Hypothermia and the Evaluation of Combination Therapies for Neonatal Hypoxic-Ischemic Brain Damage

  • Author / Creator
    Przyslupski, Ann-Marie T
  • Hypoxic-ischemic brain damage (HIBD) is still of major concern in the neonatal period, resulting in chronic neurological sequelae stemming from damage to the term newborn brain. Full-body and focal-head cooling within 6 hours of birth have proven neuroprotective in human newborns and various animal models of HIBD while independent pharmacotherapies have failed. Hence, post-ischemic cooling is the current standard of care for neonatal HIBD. However, hypothermia offers incomplete protection against the HIBD neurotoxic cascade, meaning that cooled newborns may still exhibit brain injury and neurological deficiencies. To offset this transient neuroprotection, and possibly extend the therapeutic window of opportunity, combining hypothermic cooling with pharmacotherapy has been explored. Using an established neonatal rat model of HIBD, my two studies respectively examined (1) if sulforaphane (SFN), a potent anti-oxidant and anti-inflammatory agent, could enhance hypothermic neuroprotection, and also (2) analysed the effect of hypothermia within the HIBD core and penumbra across time. Our results indicate that SFN did not further reduce gross pathological brain injury when provided with hypothermia, and that high concentrations of the compound (10 mg/kg) may have been deleterious. Our mechanistic results suggest that hypothermia differentially affects the core and penumbra. However, further studies will need to be undertaken to clarify the role played by hypothermia on cell survival/death, in this paradigm. The results of these two studies provide a stepping stone with which researchers can test promising neuroprotective therapies with post-ischemic hypothermia for newborn HIBD. Further studies are required to determine the optimal timing where additional therapy can be administered to the HIBD core and/or penumbra, as well as what type of adjunct therapy to achieve enhanced hypothermic neuroprotection. From this, treatment paradigms that effectively enhance short and long-term pathological and behavioural outcomes could be developed.

  • Subjects / Keywords
  • Graduation date
    2016-06:Fall 2016
  • Type of Item
  • Degree
    Master of Science
  • 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
    • Medical Sciences-Paediatrics
  • Supervisor / co-supervisor and their department(s)
    • Yager, Jerome (Pediatrics)
  • Examining committee members and their departments
    • Colbourne, Frederick (Psychology)
    • Osornio-Vargas, Alvaro (Pediatrics)
    • Persad, Sujata (Pediatrics)
    • Wine, Eytan (Pediatrics)
    • Yager, Jerome (Pediatrics)