Non-Additive Effects of Delayed Connexin Hemichannel Blockade and Hypothermia after Cerebral Ischemia in Near-Term Fetal Sheep

Davidson, J.; Rout, Alexandra L; Wassink, Guido; Yuill, Caroline A.; Zhang, Frank G; Green, Colin; Gunn, Alistair J.

doi:10.1038/jcbfm.2015.171

Cited by 26 publications

(24 citation statements)

References 49 publications

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“…For example, in fetal sheep after cerebral ischaemia, connexin hemichannel blockade reduced neuronal damage and restored EEG power (Davidson et al . 2012), but was non‐additive to mild hypothermia (Davidson et al . 2015 b ).…”

Section: The Mechanisms Of Hypothermic Neuroprotectionmentioning

confidence: 99%

A working model for hypothermic neuroprotection

Wassink

Davidson

Lear

et al. 2018

The Journal of Physiology

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Therapeutic hypothermia significantly improves survival without disability in near-term and full-term newborns with moderate to severe hypoxic-ischaemic encephalopathy. However, hypothermic neuroprotection is incomplete. The challenge now is to find ways to further improve outcomes. One major limitation to progress is that the specific mechanisms of hypothermia are only partly understood. Evidence supports the concept that therapeutic cooling suppresses multiple extracellular death signals, including intracellular pathways of apoptotic and necrotic cell death and inappropriate microglial activation. Thus, the optimal depth of induced hypothermia is that which effectively suppresses the cell death pathways after hypoxia-ischaemia, but without inhibiting recovery of the cellular environment. Thus mild hypothermia needs to be continued until the cell environment has recovered until it can actively support cell survival. This review highlights that key survival cues likely include the inter-related restoration of neuronal activity and growth factor release. This working model suggests that interventions that target overlapping mechanisms, such as anticonvulsants, are unlikely to materially augment hypothermic neuroprotection. We suggest that further improvements are most likely to be achieved with late interventions that maximise restoration of the normal cell environment after therapeutic hypothermia, such as recombinant human erythropoietin or stem cell therapy.

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Section: The Mechanisms Of Hypothermic Neuroprotectionmentioning

confidence: 99%

A working model for hypothermic neuroprotection

Wassink

Davidson

Lear

et al. 2018

The Journal of Physiology

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“…Previous research has revealed that unopposed connexons also play an important role. They mediate the release of paracrine molecules, which in turn transmit cell death messages by the secretion of intracellular mediators (such as ATP, Nicotinamide adenine dinucleotide (NAD + ), and glutamate), which ultimately leads to cell edema [103,104]. …”

Section: Clinical Strategies Of Antioxidants In Hiementioning

confidence: 99%

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies

Zhao

Zhu

Fujino

et al. 2016

IJMS

137

103

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Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches.

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“…Given that mild hypothermia is now standard of care, it is essential to test potential treatments in combination with hypothermia. This is particularly important as overlap with the wide array of reported mechanisms of action of hypothermia ( 47 ) may attenuate any additive effects, as discussed below ( 48 – 50 ). There are of course very large numbers of potential strategies; in this review we examine some leading examples, as summarized in Table 1 .…”

Section: Can Combination Treatment Augment Hypothermic Neuroprotectiomentioning

confidence: 99%

Therapeutic Hypothermia for Neonatal Hypoxic–Ischemic Encephalopathy – Where to from Here?

et al. 2015

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Hypoxia–ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic–ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia–ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review, we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin, and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects.

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Non-Additive Effects of Delayed Connexin Hemichannel Blockade and Hypothermia after Cerebral Ischemia in Near-Term Fetal Sheep

Cited by 26 publications

References 49 publications

A working model for hypothermic neuroprotection

A working model for hypothermic neuroprotection

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies

Therapeutic Hypothermia for Neonatal Hypoxic–Ischemic Encephalopathy – Where to from Here?

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