Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

Millar, Lancelot Jamie; Shi, Lei; Hoerder‐Suabedissen, Anna; Molnár, Zoltán

doi:10.3389/fncel.2017.00078

Cited by 252 publications

(283 citation statements)

References 763 publications

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“…The secondary energy failure occurs at least six hours after the primary injury. This phase leads to delayed neuronal death with predominant apoptosis, which is related to several mechanisms, such as excitotoxicity, oxidative stress, and inflammation (Millar et al , 2017). The delayed neuronal death contributes to a major proportion of final brain cell loss after HI insults (Figure 1).…”

Section: Neuro-immune Communication In Neonatal Hi Brain Injurymentioning

confidence: 99%

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Concepcion

Meng

et al. 2017

Progress in Neurobiology

171

189

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Perinatal hypoxia-ischemia remains the primary cause of acute neonatal brain injury, leading to a high mortality rate and long-term neurological deficits, such as behavioral, social, attentional, cognitive and functional motor deficits. An ever-increasing body of evidence shows that the immune response to acute cerebral hypoxia-ischemia is a major contributor to the pathophysiology of neonatal brain injury. Hypoxia-ischemia provokes an intravascular inflammatory cascade that is further augmented by the activation of resident immune cells and the cerebral infiltration of peripheral immune cells response to cellular damages in the brain parenchyma. This prolonged and/or inappropriate neuroinflammation leads to secondary brain tissue injury. Yet, the long-term effects of immune activation, especially the adaptive immune response, on the hypoxic-ischemic brain still remain unclear. The focus of this review is to summarize recent advances in the understanding of post-hypoxic-ischemic neuroinflammation triggered by the innate and adaptive immune responses and to discuss how these mechanisms modulate the brain vulnerability to injury. A greater understanding of the reciprocal interactions between the hypoxic-ischemic brain and the immune system will open new avenues for potential immunomodulatory therapy in the treatment of neonatal brain injury.

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Section: Neuro-immune Communication In Neonatal Hi Brain Injurymentioning

confidence: 99%

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Concepcion

Meng

et al. 2017

Progress in Neurobiology

171

189

View full text Add to dashboard Cite

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“…Oxidative stress or an elevated level of reactive oxygen species (ROS), due to excessive ROS generation and/or impaired antioxidant capacity, is a salient feature of ischaemia‐reperfusion, particularly during reperfusion when oxygen molecules, the substrate required for diverse ROS‐generating mechanisms, become available after ischaemia, and ROS is a well‐recognized factor inducing ischaemia‐reperfusion brain damage . Oxidative stress is also well documented in chronic cerebral hypo‐perfusion and hypoxic‐ischaemic brain damage . However, how oxidative stress causes ischaemia‐reperfusion and chronic cerebral hypo‐perfusion brain damage is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

TRPM2 channel: A novel target for alleviating ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemic brain damage

Mai

Mankoo

Wei

et al. 2019

J Cellular Molecular Medi

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The transient receptor potential melastatin‐related 2 (TRPM2) channel, a reactive oxygen species (ROS)‐sensitive cation channel, has been well recognized for being an important and common mechanism that confers the susceptibility to ROS‐induced cell death. An elevated level of ROS is a salient feature of ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxia‐ischaemia. The TRPM2 channel is expressed in hippocampus, cortex and striatum, the brain regions that are critical for cognitive functions. In this review, we examine the recent studies that combine pharmacological and/or genetic interventions with using in vitro and in vivo models to demonstrate a crucial role of the TRPM2 channel in brain damage by ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemia. We also discuss the current understanding of the underlying TRPM2‐dependent cellular and molecular mechanisms. These new findings lead to the hypothesis of targeting the TRPM2 channel as a potential novel therapeutic strategy to alleviate brain damage and cognitive dysfunction caused by these conditions.

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“…Both OPCs and mature OLs are highly vulnerable to inflammation and hypoxia/ischemia (HI), the main pathogenic mechanisms determining demyelination through a number of downstream cellular and molecular mechanisms (Calzà et al, ). In particular, neonatal HI is the most common cause of death, as well as of motor, sensory and cognitive disability, during the perinatal/neonatal period (Millar, Shi, Hoerder‐Suabedissen, & Molnár, ). Clinical conditions leading to neonatal HI generally occur in the time window when OPCs should switch to myelinating OLs to guarantee proper myelination, that is, from late embryonic gestation throughout early postnatal life (Fancy, Chan, Baranzini, Franklin, & Rowitch, ).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells‐derived oligodendrocyte precursor cells

Baldassarro

Marchesini

Giardino

et al. 2019

Glia

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Impaired myelination is a key feature in neonatal hypoxia/ischemia (HI), the most common perinatal/neonatal cause of death and permanent disabilities, which is triggered by the establishment of an inflammatory and hypoxic environment during the most critical period of myelin development. This process is dependent on oligodendrocyte precursor cells (OPCs) and their capability to differentiate into mature oligodendrocytes. In this study, we investigated the vulnerability of fetal and adult OPCs derived from neural stem cells (NSCs) to inflammatory and HI insults. The resulting OPCs/astrocytes cultures were exposed to cytokines to mimic inflammation, or to oxygen–glucose deprivation (OGD) to mimic an HI condition. The differentiation of both fetal and adult OPCs is completely abolished following exposure to inflammatory cytokines, while only fetal‐derived OPCs degenerate when exposed to OGD. We then investigated possible mechanisms involved in OGD‐mediated toxicity: (a) T3‐mediated maturation induction; (b) glutamate excitotoxicity; (c) glucose metabolism. We found that while no substantial differences were observed in T3 intracellular content regulation and glutamate‐mediated toxicity, glucose deprivation lead to selective OPC cell death and impaired differentiation in fetal cultures only. These results indicate that the biological response of OPCs to inflammation and demyelination is different in fetal and adult cells, and that the glucose metabolism perturbation in fetal central nervous system (CNS) may significantly contribute to neonatal pathologies. An understanding of the underlying molecular mechanism will contribute greatly to differentiating myelination enhancing and neuroprotective therapies for neonatal and adult CNS white matter lesions.

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Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

Cited by 252 publications

References 763 publications

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

TRPM2 channel: A novel target for alleviating ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemic brain damage

Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells‐derived oligodendrocyte precursor cells

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