Use of Therapeutic Hypothermia after Stroke: Beyond Neuroprotection

  • Author / Creator
    Klahr, Ana C
  • Mild therapeutic hypothermia (HYPO), decreasing brain temperature to 32-35°C, is the gold standard neuroprotectant against ischemia. Cooling also ameliorates several cell death mechanisms in other types of brain injury (e.g., traumatic brain injury). As with many other neuroprotectants, HYPO not only reduces neurodegeneration but cooling may affect repair mechanisms. Currently, HYPO is in clinical trials for ischemic and hemorrhagic stroke. Its success highly depends on our understanding of how cooling interacts with stroke pathophysiology and recovery. In turn, this allows us to customize HYPO to different types of brain insults. In this thesis, we carried out a series of experiments to elucidate the impact of HYPO beyond its neuroprotective properties. First, we conducted a study to determine whether HYPO affected plasticity in the contralesional hemisphere after motor cortex devascularization in rats. Stroke patients get HYPO to the whole brain and this may impact plasticity processes in the intact hemisphere, an important factor in recovery after stroke. We initially hypothesized that contralesional cooling would impair forelimb reaching success. Instead, we found that early contralesional HYPO did not worsen forelimb reaching but reduced the tendency for rats to use their unimpaired limb. Additionally, we tested whether HYPO affected learning of a reaching task in otherwise naïve rats. We found that reaching success was slightly lower in the rats that received cooling, although this was not significant. These findings suggest that even though HYPO is neuroprotective and safe after focal ischemia, it may still have additional effects on functional recovery after stroke. In the second set of experiments, we assessed the impact of HYPO on an often neglected aspect of intracerebral hemorrhage (ICH) pathophysiology, seizures. Seizures occur in one third of ICH patients. Cooling confers some benefit after ICH and reduces seizure activity in patients with status epilepticus and in infants with hypoxic-ischemic injury. Therefore, we hypothesized that HYPO would reduce seizure activity after ICH in rats. First, we established that seizures occurred in 66% of collagenase-induced ICH rats, but did not occur in the whole-blood model. Second, using the collagenase model we found that mild localized HYPO reduced the incidence of rats with seizures although this was not significant. Cooling may improve outcome by several mechanisms after ICH (e.g., decreasing edema, inflammation, etc.), however seizure activity may not be one of them. Altogether, my thesis work shows that HYPO may impact some aspects of stroke pathophysiology (e.g., use of impaired limb) but not others (e.g., seizures after ICH). This has implications to the patient population, as stroke victims are cooled for days or even weeks. Therefore, HYPO may impact plasticity processes that predominate during this period, possibly affecting recovery. The effectiveness of HYPO varies depending on the protocol used (e.g., duration) as well as severity and type of insult (e.g., ischemia vs. ICH). Therefore, further studies should be conducted to elucidate how to maximize HYPO neuroprotective properties while minimizing potential negative side effects (e.g., decreasing plasticity).

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Colbourne, Frederick (Psychology)
  • Examining committee members and their departments
    • Teskey, Gordon C (Psychology, University of Calgary)
    • Fouad, Karim (Centre for Neuroscience)
    • Winship, Ian (Psychiatry)
    • Yager, Jerome (Pediatrics)