Chronic North American Ginseng Administration Alters Metabolic Variables in the Rat Megan Migchels Supervisor: Dr. J. Ciriello 2011/01/24

Overview  Background Obesity Obstructive Sleep Apnea Ginseng  Hypothesis  Model  Preliminary Data  Future experiments  Questions

The Obesity Epidemic ~ 61% of Canadians are overweight This increases the risk of Cardiovascular disease Hypertension Cancer Diabetes Arguably leading cause of preventable death

Leptin  Secreted by adipocytes into the bloodstream  Acts on receptors in the hypothalamus Signals satiety Increases energy expenditure through sympathetic activation  Initially thought to be an adipocyte signal that functioned to prevent obesity Leptin deficiency results in obesity Leptin resistance in obesity ** Considered to play an important role in the development of hypertension in obesity**

Sleep Apnea (Intermittent Hypoxia)  Sleep Apnea is a serious disorder that occurs when a person's breathing is interrupted (stopped) during sleep.  Apnea is Greek for “without breath”.  People with untreated sleep apnea stop breathing repeatedly during their sleep, sometimes hundreds of times.  Holding your breath leads to decreased blood oxygen levels (hypoxia), which has serious consequences on the body.

Obstructive Sleep Apnea (OSA) OSA- intermittent, cyclical cessations or reductions of airflow because of an obstructed airway Prevalence of OSA is expected to rise in the coming years in response to the current obesity epidemic

Metabolic Syndrome

Ginseng  Ginseng has been used for centuries as a medicinal herb to replenish energy, reduce susceptibility to illness and promote health  Panax ginseng- Asian ginseng  Panax quinquefolius- North American ginseng  Most researched herb in the world Approximately 5% of the population of Western countries consume ginseng

Ginsenosides- active ingredient The two types of ginseng differ in chemical composition and have specific biological effects Previous studies: Asian Ginseng Suggested to have anti-obesity effects, to decrease plasma triglyceride and leptin levels (Lee, 2010) Suggested to be anti-hypertensive (Yanai, 2006) Improves the metabolic syndrome (Yun, 2007) However, little is known about the effects of North American ginseng on cardiovascular disease and obesity

North American Ginseng contains 3-5x greater ginsenoside content than Asian Ginseng. North American Ginseng contains greater levels of ginsenoside Rb1, a phytoestrogen which has been seen to have hypotensive effects. North American Ginseng contains greater levels of ginsenoside Re which has vasodilatory and antihyperlipidemic properties.

Obstructive Sleep Apnea Sympathetic Activity Renin-Angiotensin Oxidative Stress Insulin Resistance Hypoxemia Vascular Inflammation Obesity Insulin Resistance Vascular Inflammation Oxidative Stress Endothelial Dysfunction Sympathetic Activity Renin-Angiotensin Obstructive Sleep Apnea Increases the Risk of Cardiovascular Disease Mechanical Obstruction of Airway Risk Factors Dr. John Ciriello, BSc, MSc, PhD Professor of Physiology, Pharmacology and Neuroscience Schulich School of Medicine and Dentistry University of Western Ontario – Cardiovascular Disease (Risk Factors) Hypertension Stroke Ischemic Heart Disease Cardiac Arrhythmias Atherosclerosis Patients with essential hypertension exhibit augmented increases in sympathetic nerve activity to hypoxia Obese patients exhibit augmented increases in sympathetic nerve activity Ginseng?

 Cardiovascular disease is a growing concern in our society Hypertension Obesity Obstructive Sleep Apnea Rationale

 Overall Objective: Investigate the effects of NAG treatment on the metabolic and arterial pressure effects induced by chronic intermittent hypoxia (CIH) in normal and obese rats.  Hypothesis 1 (current ongoing study):  Chronic ingestion of NAG will reduce circulating levels of leptin This reduction in leptin will ameliorate the effects of obesity and CIH on the development of hypertension, dislipidemia, and insulin resistance in the obese rat.

 Sprague Dawley normotensive rats on a standard rat chow diet  Sprague Dawley rats on a high-fat diet (45kcal fat)  Normal and obese Sprague Dawley rats exposed to Chronic Intermittent Hypoxia (60s episode at 6-7% O 2 followed by 2 mins room air 20.5% O 2. )  Ethanol extract of Panax quinquefolius by gavage: 0 or 250mg/kg in 0.9%saline every day before 1900 hrs for 28 days Model

 Weekly measurements of Blood pressure and heart rate by indirect tail cuff method (CODA system) Body weight Metabolism: Food/water intake, Urinary output, Urine Na+, K+  After sacrifice Brainstem effects: Fos/Fra to detect central areas activated in response to administration of ginseng Circulating levels of leptin, insulin Obesity study:  Lipid profiles o Triglycerides o Cholesterol  Retroperitoneal fat pad  Epididymal fat pad

Cumulative Weight Change * (n= 5)

Food Intake (n= 4-5) * * ** * * **

Retroperitoneal Fat Pad * * * *

Epididymal Fat Pad * * * *

Plasma Leptin Concentration * * * * * *

Plasma Triglycerides

Total plasma cholesterol

Blood Glucose Diet * *

Plasma Insulin

Insulin Resistance

Mean Arterial Pressure Normal Diet High Fat Diet

Heart Rate Normal Diet High Fat Diet

Normal Diet  No statistical differences were seen in Heart weight Kidney weight Hematocrit Water intake Urine output

Ongoing Studies  Increasing ‘n’ values Normal/High fat diets  Analyze brain sections processed for cfos/Fra immunohistochemistry  Western blot and qPCR for long form of leptin receptor in brainstem/hypothalamus  Chronic Intermittent Hypoxia Model of Obstructive Sleep Apnea

Questions