Wilfrid Laurier University Scholars Commons @ Laurier Theses and Dissertations (Comprehensive) 2009 Neural and Behavioural Effects of the Ginkgo biloba Leaf Extract Egb 761 Elham Satvat Wilfrid Laurier University Follow this and additional works at: https://scholars.wlu.ca/etd Part of the Behavior and Behavior Mechanisms Commons Recommended Citation Satvat, Elham, "Neural and Behavioural Effects of the Ginkgo biloba Leaf Extract Egb 761" (2009). Theses and Dissertations (Comprehensive). 1070. https://scholars.wlu.ca/etd/1070 This Dissertation is brought to you for free and open access by Scholars Commons @ Laurier. It has been accepted for inclusion in Theses and Dissertations (Comprehensive) by an authorized administrator of Scholars Commons @ Laurier. For more information, please contact [email protected]. Neural and Behavioural Effects of the Ginkgo biloba Leaf Extract EGb 761 by Elham Satvat Bachelor of Art in Psychology, Wilfrid Laurier University, 2003 Master of Science in Psychology (Brain & Cognition) Wilfrid Laurier University, 2004 DISSERTATION Submitted to the Department of Psychology in partial fulfillment of the requirements for Doctor of Philosophy in Psychology (Brain & Cognition) Wilfrid Laurier University 2009 © Elham Satvat 2009 Library and Bibliotheque et 1*1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-49970-2 Our file Notre reference ISBN: 978-0-494-49970-2 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library permettant a la Bibliotheque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Plntemet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans loan, distribute and sell theses le monde, a des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, electronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in et des droits moraux qui protege cette these. this thesis. Neither the thesis Ni la these ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent etre imprimes ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. In compliance with the Canadian Conformement a la loi canadienne Privacy Act some supporting sur la protection de la vie privee, forms may have been removed quelques formulaires secondaires from this thesis. ont ete enleves de cette these. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. Canada 11 Abstract Numerous studies have documented the cognitive-enhancing effects of standardized Ginkgo biloba leaf extracts (Gingko) both in humans and in rodents. In addition to its antioxidant and platelet-activating factor inhibiting properties, Ginkgo has been shown to protect cellular membrane fluidity, to enhance cerebral blood flow and microcirculation, and to modulate cholinergic system functioning, properties that have been suggested to underlie its cognitive-enhancing effects. However, the possible neurogenic-enhancing effects of Ginkgo on adult hippocampal neurogenesis as a possible mechanism underlying its nootropic effects have not been evaluated. The experiments discussed in the present thesis assessed such a possibility. Chapter 1 reviews studies that have evaluated the nootropic effects of Ginkgo in humans and in rodents. The anti-stress properties of Ginkgo as well as several molecular mechanisms proposed to account for its beneficial effects on central nervous system functioning are also discussed. Experiments presented in Chapter 2 used c-Fos immunoreactivity to characterize functional activity in selected brain regions following acute oral (150 mg/kg) and intraperitoneal (2.5-25 mg/kg, i.p.) administration of Ginkgo. Both routes of administration increased c-Fos immunoreactivity in the insular cortex and amygdala. However, some additional regions including the nucleus accumbens and dentate gyrus showed increased c-Fos immunoreactivity only in response to parenteral administration. Experiments presented in Chapter 3 evaluated the possible neurogenic properties of Ginkgo. The anxiolytic effects of the extract using the elevated plus maze, light/dark emergence and social interaction tests were also assessed. Acute administration of iii Ginkgo (2.5-25 mg/kg, i.p.) had neither stimulating nor depressive effects on cell proliferation in the adult dentate gyrus. Survival of newborn neurons in the dentate gyrus of adult male rats was also not affected by chronic Ginkgo administration. Furthermore, the results showed that chronic administration of Ginkgo treatment had neither anxiolytic nor anxiogenic properties; however acute administration of a high and moderate dose of Ginkgo induced anxiety in some measures. Experiments described in Chapter 4 investigated whether suppressed neurogenesis induced by corticosterone (CORT) treatment could be restored by Ginkgo co-treatment. The results revealed that survival of newborn cells was inhibited in the dorsal dentate gyrus of rats chronically treated with CORT; however, Ginkgo co-treatment did not buffer this effect. Finally, experiments described in Chapter 5 evaluated the cognitive-enhancing effects of Ginkgo on young adult male rats using a food-reinforced two-component double Y-maze task. Results showed that Ginkgo-tieated rats reached the training criteria faster, and made fewer errors. Rats treated with Ginkgo during the learning phase made fewer working memory errors. However, neither acute nor chronic post-training treatment with Ginkgo enhanced spatial working memory. Taken together, the results of the present dissertation showed that Ginkgo increased c-Fos immunoreactivity in several brain structures involved in learning and memory. Moreover, Ginkgo enhanced acquisition and performance of a double-Y maze task, but did not offer any continued benefits in an already-learned working memory task. Interestingly, a dose of Ginkgo (13.75 mg/kg) that was found to improve cognitive function failed to promote either cell proliferation or cell survival in the adult dentate iv gyrus. It also failed to restore the suppressive effects of CORT on dentate gyrus cell survival. It is concluded that Ginkgo pre-treatment subtly enhances learning, but this effect is likely not related to a modulatory effect on adult hippocampal neurogenesis. V Acknowledgments First and foremost I would like to express my deepest and sincerest thanks to my PhD advisor Dr. Paul Mallet for his continuous guidance and mentorship throughout the past few years. I am forever thankful to him for having confidence in me and accepting me in his lab so soon after joining the Faculty of Science at Wilfrid Laurier University. I am truly thankful for all the time he spent not just discussing thesis-related issues but also teaching me his many information technology and laboratory technical skills. My sincere gratitude also goes to my committee members, Dr. Rudy Eikelboom and Dr. Diano-Fabio Marrone for their very valuable feedback and support. The time they spent reading and commenting on my thesis is greatly appreciated. I am truly thankful to Dr. Eikelboom and also Dr. Jeff Jones for their support during a very difficult time before Dr. Mallet joined the Faculty of Science. Their words of encouragement kept me in the PhD program. I would also like to acknowledge and thank Melissa Collie and Clinton Moore who assisted with the data collection for parts of Experiment 1 and 2, respectively, at the University of New England, Australia. I am also thankful to the animal care facility staff: Kelley Putzu, Kristin Lukashal and Darlene Casemore. Their hard work in the animal facility made it possible to conduct the research described in this thesis. I would like to thank many students and volunteers from Dr. Mallet's laboratory, namely Marc Schaus, Laura Flannery, Heather Heipel, Brittany Ford, Sarah List, Jon Behich, Clark Chami, and Ali Sabet, as well as students from other laboratories (Graham Parfeniuk and Ali Gheidi) for lending a hand with various parts of my experiments. I also thank Page Burton for editorial comments on the first draft of Chapter 5. My very special thanks go to one of my very best friends Dr. Shadna Rana, who on many occasions helped out with many parts of my experiments, in particular with perfusions. All her unconditional help, emotional support, and words of encouragements during the past few years are greatly appreciated. I am also grateful to Dr. Pat Wainwright for reading and commenting on my dissertation. I would also like to express my appreciation to Mrs. Rita Sharkey, the graduate program assistant, for all the paper work she has done for me throughout the past few years. I also acknowledge Ontario Graduate Scholarship for their funding support during the past two years. Finally, I am greatly thankful to my parents, my brother