1. MATTHEW BARNES SUPERVISOR: LIQUE COOLEN THE UNIVERSITY OF WESTERN ONTARIO Effects of American Ginseng on Erectile Function and Sexual Behaviour

2. Introduction: Erectile dysfunction There is a growing demand for phosphodiesterase 5 (PDE5) inhibiters (Wessells et al 2001) Furthermore, men with type 2 diabetes have a 28% prevalence of erectile dysfunction (Feldman et al 1994) HOWEVER, 46% of men with type 2 diabetes don’t respond to PDE5 inhibitors (Rendell et al 1999) Finally, after a year of treatment, men with type 2 diabetes who respond positively to treatment may revert back to pretreatment conditions (Penson et al 2003)

3. Prevalence of Erectile Dysfunction in Older Men

4. Ginseng improves erectile function Ginseng (North American and Korean Red)  Facilitates sexual behavior in rats (Murphy et al 1998) Korean Red Ginseng:  Causes vasodilation in erectile tissue: corpus cavernosum (rabbit, canine) (Kang et al 2005, Chen and Lee 1995)

5. Ginsenoside effects on erectile physiology

6. Ginseng and Diabetes Decreased eNOS mRNA and expression (Xie et al 2007)  Increase eNOS phosphorylation Yu et all 2007) Decreased VEGF expression and mRNA (Musicki et al 2004)  Increase VEGF expression via glucocorticoid receptor activation (Leung et al 2006) Hyperglycemia → ROS → lipid peroxidation and upregulated cytokines and adhesion molecules → vascular damage (Yan et al 2008)  Antioxidant (Cho et al 2006)  Increase glutathione and decrease markers for lipid peroxidation (Ryu et al 2005)  Decreasing glucose levels in blood (Ji and Gong 2007)

7. Overview Research Goals Test the hypothesis that North American (Ontario) Ginseng facilitates erectile function and sexual behavior: 1. In healthy male rats 2. In diabetic male rats

8. Objectives – Current study Investigate the effects of Ontario ginseng on sexual behavior and erectile function in healthy, adult male rats Determine the effects of ginseng on anxiety and other non-sexual effects in healthy male rats. Determine if ginseng acts centrally, peripherally, or both.

9. Animal Model Rat  Long Evans  Hooded rat: will also be used for diabetic model (Zucker Fatty rat)  Show more psychogenic erections than albino rats

10. Ontario ginseng Composite from 5 Ontario farms Tested for heavy metal and herbicide levels, as well as adulteration Delivery: Oral by gavage daily 2 – 4 hours after lights off. Dosages:  aqueous extract (125 or 250 mg/kg) or saline  ethanol extract (125 or 250 mg/kg) or saline

11. Timeline Start Injections Reward/ Aversio n Conditioned Place Preference Anxiety Tests Elevated Plus Maze Open Field Sexual Behaviour Sexual Motivation Erection Tests Non- Contact Erections Week 3 Week 6 Week 5 Week 4

12. Reward/Aversion Aqueous extract was not rewarding or aversive Conditioned Place Preference Ethanol extract is rewarding Aqueous n = 8, Ethanol n = 10

13. Anxiety Aqueous or ethanol extracts did not cause or reduce anxiety Elevated Plus Maze Open Field Test Aqueous n = 8

14. Overview NA ginseng does not cause aversion nor anxiety Therefore: any effects on sexual behaviour will not be secondary to these influences.

15. Sexual Behavior Aqueous extract slightly increased erectile function Aqueous n = 8

16. Sexual Behavior Ethanol extract did not affect erectile function but increased motivation. Ethanol n = 10

17. Non-contact Erections Aqueous extract did not affect non-contact erections (psychogenic erections) Ethanol extract also had no effect Aqueous n = 8, Ethanol n = 10

18. Conclusions – Healthy rats Aqueous extract: increase copulation efficiency; suggestive of increased erectile function during mating. Ethanol extract: decreases mount and intromission latency; suggestive of increased sexual arousal. A trend exists of decreased mount frequency. No effects on any other parameter of sexual behaviour or erectile function induced by distal cues.

19. Ongoing studies Determine sites of action: central or peripheral  Peripheral:  Erectile tissues (quantitative PCR, NO activity assays)  Central Nervous System:  Neural activity mapping to visualize neurons activated by ginseng following acute and chronic administration

20. Future studies Determine effects of Ginseng on sexual/erectile function in rat model of diabetes Zucker rats have a mutated leptin gene Most are diabetic displaying phenotypes similar to type 2 diabetes patients:  Obesity  Insulin resistance  Impaired vasodilation  Hypertension (Kasiske et al 1992)

21. Future Studies Test effects of both extracts on erectile function in Zucker Fatty rats:  Sexual behaviour  Intercavernous pressure recordings

22. Thank you! _____________________________________________________________________________________________________ Dr. Coolen, Dr. Lui, Dr. Hammond, Dr. Feng Ontario Ministry of Research and Innovation HAVE YOU HAD YOUR GINSENG TODAY?