Neural and Behavioural Effects of the \u3cem\u3eGinkgo biloba\u3c/em\u3e Leaf Extract Egb 761

Numerous studies have documented the cognitive-enhancing effects of standardized Ginkgo biloba leaf extracts (Ginkgo) both in humans and in rodents. In addition to its antioxidant and platelet-activating factor inhibiting properties, Gingko 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 cortext 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 emergencec and social interaction tests were also assessed. Acute administration of 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-treated 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 Gingko 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 functioned failed to promote either cell proliferation or cell survival in the adult dentate 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