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Bilateral Uterine Artery Ligation in Rats cultivates Long Term Neurological Deficits reminiscent of Human Cerebral Palsy: A model for Therapeutic Intervention. Open Access


Other title
Placental Insufficiency
Cerebral Palsy
Bilateral uterine artery ligation
Animal Model
Intrauterine growth restriction
Type of item
Degree grantor
University of Alberta
Author or creator
Corrigan, Jennifer
Supervisor and department
Jerome Yager, Department of Paediatrics
Sandra Davidge, Department of Obstetrics, Gynecology and Physiology
Examining committee member and department
Rhonda Bell, Department of Agriculture, Food and Nutritional Science
Po-Yin Cheung, Department of Paediatrics, Pharmacology and Surgery
Fred Colbourne, Department of Psychology
Medical Sciences-Paediatrics

Date accepted
Graduation date
Master of Science
Degree level
Introduction Cerebral Palsy (CP) is a ubiquitous term used to describe a group of permanent, non-progressive disorders of movement, posture, and behaviour. Despite countless advances in neonatal medicine, the incidence of CP has remained constant in term infants over the last three decades. More so, the overall incidence has increased due to the survival of premature births. With the exception of hypothermia, which is restricted to a subset of patients, no effective prevention of CP exists. Recent literature has implicated placental insufficiency in the development of CP. Objectives The purpose of this experiment is to validate the use of bilateral uterine artery ligation (BUAL) in Long-Evans rats as a model of CP using functional and histological assessment. Specific objectives include determining whether BUAL results in offspring that exhibit (1) Intrauterine growth restriction (IUGR) at birth; (2) motor, cognitive and behaviour impairment after P35 and (3) white and grey matter injury at P80. Methods Timed pregnancy was achieved in virgin rats. On gestational day 20 (E20), pregnant dams were randomly allocated to either BUAL or SHAM surgery. Offspring were divided based on treatment and sex to form the following four study groups: 1) SHAM Males, 2) SHAM Females, 3) IUGR Males, and 4) IUGR Females. Each group underwent one month of functional assessment commencing on post-natal day 35 (P 35). Functional assessment included: 1) motor testing using beam walking, skilled reaching, and gait analysis; 2) cognitive testing using object recognition and Morris water maze and 3) behaviour testing using elevated plus maze and open field. Animals were euthanized on P80 and brains were collected and fresh frozen for histological evaluation. Fresh frozen brains were stained with haematoxylin and eosin (H+E), myelin basic protein (MBP) and Olig-2. Hippocampal cell counting was used to detect grey matter injury. Lateral ventricle volumes, immunodensity of MBP and Olig-2+ cell counts were used to assess for white matter injury. Results BUAL resulted in a statistically significant increase in mortality and growth restriction (IUGR) in surviving rat pups. Both IUGR males and females made significantly more faults than SHAM controls in beam walking and skilled reaching. IUGR males were found to have a significantly wider hind limb stance than SHAM males. IUGR males utilized a significantly less efficient swim strategy in the Morris water maze than controls. No differences in open field or object recognition were detected. Both IUGR males and females made significantly more entries into the open arms of the elevated plus maze than their respective controls. The number of pyramidal neurons in the CA3 region of the hippocampus in IUGR males was significantly reduced. No differences in white matter were detected. Conclusion BUAL in the pregnant Long Evans rat leads to IUGR and permanent neurological deficits in offspring that are reminiscent of CP. Both males and females demonstrated significant motor impairment. Cognitive impairment and neuropathology were only significant in males. This is congruent with a higher prevalence of CP in human males. Moreover, the etiological and functional similarities of this model to CP, in combination with its long term sustainability, make it an excellent template for the pre-clinical testing of therapeutic interventions.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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