Prolonged but Delayed Postischemic Hypothermia: A Long-term Outcome Study in the Rat Middle Cerebral Artery Occlusion Model

Colbourne, Frederick; Corbett, Dale; Zhao, Zonghang; Yang, Jiancheng; Buchan, Alastair

doi:10.1097/00004647-200012000-00009

Cited by 208 publications

(121 citation statements)

References 33 publications

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“…82 This chronic loss could be prevented by extending the duration of moderate (32 to 34°C ) hypothermia to 48 hours or more, even when the start of cooling was delayed until 6 hours after reperfusion. 83,84 How much should we cool?…”

Section: The 'Pharmacodynamics' Of Hypothermiamentioning

confidence: 99%

Hypothermic neuroprotection

Gunn

Thoresen

2006

NeuroRX

213

128

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Summary:The possibility that hypothermia during or after resuscitation from asphyxia at birth, or cardiac arrest in adults, might reduce evolving damage has tantalized clinicians for a very long time. It is now known that severe hypoxia-ischemia may not necessarily cause immediate cell death, but can precipitate a complex biochemical cascade leading to the delayed neuronal loss. Clinically and experimentally, the key phases of injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. Studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Two large controlled trials, one of head cooling with mild hypothermia, and one of moderate whole body cooling have demonstrated that post resuscitation cooling is generally safe in intensive care, and reduces death or disability at 18 months of age after neonatal encephalopathy. These studies, however, show that only a subset of babies seemed to benefit. The challenge for the future is to find ways of improving the effectiveness of treatment.

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Section: The 'Pharmacodynamics' Of Hypothermiamentioning

confidence: 99%

Hypothermic neuroprotection

Gunn

Thoresen

2006

NeuroRX

213

128

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“…Mild (33-36°C) or moderate (28-32°C) hypothermia is one of the strongest neuroprotectants identified to date that protect against cerebral ischemia [1,3,14], but the exact mechanisms for its protective effects are not fully understood [15]. We have previously reported that intraischemic moderate hypothermia (30 °C) reduces infarct size in focal ischemia by regulating the Akt survival pathways [14].…”

Section: Introductionmentioning

confidence: 99%

Hypothermia blocks β-catenin degradation after focal ischemia in rats

Zhang¹,

Ren²,

Gao³

et al. 2008

Brain Research

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Dephosphorylated and activated glycogen synthase kinase (GSK) 3β hyperphophorylates β-catenin, leading to its ubiquitin-proteosome-mediated degradation. β-catenin-knockdown increases while β-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of β-catenin are reduced in the brain of Alzheimer's patients. However, whether β-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK3 β and β-catenin, and the protective effect of moderate hypothermia (30 °C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK3 β was dephosphorylated at 5 and 24 hours after stroke in the normothermic (37 °C) brain; hypothermia augmented GSK3β dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK3β dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK3β protein. Corresponding to GSK3β activity in normothermic rats, β-catenin phosphorylation transiently increased at 5 hours in both the ischemic penumbra and core, and the total protein level of β-catenin degraded after normothermic stroke. Hypothermia did not inhibit β-catenin phosphorylation, but it blocked β-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize β-catenin, which may contribute to the protective effect of moderate hypothermia.

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“…Early studies established that cooling during global or focal cerebral ischemia greatly diminishes cell death and promotes functional recovery (for comprehensive reviews, see Ginsberg et al, 1992;Maher and Hachinski, 1993;Thornhill and Corbett, 2001;Wagner and Zuccarello, 2005). Although initially controversial (Dietrich et al, 1993), delayed postischemic hypothermia also reduces cell death and improves functional recovery (Carroll and Beek, 1992;Colbourne and Corbett, 1995;Colbourne et al, 2000;Maier et al, 1998;Yanamoto et al, 1996); therefore, hypothermia has great potential as a clinical therapy. Indeed, recent studies show that systemic hypothermia improves survival and recovery in outof-hospital cardiac arrest victims (Bernard et al, 2002; The Hypothermia After Cardiac Arrest Study Group, 2002).…”

Section: Introductionmentioning

confidence: 99%

A Simple Method to Induce Focal Brain Hypothermia in Rats

Clark

Colbourne

2007

J Cereb Blood Flow Metab

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Hypothermia reduces cell death and promotes recovery in models of cerebral ischemia, intracerebral hemorrhage and trauma. Clinical studies report significant benefit for treating cardiac arrest and studies are investigating hypothermia for stroke and related conditions. Both local (head) and generalized hypothermia have been used. However, selective brain cooling has fewer side effects than systemic cooling. In this study, we developed a method to induce local (hemispheric) brain hypothermia in rats. The method involves using a small metal coil implanted between the Temporalis muscle and adjacent skull. This coil is then cooled by flushing it with cold water. In our first experiment, we tested whether this method induces focal brain hypothermia in anesthetized rats. Brain temperature was assessed in the ipsilateral cortex and striatum, and contralateral striatum, while body temperature was kept normothermic. Focal, ipsilateral cooling was successfully produced, while the other locations remained normothermic. In the second experiment, we implanted the coil, and brain and body temperature telemetry probes. The coil was connected via overhead swivel to a cold-water source. Brain hypothermia was produced for 24 h, while body temperature remained normothermic. A third experiment measured brain and body temperature along with heart rate and blood pressure. Brain cooling was produced for 24 h without significant alterations in pressure, heart rate or body temperature. In summary, our simple method allows for focal brain hypothermia to be safely induced in anesthetized or conscious rats, and is, therefore, ideally suited to stroke and trauma studies.

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Prolonged but Delayed Postischemic Hypothermia: A Long-term Outcome Study in the Rat Middle Cerebral Artery Occlusion Model

Cited by 208 publications

References 33 publications

Hypothermic neuroprotection

Hypothermic neuroprotection

Hypothermia blocks β-catenin degradation after focal ischemia in rats

A Simple Method to Induce Focal Brain Hypothermia in Rats

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