging and further study of the underlying molecular mechanism is needed. It is known that apoptosis contributes to hyperthermia-induced tumor killing alone or when combined with other therapies [36]. Initiation of apoptosis directly regulates cell fate decisions and the ratio of Bcl-2 family members is a crucial modulating factor in the process [37].…”

Section: Resultsmentioning

confidence: 99%

Effective elimination of liver cancer stem-like cells by CD90 antibody targeted thermosensitive magnetoliposomes

Yang

Miao

et al. 2016

Oncotarget

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AimTo investigate the use of thermosensitive magnetoliposomes (TMs) loaded with magnetic iron oxide (Fe3O4) and the anti-cancer stem cell marker CD90 (CD90@TMs) to target and kill CD90+ liver cancer stem cells (LCSCs).MethodsThe hepatocellular carcinoma cell line Huh7 was used to separate CD90+ LCSCs by magnetic-activated cell sorting. CD90@TMs was characterized and their ability to target CD90+ LCSCs was determined. Experiments were used to investigate whether CD90@TMs combined with magnetic hyperthermia could effectively eliminate CD90+ LCSCs.ResultsThe present study demonstrated that CD90+ LCSCs with stem cells properties were successfully isolated. We also successfully prepared CD90@TMs that was almost spherical and uniform with an average diameter of 130±4.6 nm and determined that magnetic iron oxide could be incorporated and retained a superparamagnetic response. CD90@TMs showed good targeting and increased inhibition of CD90+ LCSCs in vitro and in vivo compared to TMs.ConclusionCD90@TMs can be used for controlled and targeted delivery of anticancer drugs, which may offer a promising alternative for HCC therapy.

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Section: Resultsmentioning

confidence: 99%

Effective elimination of liver cancer stem-like cells by CD90 antibody targeted thermosensitive magnetoliposomes

Yang

Miao

et al. 2016

Oncotarget

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“…Following 72 hours of cooling, infants should be slowly rewarmed (0.5°/hour). This is based on animal data showing increased seizures68 and increased cortical apoptosis69 with rapid rewarming. Longer or deeper cooling to <33.5° and/or for >72 hours has not been shown to be of benefit, and is harmful 70…”

Section: Neuroprotective Therapy In Hiementioning

confidence: 99%

Management and investigation of neonatal encephalopathy: 2017 update

Martinello

Hart

Yap

et al. 2017

Arch Dis Child Fetal Neonatal Ed

157

122

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This review discusses an approach to determining the cause of neonatal encephalopathy, as well as current evidence on resuscitation and subsequent management of hypoxic-ischaemic encephalopathy (HIE). Encephalopathy in neonates can be due to varied aetiologies in addition to hypoxic-ischaemia. A combination of careful history, examination and the judicious use of investigations can help determine the cause. Over the last 7 years, infants with moderate to severe HIE have benefited from the introduction of routine therapeutic hypothermia; the number needed to treat for an additional beneficial outcome is 7 (95% CI 5 to 10). More recent research has focused on optimal resuscitation practices for babies with cardiorespiratory depression, such as delayed cord clamping after establishment of ventilation and resuscitation in air. Around a quarter of infants with asystole at 10 min after birth who are subsequently cooled have normal outcomes, suggesting that individualised decision making on stopping resuscitation is needed, based on access to intensive treatment unit and early cooling. The full benefit of cooling appears to have been exploited in our current treatment protocols of 72 hours at 33.5°C; deeper and longer cooling showed adverse outcome. The challenge over the next 5–10 years will be to assess which adjunct therapies are safe and optimise hypothermic brain protection in phase I and phase II trials. Optimal care may require tailoring treatments according to gender, genetic risk, injury severity and inflammatory status.

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“…[1] However, approximately half of survivors have persistent neurodevelopmental disabilities despite receiving hypothermia. [1, 2] We theorize that adverse effects from delaying the induction of hypothermia [3] and rewarming [4, 5] may be partially responsible for these neurologic impairments. We previously demonstrated that rewarming increases cortical neuronal apoptosis and caspase-3 cleavage after hypoxia-ischemia (HI) in a piglet model.…”

Section: Introductionmentioning

confidence: 99%

“…We previously demonstrated that rewarming increases cortical neuronal apoptosis and caspase-3 cleavage after hypoxia-ischemia (HI) in a piglet model. [4] Hypothermia and rewarming also promote glial apoptosis in the white matter, an effect that may be independent of HI in some brain regions. [5] Cortical and white matter injuries on MRI predict neurodevelopmental and motor impairments in survivors of HIE.…”

Section: Introductionmentioning

confidence: 99%

Hypothermia and Rewarming Activate a Macroglial Unfolded Protein Response Independent of Hypoxic-Ischemic Brain Injury in Neonatal Piglets

Lee¹,

Wang²,

Reyes³

et al. 2016

Dev Neurosci

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Therapeutic hypothermia provides incomplete neuroprotection after hypoxia-ischemia (HI)-induced brain injury in neonates. We previously showed that cortical neuron and white matter apoptosis are promoted by hypothermia and early rewarming in a piglet model of HI. The unfolded protein response (UPR) may be one of the potential mediators of this cell death. Here, neonatal piglets underwent HI or sham surgery followed by 29 h of normothermia, 2 h of normothermia + 27 h of hypothermia or 18 h of hypothermia + rewarming. Piglets recovered for 29 h. Immunohistochemistry for endoplasmic reticulum to nucleus signaling-1 protein (ERN1), a marker of UPR activation, was used to determine the ratios of ERN1+ macroglia and neurons in the motor subcortical white matter and cerebral cortex. The ERN1+ macroglia were immunophenotyped as oligodendrocytes and astrocytes by immunofluorescent colabeling. Temperature (p = 0.046) and HI (p < 0.001) independently affected the ratio of ERN1+ macroglia. In sham piglets, sustained hypothermia (p = 0.011) and rewarming (p = 0.004) increased the ERN1+ macroglia ratio above that in normothermia. HI prior to hypothermia diminished the UPR. Ratios of ERN1+ macroglia correlated with white matter apoptotic profile counts in shams (r = 0.472; p = 0.026), thereby associating UPR activation with white matter apoptosis during hypothermia and rewarming. Accordingly, macroglial cell counts decreased in shams that received sustained hypothermia (p = 0.009) or rewarming (p = 0.007) compared to those in normothermic shams. HI prior to hypothermia neutralized the macroglial cell loss. Neither HI nor temperature affected ERN1+ neuron ratios. In summary, delayed hypothermia and rewarming activate the macroglial UPR, which is associated with white matter apoptosis. HI may decrease the macroglial endoplasmic reticulum stress response after hypothermia and rewarming.

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Rewarming from Therapeutic Hypothermia Induces Cortical Neuron Apoptosis in a Swine Model of Neonatal Hypoxic–Ischemic Encephalopathy

Cited by 59 publications

References 46 publications

Effective elimination of liver cancer stem-like cells by CD90 antibody targeted thermosensitive magnetoliposomes

Effective elimination of liver cancer stem-like cells by CD90 antibody targeted thermosensitive magnetoliposomes

Management and investigation of neonatal encephalopathy: 2017 update

Hypothermia and Rewarming Activate a Macroglial Unfolded Protein Response Independent of Hypoxic-Ischemic Brain Injury in Neonatal Piglets

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