Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy

Wassink, Guido; Davidson, John B.; Dhillon, Simerdeep K; Zhou, Kelly Q; Bennet, Laura; Thoresen, Marianne; Gunn, Alistair J.

doi:10.1007/s11910-019-0916-0

Cited by 96 publications

(90 citation statements)

References 78 publications

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“…Hypoxic-ischemic encephalopathy is, in fact, a still frequent condition responsible for neonatal morbidity and mortality [26]. Brain or whole-body hypothermia is currently the only therapeutic option offering amelioration in the prognosis, as from preclinical and clinical data [26,[43][44][45]. In addition, evidence of a benefit from adjunctive therapy with melatonin has been described [46,47], and a recent study on melatonin safety, pharmacokinetics (PK), and dosage in the neonatal population reported positive results [25].…”

Section: Discussionmentioning

confidence: 99%

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

et al. 2020

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Melatonin exerts direct neuroprotection against cerebral hypoxic damage, but the mechanisms of its action on microglia have been less characterized. Using both in vitro and in vivo models of hypoxia, we here focused on the role played by silent mating type information regulation 2 homolog 1 (SIRT1) in melatonin’s effects on microglia. Viability of rat primary microglia or microglial BV2 cells and SH-SY5Y neurons was significantly reduced after chemical hypoxia with CoCl2 (250 μM for 24 h). Melatonin (1 μM) significantly attenuated CoCl2 toxicity on microglia, an effect prevented by selective SIRT1 inhibitor EX527 (5 μM) and AMP-activated protein kinase (AMPK) inhibitor BML-275 (2 μM). CoCl2 did not modify SIRT1 expression, but prevented nuclear localization, while melatonin appeared to restore it. CoCl2 induced nuclear localization of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-kB), an effect contrasted by melatonin in an EX527-dependent fashion. Treatment of microglia with melatonin attenuated potentiation of neurotoxicity. Common carotid occlusion was performed in p7 rats, followed by intraperitoneal injection of melatonin (10 mg/kg). After 24 h, the number of Iba1+ microglia in the hippocampus of hypoxic rats was significantly increased, an effect not prevented by melatonin. At this time, SIRT1 was only detectable in the amoeboid, Iba1+ microglial population selectively localized in the corpus callosum. In these cells, nuclear localization of SIRT1 was significantly lower in hypoxic animals, an effect prevented by melatonin. NF-kB showed an opposite expression pattern, where nuclear localization in Iba1+ cells was significantly higher in hypoxic, but not in melatonin-treated animals. Our findings provide new evidence for a direct effect of melatonin on hypoxic microglia through SIRT1, which appears as a potential pharmacological target against hypoxic-derived neuronal damage.

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Section: Discussionmentioning

confidence: 99%

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

et al. 2020

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“…At present, there are few ways to effectively treat neonatal hypoxic-ischemic injury. Among these, hypothermia is the most widely used (Wassink et al, 2019). Hypothermia can intervene some critical steps in the excitatory oxidative cascade.…”

Section: Treatment Of Neonatal Hypoxic-ischemic Encephalopathymentioning

confidence: 99%

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

2020

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Hypoxic-ischemic encephalopathy (HIE) is one of the main forms of neonatal brain injury which could lead to neonatal disability or even cause neonatal death. Therefore, HIE strongly affects the health of newborns and brings heavy burden to the family and society. It has been well studied that N-methyl-D-aspartate (NMDA) receptors are involved in the excitotoxicity induced by hypoxia ischemia in adult brain. Recently, it has been shown that the NMDA receptor also plays important roles in HIE. In the present review, we made a summary of the molecular mechanism of NMDA receptor in the pathological process of HIE, focusing on the distinct role of GluN2A-and GluN2Bcontaining NMDA receptor subtypes and aiming to provide some insights into the clinical treatment and drug development of HIE.

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“…In high-income countries, the incidence of HIE is around 1.6 per 1000 infants, while the risk is around 10-fold higher in low-income countries [3]. Therapeutic hypothermia (TH) initiated within 6 h of birth constitutes the standard of care for infants with moderate or severe HIE reducing mortality and improving neurodevelopmental outcome in survivors [4].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Phenotypes of Hypoxic-Ischemic Encephalopathy with Normal vs. Pathologic Magnetic Resonance Imaging Outcomes

et al. 2020

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Hypoxic-Ischemic Encephalopathy (HIE) is one of the most relevant contributors to neurological disability in term infants. We hypothesized that clinical outcomes of newborns with (HIE) can be associated with changes at plasma metabolic level enabling the detection of brain injury. Plasma samples of a cohort of 55 asphyxiated infants who evolved to moderate/severe HIE were collected between birth and completion of therapeutic hypothermia (TH). Samples were analyzed employing a quantitative gas chromatography–mass spectrometry method for the determination of lactate and pyruvate and an untargeted liquid chromatography–time-of-flight mass spectrometry method for metabolic fingerprinting. Brain injury was assessed employing magnetic resonance imaging (MRI). A critical assessment of the usefulness of lactate, pyruvate, and pyruvate/lactate for outcome prediction was carried out. Besides, metabolic fingerprinting identified a dynamic perturbation of eleven metabolic pathways, including amino acid and purine metabolism, and the steroid hormone biosynthesis, in newborns with pathologic MRI outcomes. Although data suggest the usefulness of lactate and pyruvate monitoring during 72 h for discerning outcomes, only the steroid hormone biosynthesis pathway was significantly altered in early plasma samples (i.e., before the initiation of TH). This study highlights pathways that might potentially be targeted for biomarker discovery or adjuvant therapies to be combined with TH.

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Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy

Cited by 96 publications

References 78 publications

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

Metabolic Phenotypes of Hypoxic-Ischemic Encephalopathy with Normal vs. Pathologic Magnetic Resonance Imaging Outcomes

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