Mechanisms of Hypothermic Neuroprotection

https://doi.org/10.1016/j.clp.2013.10.005Get rights and content

Section snippets

Key points

  • Prolonged, mild hypothermia can improve outcomes from neonatal hypoxic-ischemic encephalopathy.

  • Hypothermia during hypoxia-ischemia/reperfusion helps reduce anoxic depolarization, excitotoxicity, free radical exposure, and blood-brain barrier dysfunction.

  • The latent phase of recovery, before delayed deterioration after hypoxia-ischemia, represents the window of opportunity for hypothermic neuroprotection.

  • Key targets of delayed hypothermia in the latent phase include programmed cell death,

The evolution of HI injury

The central insight that underpinned development of therapeutic hypothermia was that HI injury evolves over time. It is now known that although neurons may die during the actual ischemic or asphyxial event (the primary phase), many cells initially recover at least partially from the primary insult in a latent phase during which oxidative metabolism is at least partially restored despite continuing suppression of electroencephalogram activity.6, 7, 8 After moderate to severe injury, this is

What can be learned from the window of opportunity for hypothermia?

It is not completely clear when in this process evolving cell death becomes irreversible. Empirically, neuroprotection requires that hypothermia is started during the so-called latent or early recovery phase of transient restoration of cerebral oxidative metabolism, before secondary failure of oxidative metabolism, and continued until after resolution of the secondary phase.9, 13, 14, 15, 16 Thus, pragmatically, the window for treatment seems to close after the start of secondary energy

Mechanisms of action of hypothermia during HI

At the most fundamental level, injury requires a period of insufficient delivery of oxygen and substrates, such as glucose (and lactate in the fetus), such that neurons and glia cannot maintain homeostasis. As outlined in Fig. 1, the key mechanism of primary injury and death includes anoxic depolarization. Once the neuron’s supply of high-energy metabolites, such as ATP, can no longer be maintained during HI, the energy-dependent mechanisms of intracellular homeostasis including the Na+/K+

Cooling during reperfusion

After cerebral circulation and oxygenation are restored at the end of the insult, oxidative metabolism rapidly recovers in surviving cells and cytotoxic edema resolves over approximately 30 to 60 minutes.7, 19, 32 The key events outlined in Fig. 2 include (1) EAA levels rapidly fall in parallel with resolution of the acute cell swelling19; (2) the rapid restoration of tissue oxygenation is associated with a further rapid burst of NO and superoxide formation27; and (3) breakdown of the

Are excitotoxicity and free radicals relevant to postinsult cooling?

Both extracellular accumulation of EAAs and excess free radical production largely resolve during reperfusion after the insult and seem to have returned to normal values during the latent phase of recovery from HI.19, 21, 27, 36 In vitro, intrainsult hypothermia did not prevent intracellular accumulation of calcium during cardiac arrest in vivo,37 or during EAA exposure in vitro.38 Cooling initiated after wash-out of EAAs prevented neuronal degeneration in vitro.38

Thus, the ability of

Cell death mechanisms in the latent phase

Although the mechanisms of delayed cell loss are clearly multifactorial, there is increasing evidence that key pathways include activation of programmed cell death pathways, augmented by the inflammatory reaction and abnormal receptor activity as shown in Fig. 3. Programmed cell death is activated by (1) excessive calcium influx during and after HI,39 which promotes depolarization of the mitochondria (the intrinsic pathway of apoptosis),40 leading to permeabilization of the outer membrane of

Hypothermia in the secondary phase

There is compelling evidence that hypothermia started in the latent phase must be continued for 48 hours or more to achieve optimal neuroprotection.11 The precise reasons are unknown. The most likely explanation is that it is necessary to continue suppressing the programmed cell death and inflammatory pathways until normal homeostasis returns. However, it could in part reflect suppression of secondary events in this phase, including hyperperfusion, cytotoxic edema, and delayed seizures (Box 2,

Summary

The mechanisms underlying hypothermic neuroprotection are multifactorial, as summarized in Table 1. Suppression of excitotoxicity, oxidative stress, inflammation, intracellular signaling, and programmed cell death are all effects of hypothermia at different times. Critically, it is suppression of downstream events after anoxic depolarization and excitotoxity that seems to be critical to hypothermic neuroprotection. We speculate that the differential effects of mild hypothermia to suppress

First page preview

First page preview
Click to open first page preview

References (87)

  • N.M. Druzhyna et al.

    Cytokines induce nitric oxide-mediated mtDNA damage and apoptosis in oligodendrocytes. Protective role of targeting 8-oxoguanine glycosylase to mitochondria

    J Biol Chem

    (2005)
  • Q.S. Si et al.

    Hypothermic suppression of microglial activation in culture: inhibition of cell proliferation and production of nitric oxide and superoxide

    Neuroscience

    (1997)
  • K.R. Schmitt et al.

    Hypothermia suppresses inflammation via ERK signaling pathway in stimulated microglial cells

    J Neuroimmunol

    (2007)
  • M.A. Yenari et al.

    Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFkappaB)

    Neurochem Int

    (2006)
  • R.D. Barrett et al.

    Effect of cerebral hypothermia and asphyxia on the subventricular zone and white matter tracts in preterm fetal sheep

    Brain Res

    (2012)
  • J.M. Dean et al.

    Suppression of post hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep

    Neuropharmacology

    (2006)
  • L. Canevari et al.

    Effect of postischaemic hypothermia on the mitochondrial damage induced by ischaemia and reperfusion in the gerbil

    Brain Res

    (1999)
  • A. Nakai et al.

    Influence of mild hypothermia on delayed mitochondrial dysfunction after transient intrauterine ischemia in the immature rat brain

    Brain Res Dev Brain Res

    (2001)
  • C.W. Callaway et al.

    Brain-derived neurotrophic factor does not improve recovery after cardiac arrest in rats

    Neurosci Lett

    (2008)
  • P. Srinivasakumar et al.

    Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury

    J Pediatr

    (2013)
  • H.C. Glass et al.

    Seizures and magnetic resonance imaging-detected brain injury in newborns cooled for hypoxic-ischemic encephalopathy

    J Pediatr

    (2011)
  • S. Shankaran et al.

    Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy

    Arch Dis Child Fetal Neonatal Ed

    (2012)
  • A.D. Edwards et al.

    Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data

    BMJ

    (2010)
  • R. Guillet et al.

    Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy

    Pediatr Res

    (2012)
  • S. Shankaran et al.

    Childhood outcomes after hypothermia for neonatal encephalopathy

    N Engl J Med

    (2012)
  • D. Azzopardi et al.

    Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy

    Pediatr Res

    (1989)
  • O. Iwata et al.

    Supra- and sub-baseline phosphocreatine recovery in developing brain after transient hypoxia-ischaemia: relation to baseline energetics, insult severity and outcome

    Brain

    (2008)
  • L. Bennet et al.

    Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep

    J Physiol

    (2006)
  • A.J. Gunn et al.

    Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs

    J Clin Invest

    (1997)
  • A. Lorek et al.

    Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy

    Pediatr Res

    (1994)
  • C.E. Williams et al.

    Outcome after ischemia in the developing sheep brain: an electroencephalographic and histological study

    Ann Neurol

    (1992)
  • H. Sabir et al.

    Immediate hypothermia is not neuroprotective after severe hypoxia-ischemia and is deleterious when delayed by 12 hours in neonatal rats

    Stroke

    (2012)
  • V. Roelfsema et al.

    The window of opportunity for cerebral hypothermia and white matter injury after cerebral ischemia in near-term fetal sheep

    J Cereb Blood Flow Metab

    (2004)
  • A.J. Gunn et al.

    Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep

    Pediatrics

    (1998)
  • A.J. Gunn et al.

    Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep

    Pediatr Res

    (1999)
  • A.J. Gunn et al.

    Head cooling for neonatal encephalopathy: the state of the art

    Clin Obstet Gynecol

    (2007)
  • W.K. Tan et al.

    Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep

    Pediatr Res

    (1996)
  • R. Bagenholm et al.

    Free radicals are formed in the brain of fetal sheep during reperfusion after cerebral ischemia

    Pediatr Res

    (1998)
  • M. Fraser et al.

    Extracellular amino acids and peroxidation products in the periventricular white matter during and after cerebral ischemia in preterm fetal sheep

    J Neurochem

    (2008)
  • C.J. Hunter et al.

    Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep

    Stroke

    (2003)
  • A.R. Laptook et al.

    Quantitative relationship between brain temperature and energy utilization rate measured in vivo using 31P and 1H magnetic resonance spectroscopy

    Pediatr Res

    (1995)
  • R.D. Bart et al.

    Interactions between hypothermia and the latency to ischemic depolarization: implications for neuroprotection

    Anesthesiology

    (1998)
  • K. Nakashima et al.

    Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization

    Stroke

    (1996)
  • Cited by (0)

    Disclosure/Conflict of Interest: All authors report no conflict of interest.

    This work was supported by grants from the Health Research Council of New Zealand, the Auckland Medical Research Foundation, and Lottery Health Grants Board New Zealand. P.P. Drury was supported by the New Zealand Neurologic Foundation W&B Miller Doctoral Scholarship.

    View full text