• The President’s Desk  — Reforming Health Care

• Blood Pressure Control  — New Combination of Nutrients Addresses Three Critical Factors

• Can Stress Sabotage Weight Loss Efforts?  — 

• Resveratrol  — Remarkable Longevity Enhancer and Heart Protector

• Building Brain Health with Memory-Boosting, Anti-Inflammatory Supplement  — 

• Pet Corner  — Leaky Gut Syndrome in Pets

• Lithium Orotate  — The Mood-Enhancing Mineral

• Nutrition Review  — Latest Research on Fatigue, Digestive Health, Blood Pressure and More

• Osteopenia and Bursitis
• Edema of Lower Legs
• Broken Arm
• Chronic Constipation, Gastric Pain
• Congestive Heart Failure
• Fat Blockers and Glabrinex™
• Thyroid Medication Resistance
• Sinus Health, Immunity
• Torn Ligament
• Kidney Health
• Idiopathic Disease

There is currently an atmosphere of change in this country with many politicians recognizing that one of the areas most in need of reform is our country’s health care system.

For real change to occur, however, lawmakers must put aside the notion that healthcare encompasses only drugs and surgery and instead incorporate a philosophy of wellness rather than one that embraces solely the treatment of disease. To achieve a healthier America, our Senators, Congress people and President must learn to approach health care from a perspective that is good for the citizens of this country rather than for the pockets of the pharmaceutical companies.

For our health care system to be truly reformed, lawmakers need to recognize the key role that nutritional supplements play in maintaining optimal health. They need to discard the prejudice that exists against nutritional supplements and explore the science that demonstrates the effectiveness of various vitamins, minerals, botanicals and amino acids.

“Wellness has to be cool and prevention has to be a hot thing,” Senator Tom Daschle, the new Secretary, US Department of Health and Human Services recently said. But to many of us, it’s not only about transforming wellness into a hot topic. It’s also about rewriting the definition of wellness to one that includes being able to pursue our journey to health in our own way. Wellness means empowering individuals to learn about their health and to have the choice to seek out every option available, including nutritional supplements that are scientifically documented to be effective and affordable. Together, by contacting our Senators and Congress people and letting them know the value we place on science-backed supplements, we can ensure that health reform equals health freedom.

In past articles in Vitamin Research News (“Anti-Hypertension Protocol Using Shark Cartilage and Cordyceps Sinesis”) we have discussed how too much parathyroid hypertensive factor (PHF) will increase intracellular calcium and how lowering PHF will reduce calcium entry into vascular smooth muscle, reducing blood pressure. This still remains a very important component of blood pressure control, yet, this is only part of the story. Only 30 percent or more of hypertensive patients have increased PHF levels, leaving a large number of individuals whose hypertension originates due to causes other than high PHF. Nitric Oxide deficiency and the activity of angiotensin-converting enzyme (ACE) are two other equally important factors. Additionally, minimizing arterial calcification also can have impressive effects on blood pressure by improving dilation and blood flow through the arteries. Because physicians can never be certain which of these factors are contributing to an individual patient’s hypertension, they will often experiment with various approaches that address each of these issues until they find the solution.

In this article, I will go beyond the issue of PHF to explain three other causes behind hypertension. I will explain the role that nitric oxide can play in maintaining healthy blood pressure levels. Furthermore, I will discuss how the ACE enzyme is often implicated in high blood pressure and why any blood pressure regimen should also seek to improve arterial function. Finally, I will explain how a new combination of nutritional substances can address all three of these factors.

Nitric Oxide—Say Yes to NO

Optimal blood pressure measurements rely on balanced levels of the gaseous molecule nitric oxide (NO), which signals the blood vessels to relax. NO is produced in the body from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by reduction of inorganic nitrate. The inner lining of the blood vessels, known as the endothelium, also produces NO and uses it to signal the surrounding smooth muscle to relax. This causes the widening of the blood vessels, known as vasodilation, which increases blood flow and decreases blood pressure. The higher levels of NO activate another enzyme that leads to further relaxation of the vascular smooth muscle. NO can reduce platelet aggregation (the sticking together of blood platelets), thus stopping an excessive number of platelets from adhering to the vessel walls.

Endothelial dysfunction that occurs with lowered NO levels has been linked to hypertension as well as coronary artery disease and atherosclerosis.

Overactive ACE

Kidney cells produce the enzyme renin, which causes an enzymatic cascade that eventually results in hypertension. In the blood, renin splits a globular protein called angiotensinogen into a smaller peptide called angiotensin 1, which is then converted into angiotensin 2 by another enzyme called the angiotensin-converting enzyme (ACE). This process causes blood pressure to rise in high-renin patients. In fact, many anti-hypertensive drugs (called ACE inhibitors) block this enzyme, helping decrease the conversion of angiotensin 1 into 2 that results in hypertension.

Angiotensin 2 is known to have a number of adverse effects. It constricts blood vessels (vasoconstriction) partially by inhibiting bradykinin, a substance responsible for relaxing blood vessels, thereby decreasing blood pressure. However, when bradykinin levels drop due to the release of ACE into the blood, the blood vessels will constrict. Angiotensin 2 also constricts the minute arteries that carry blood away from the kidney, causing increased pressure in the capillary networks of the kidney, and can cause ventricular remodeling of the heart, which may lead to ventricular hypertrophy and congestive heart failure. Furthermore, angiotensin 2 stimulates the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules to retain sodium and chloride ions and excrete potassium. The increased sodium leads to retention of water, which in turn leads to increased blood volume and therefore a further increase in blood pressure. Angiotensin 2 also stimulates the posterior pituitary to release vasopressin (also known as anti-diuretic hormone, ADH), which acts on the kidneys to increase water retention.

Overactive ACE, through its role in the production of angiotensin 2, is implicated not only in hypertension but also congestive heart failure (CHF), left ventricular dysfunction, fibrosis, sarcoidosis and nephropathy in diabetes mellitus. Consequently, ACE inhibitors are frequently used in patients experiencing any of these conditions.

Arterial Calcification

When calcium deposits accumulate on arterial walls, it reduces the elasticity of the blood vessels and this stiffening interferes with the ability of the artery to expand and contract during each heartbeat. Studies have shown that high blood pressure is linked to coronary artery calcification even in healthy adults. In one study of women ages 20 to 35 years, each 10-mmHg change in systolic blood pressure while experiencing a stress-causing activity (playing video games) was associated with a 24 percent increase in the odds of having coronary artery calcification at follow-up. Blood pressure changes that occurred while the subjects played the video game predicted the presence of coronary artery calcification 13 years later.

“To our knowledge, this is the first study that reports blood pressure reactivity to a stressor being related to calcification in the coronary arteries,” the researchers wrote.¹

Clearly, protecting the elasticity of the arteries is of concern to anyone who wants to maintain optimal blood pressure levels.

Three-Part Approach

Maintaining healthy blood pressure levels often involves improving nitric oxide levels, inhibiting the enzyme ACE and strengthening arterial health. This approach can be accomplished with a single formula that contains extracts of grape seed and blueberry combined with vitamin K2.

Increasing Nitric Oxide Levels

Grape seed extract is emerging as a nutrient that has profound effects on nitric oxide production. This mechanism of action is thought to be the reason why it can maintain healthy blood pressure levels.

A number of studies have investigated the beneficial effects of grape seed extract. In a study presented at the FASEB 2007 conference, researchers examined the effect of a unique, patented form of grape seed extract on blood pressure in 22 subjects with pre-hypertension. In the United States, more than 69 million adults are prehypertensive and are consequently at a higher risk for heart disease. The current study, therefore, sought to take a look at grape seed’s effect on this condition, which is a threat to cardiovascular health.

Subjects with a systolic blood pressure between 120 and 139 mmHg and/or a diastolic pressure between 80 and 89 mmHg were randomized into a placebo group or an experimental group. The experimental group was given grape seed extract at a dose of 300 mg/day for 8 weeks. The blood pressure was recorded using an ambulatory blood pressure monitoring device at the start of the treatment period and at the end. Subjects taking the grape seed experienced a reduction in systolic blood pressure of 8.3 mmHg and 5.7 mmHg diastolic blood pressure.²

Another study of subjects with the metabolic syndrome was undertaken to determine whether grape seed extract could lower blood pressure in this group of subjects. Researchers randomized the 24 subjects into three groups. One group received 300 mg per day of the extract, another group received 150 mg/day and a third group received a placebo. A 12-hour ambulatory BP recording was made at the start of the study and after 4 weeks of treatment. Serum lipids, blood glucose, plasma insulin and oxidized LDL were measured at the start and end of the study. After 4 weeks subjects receiving both 150 mg and 300 mg of grape seed extract significantly lowered their blood pressure while those on the placebo showed no significant change. The fasting blood glucose, plasma insulin, serum lipids and plasma oxidized LDL concentrations were unchanged. The study results showed that patients on the 150 mg dose of grape seed extract experienced a 13-mmHg drop in systolic blood pressure and a 6-mmHg drop in diastolic measurements. The group receiving the 300 mg per day experienced a 12-mmHG reduction in systolic blood pressure and an 8-mmHg reduction in diastolic blood pressure.³

In exploring the reasoning behind grape seed’s blood-pressure lowering effects, researchers have determined that the extract causes an endothelium-dependent relaxation of blood vessels and that the mechanism behind this response involves the induction of endothelial nitric oxide synthase.⁴

In animal experiments, grape seed’s effects on blood pressure were the result of both raising nitric oxide levels and the extract’s ability to act as a calcium channel blocker. This led one group of researchers to conclude that grape seed “has a vasodilation effect not only in an endothelium-dependent, nitric oxide involved manner, but in inhibition of calcium release and blockage of potential-dependent calcium channels.”⁵

ACE Inhibition

As mentioned above, the enzyme ACE plays a significant role in the elevation of blood pressure as well as other conditions. Research is now showing that a special extract of blueberries may support healthy blood pressure levels by inhibiting ACE.
In a preliminary study, researchers treated cells with ACE, then exposed the cells to two different concentrations of the blueberry extract. ACE was inhibited by 98 percent in the cells treated with the highest concentration of the blueberry extract. This preliminary study confirms other studies conducted in rats that showed that blueberry-rich diets affected the vascular smooth muscle contractile machinery of the animals.⁶

Improving Arterial Elasticity

Vitamin K2 (menaquinone) is a known promoter of arterial elasticity, while vitamin K1 (phylloquinone) is not thought to provide these effects. In a recent study, scientists sought to compare the effects of both forms of vitamin K on arterial calcification. Researchers evaluated the intake of vitamin K1 and vitamin K2 of 564 post-menopausal women by using a food-frequency questionnaire. The study authors then determined that 62 percent (360) of the women had coronary calcification.

Vitamin K1 intake was not associated with reduction of coronary calcification. However, intake of vitamin K2 was associated with decreased coronary calcification.⁷

“This study shows that high dietary menaquinone intake, but probably not phylloquinone, is associated with reduced coronary calcification,” the researchers wrote. “Adequate menaquinone intakes could therefore be important to prevent cardiovascular disease.”

The mechanism behind vitamin K2’s anti-calcification effect is thought to involve the Matrix Gla-Protein (MGP). Scientists have called this substance “the calcification inhibitor in need of vitamin K.” MGP’s pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in arteries other than that performed by MGP. In order to prevent calcification, Matrix Gla-protein must have sufficient supplies of vitamin K2.⁸

Conclusion

High blood pressure can be caused by a number of factors including 1) parathyroid hypertensive factor’s role in increasing intracellular calcium; 2) a deficiency of nitric oxide; 3) increased activity of the ACE enzyme and 4) arterial calcification. In individuals whose blood pressure issues are caused by an increase in intracellular calcium, substances such as cordyceps and shark cartilage (PRESSURE-fX™) may be of interest. On the other hand, for individuals with nitric oxide deficiency, increased ACE activity and arterial calcification, a supplement that contains grape seed and blueberry extract plus vitamin K2 (Circutrol BP™) may play a positive role in achieving optimal blood pressure levels.

References
1. Matthews KA, Zhu S, Tucker DC, Whooley MA. Blood pressure reactivity to psychological stress and coronary calcification in the Coronary Artery Risk Development in Young Adults Study. Hypertension. 2006 Mar;47(3):391-5.
2. Lu B, Robinson M, Kappagoda T. Effect of a Novel Grape Seed Extract on Blood Pressure in Subjects with Prehypertension. Presented at the FASEB Experimental Biology Conference, Washington, DC, April 30, 2007.
3. Siva B, Edirisinghe I, Randolph J, Steinberg F, Kappagoda T. Effect of a polyphenolics extract of Grape Seeds (GS) on Blood Pressure(BP) in patients with the Metabolic Syndrome (MetS). Presented at the FASEB Experimental Biology Conference, San Francisco, April 2, 2006.
4. Edirisinghe I, Burton-Freeman B, Tissa Kappagoda C. Mechanism of the endothelium-dependent relaxation evoked by a grape seed extract. Clin Sci (Lond). 2008 Feb;114(4):331-7.
5. Zhang TX, Niu CQ, Hu JM, Liu H, Jing HE. Vasorelaxational effects of procyanidins on rabbit aorta in vitro and decreasing arterial blood pressure in vivo. Zhongguo Zhong Yao Za Zhi. 2008 Jul;33(14):1720-3.
6. Norton C, Kalea AZ, Harris PD,  Klimis-Zacas DJ. Wild Blueberry-Rich Diets Affect the Contractile Machinery of the Vascular Smooth Muscle in the Sprague–Dawley Rat. Journal of Medicinal Food. March 1, 2005; 8(1): 8-13.
7. Beulens JWJ, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JCM, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. Published online 26 August 2008.
8. Schurgers LJ, Cranenburg EC, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. 2008 Oct;100(4):593-603.

Stress and inflammation are two topics with which readers of this newsletter are extensively familiar. However, recent research has uncovered a fascinating link correlating the role that psychological stress plays in the inflammatory process and how this, in turn, may lead to the accumulation of abdominal fat. Consequently, individuals undergoing chronic stress may find their weight loss efforts sabotaged by the inflammatory process occurring in their bodies.

Psychological stressors induce several biochemical pathways. These include the hypothalamus-pituitary-adrenal (HPA) axis, which secretes the primary stress hormone cortisol; the sympathetic nervous system, which modulates the release of epinephrine and norepinephrine; the renin-angiotensin system, which regulates blood pressure; and the immune response, which regulates inflammation. In addition, the stress response induces the release of various cellular messengers known as cytokines. These stress-related hormones and cytokines initiate the acute phase response and the induction of acute phase proteins, which are the primary mediators of inflammation.¹ Stress hormones induce numerous pro-inflammatory mediators such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha and C-reactive protein (CRP).² Thus, psychological stressors induce inflammation in the body.

Stress-Related Inflammation Compromises Weight Loss

Researchers have shown that activation of the stress response is associated with weight gain, particularly the accumulation of visceral fat. As we’ve discussed in past newsletter articles, visceral fat is adipose tissue that surrounds the abdominal organs and, unlike the fat found under the skin, is highly physiologically active. It is believed that both hormones and pro-inflammatory cytokines play a role in the accumulation of visceral fat. More specifically, cortisol, IL-6, and angiotensin 2 are associated with increased appetite, fat accumulation, and obesity.³ Interestingly, stress induces the accumulation of visceral fat, which in turn, leads to dysfunction of the HPA axis, causing a vicious cycle resulting in additional fat deposition. HPA axis activation increases cortisol production, which has been shown to cause increased food ingestion and decreased fat-burning effects. The glucocorticoid hormones such as cortisol affect the visceral fat more than subcutaneous fat due to an increase in blood supply, more cells per mass, and an increased number of glucocorticoid receptors. It is suggested that increased cortisol may play an important role not only in the development of increased abdominal fat, but also in all metabolic abnormalities related to abdominal obesity.⁴

Recent research indicates that inflammation may be the common link between increased stress and weight gain. Researchers have found that the stress-induced inflammatory response affects the amount and activity of visceral or abdominal fat. Increased visceral fat mass (central obesity) is associated with several conditions such as diabetes, metabolic syndrome, and cardiovascular disease. Visceral fat releases numerous pro-inflammatory molecules such as IL-6, TNF-alpha, leptin, resistin, adipokines, and acute phase proteins. This inflammatory response of visceral fat is associated with the accumulation of adipose (fat) tissue.

Additional factors also play a role in stress-induced fat deposition. Obese patients have increased levels of leptin, TNF-alpha, and IL-6, with decreased levels of adiponectin. Leptin is a hormone produced by adipose tissue that controls food intake and body weight. Pro-inflammatory cytokines can stimulate leptin production from fat, which then stimulates the HPA axis and sympathetic nervous system. Research has also shown that in patients with type 2 diabetes, those with an increased stress response have increased levels of cortisol and leptin, independent of the body mass index (BMI).⁵ Adiponectin is a hormone that acts as an insulin-sensitizer, and is decreased in patients with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin promotes the breakdown of fatty acids in skeletal muscle and counteracts the pro-inflammatory actions of TNF-alpha, and thus, may protect against insulin resistance and atherosclerosis.⁶

The Common Link

Central obesity is associated with several conditions including diabetes, coronary artery disease, and metabolic syndrome. There is a strong association between stress, inflammation, abnormal lipid and carbohydrate metabolism, obesity, insulin resistance, and atherosclerosis. Some researchers suggest that the pro-inflammatory cytokine TNF-alpha is the common link.⁷

Researchers have shown that the combination of stress, visceral fat, and insulin resistance is strongly associated with metabolic syndrome,⁸ yet total body fat was not.⁹ Researchers have shown that in obese women with normal blood pressure, pro-inflammatory mediators such as IL-6, TNF-alpha, and CRP correlate with both cardiovascular abnormalities and an increased amount of intra-abdominal fat, and thus may support that visceral fat predisposes to cardiac dysfunction, possibly through a low-grade inflammatory state.¹⁰ Similarly, studies have also shown that normal-weight women with increased visceral fat adiposity (metabolic obesity) had increased blood pressure, insulin, triglycerides, free fatty acids, oxidized LDL, leptin, TNF-alpha, IL-6, and lower levels of adiponectin compared to the control group of women with normal visceral adiposity, thus showing an increase in inflammatory and cardiovascular disease risk factors with increased visceral fat.¹¹

Insulin resistance also is associated with increased inflammation. Atherosclerosis and insulin resistance share similar pathology, mainly due to TNF-alpha and IL-6. Abdominal obesity is strongly associated with diabetes, possibly due to the decrease in insulin sensitivity seen with increased abdominal fat. Research also suggests that the cytokines secreted from visceral fat such as IL-6 and TNF-alpha have a direct adverse effect on the beta cells of the pancreas which secrete insulin.¹²

Reducing Visceral Fat

Individuals who are experiencing elevated levels of stress and the subsequent increase in abdominal fat can enhance the effectiveness of their weight loss program by including Glabrinex™, a Glycyrrhiza glabra root extract standardized for the flavonoid glabridin. This flavonoid has been shown to decrease visceral fat, and has antioxidant and blood-sugar lowering properties as well. Glabridin down-regulates the synthesis of fat while increasing the activity of the enzymes responsible for the breakdown of fat tissue. In one study, obese rats fed a high-fat diet were supplemented with the Glycyrrhiza extract. The results showed that the addition of Glycyrrhiza extract significantly decreased the weight of the abdominal adipose tissue, as well as lowered levels of plasma and liver triglycerides.¹³

In a similar study, diabetic obese mice were fed a high-fat diet and supplemented with Glycyrrhiza extract for 4 weeks. The Glycyrrhiza group showed significantly decreased body weight gain, weight of abdominal adipose tissues, and blood glucose levels compared to the control group.¹⁴ Another study demonstrated that obese mice fed a high-fat diet with the Glycyrrhiza extract showed a reduction in the weight of abdominal adipose tissues and body weight gain, smaller adipose cells, and improvement in the fatty degenerative state of the liver cells.¹⁵

Human studies have shown similar results. In a randomized, double-blind, placebo-controlled trial, overweight subjects were supplemented with 300 mg per day of Glycyrrhiza extract for 12 weeks. The results showed a significant difference in the changes in body weight and BMI between the treatment group and the placebo group. Additionally, the researchers found that the weight-reducing effect of the Glycyrrhiza extract was specifically due to a reduction in body fat.¹⁶ In another clinical trial, overweight subjects were given 300 mg, 600 mg, or 900 mg of Glabrinex per day for 8 weeks. All three dosage groups showed a significant decrease from baseline measurements in fat mass. In the group supplemented with 900 mg per day, the subjects showed a significant decrease in body weight, BMI, and visceral fat mass.¹⁶

Glabridin has also been shown to exhibit direct anti-inflammatory activity,¹⁷ has demonstrated neurological¹⁸ and cardiovascular¹⁹ protective functions, inhibits the re-uptake of serotonin possibly benefiting mild to moderate depression,²⁰ and has anti-microbial and antioxidant properties.^21-22 Research has shown that even modest weight loss is associated with a decrease in inflammatory mediators, resulting in a decreased risk for several inflammatory related conditions.

Conclusion

Psychological stressors are unavoidable. However, the adverse health effects of inflammation and weight gain associated with stress may be more readily modified. Glabrinex may be beneficial for individuals with increased stress, central weight gain, and related inflammatory conditions.

References
1. Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun. 2002 Dec;16(6):622-53.
2. Elenkov IJ, Iezzoni DG, Daly A, et al. Cytokine dysregulation, inflammation and well-being. Neuroimmunomodulation. 2005;12(5):255-69.
3. Black PH. The inflammatory consequences of psychologic stress: relationship to insulin resistance, obesity, atherosclerosis and diabetes mellitus, type II. Med Hypotheses. 2006;67(4):879-91.
4. Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S47-9.
5. Pickup JC, Chusney GD, Mattock MB. The innate immune response and type 2 diabetes: evidence that leptin is associated with a stress-related (acute-phase) reaction. Clin Endocrinol (Oxf). 2000 Jan;52(1):107-12.
6. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006 Mar;17(1):4-12.
7. Grimble RF. Inflammatory status and insulin resistance. Curr Opin Clin Nutr Metab Care. 2002 Sep;5(5):551-9.
8. Chandola T, Britton A, Brunner E, et al. Work stress and coronary heart disease: what are the mechanisms? Eur Heart J. 2008 Mar;29(5):640-8.
9. Druet C, Baltakse V, Chevenne D, et al. Independent effect of visceral adipose tissue on metabolic syndrome in obese adolescents. Horm Res. 2008;70(1):22-8.
10. Malavazos AE, Corsi MM, Ermetici F, et al. Proinflammatory cytokines and cardiac abnormalities in uncomplicated obesity: relationship with abdominal fat deposition. Nutr Metab Cardiovasc Dis. 2007 May;17(4):294-302.
11. Hyun YJ, Koh SJ, Chae JS, et al. Atherogenecity of LDL and unfavorable adipokine profile in metabolically obese, normal-weight woman. Obesity (Silver Spring). 2008 Apr;16(4):784-9.
12. Bonora E, Brangani C, Pichiri I. Abdominal obesity and diabetes. G Ital Cardiol (Rome). 2008 Apr;9(4 Suppl 1):40S-53S.
13. Kamisoyama H, Honda K, Tominaga Y, et al. Investigation of the anti-obesity action of licorice flavonoid oil in diet-induced obese rats. Biosci Biotechnol Biochem. 2008 Dec;72(12):3225-31.
14. Nakagawa K, Kishida H, Arai N, et al. Licorice flavonoids suppress abdominal fat accumulation and increase in blood glucose level in obese diabetic KK-A(y) mice. Biol Pharm Bull. 2004 Nov;27(11):1775-8.
15. Aoki F, Honda S, Kishida H, et al. Suppression by licorice flavonoids of abdominal fat accumulation and body weight gain in high-fat diet-induced obese C57BL/6J mice. Biosci Biotechnol Biochem. 2007 Jan;71(1):206-14.
16. Tominaga Y, Mae T, Kitano M, et al. Licorice flavonoid oil effects body weight loss by reduction of body fat mass in overweight subjects. J Health Sci. 2006;52(6):672-683.
17. Kwon HS, Oh SM, Kim JK. Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis. Clin Exp Immunol. 2008 Jan;151(1):165-73.
18. Yu XQ, Xue CC, Zhou ZW, et al. In vitro and in vivo neuroprotective effect and mechanisms of glabridin, a major active isoflavan from Glycyrrhiza glabra (licorice). Life Sci. 2008 Jan 2;82(1-2):68-78.
19. Kang JS, Yoon YD, Cho IJ, et al. Glabridin, an isoflavan from licorice root, inhibits inducible nitric-oxide synthase expression and improves survival of mice in experimental model of septic shock. J Pharmacol Exp Ther. 2005 Mar;312(3):1187-94.
20. Ofir R, Tamir S, Khatib S, et al. Inhibition of serotonin re-uptake by licorice constituents. J Mol Neurosci. 2003 Apr;20(2):135-40.
21. Carmeli E, Harpaz Y, Kogan NN, et al. The effect of an endogenous antioxidant glabridin on oxidized LDL. J Basic Clin Physiol Pharmacol. 2008;19(1):49-63.
22. Haraguchi H, Yoshida N, Ishikawa H, et al. Protection of mitochondrial functions against oxidative stresses by isoflavans from Glycyrrhiza glabra. J Pharm Pharmacol. 2000 Feb;52(2):219-23.

For the past few years, resveratrol, a compound found in red grapes, has attracted widespread medical attention as the long sought-after fountain of youth. This is because research has begun to indicate that this phytonutrient does indeed seem to have longevity-enhancing effects and that it also can play a critical role in heart health. Since 2003, when Harvard researchers discovered that resveratrol increases the life span of yeast cells by as much as 70 percent, scientists have eagerly studied its effects in increasingly complex forms of life. Following up on research that resveratrol extended the life of roundworms and fruit flies, the most recent studies reveal for the first time that resveratrol also extends life span in mammals.

Resveratrol Promotes Longevity

A groundbreaking study in 2006, investigating resveratrol in mammals, found that dietary supplementation with resveratrol protected obese mice on a high-calorie diet, improving their health and extending their life span.¹ The study, conducted by the National Institute on Aging and a group co-led by pioneering researcher Dr. David Sinclair, compared three groups of middle-aged mice on three diets: a standard diet and a high-calorie diet (60 percent of calories from fat) with and without resveratrol (22.4 mg/kg/day). As expected, the mice in the untreated high-calorie group showed signs of obesity, developing enlarged livers, muscle inflammation, early signs of diabetes and heart disease, and dying much sooner than those on the standard diet. However, the resveratrol-supplemented mice developed none of these complications despite being obese. The mice given the high-fat diet and resveratrol lived as long as the mice fed the standard diet and up to 31 percent longer than the untreated obese group. This study dramatically showed for the first time that resveratrol increases life span for obese mammals, which would otherwise be expected to develop chronic diseases, especially type 2 diabetes, and to die sooner. Of the 153 biochemical pathways significantly altered in the high-calorie group, resveratrol opposed the effects of high-caloric intake in 144 of them (94 percent). Although the resveratrol-treated mice lost no weight, the supplement effectively offset the detrimental effects of a high-calorie diet by shifting their overall physiology towards that of the control group and preventing many of the obesity-associated pathologies.¹

Increasing Energy Expenditure

Soon after this study, French researchers shed some light as to what was going on. They fed healthy young mice large amounts of resveratrol (400 mg/kg/day) for 15 weeks.² The team discovered that it greatly enhanced the aerobic capacity of the mice, doubling their physical endurance during exercise, increasing oxygen consumption efficiency, and significantly increasing grip strength.

The investigators also found that the size and number of mitochondria, the powerhouses of cells, were dramatically increased in muscle fibers, which explained the greater energy-output capacity and endurance of the mice. As a result of the increased energy expenditure, the resveratrol-treated mice in the high-calorie group were able to burn off most of their excess calories rather than storing them as fat, preventing weight gain.²

SIRT1: The Longevity Gene

Scientists are still uncertain of the exact mechanism by which resveratrol works, but believe it acts in a similar way to calorie restriction, which switches on a longevity gene called SIRT1.^1-2 SIRT1 is thought to be triggered in times of famine to ensure the survival of a species. In times of caloric restriction, SIRT1 appears to act both as a sensor of nutrient availability and a regulator of gluconeogenic and glycolytic pathways in the liver.³

The activity of SIRT1 increases in fat cells after food limitation, which plays a key role in lipid metabolism by moving fat stores from the cells into the bloodstream for conversion to energy in other tissues. Researchers have found that mice genetically engineered to have increased levels of SIRT1 and fed a high-calorie diet do not gain any more weight than controls since the excess calories are offset by increased energy expenditure.⁴

Another recent study supports these findings. It showed that SIRT1 levels are reduced in insulin-resistant cells and tissues.⁵ Furthermore, treatment with SIRT1 inhibitors causes insulin resistance, while resveratrol improves insulin sensitivity in vitro in a SIRT1-dependent manner. In vivo, resveratrol, 2.5 mg/kg/day, reduces insulin resistance in the cells of animals fed a high-fat diet.⁵

Resveratrol: A Calorie-Restriction Mimetic

Studies in the past year confirm that resveratrol mimics the favorable gene-expression changes seen with calorie restriction. In a study co-led by Sinclair, middle-aged mice were placed on three different diets: a standard diet, dietary restriction by every-other-day feeding of a nutritious diet, and a high-calorie diet (60 percent calories from fat).⁶ The mice in each group were also divided into treatment with and without resveratrol (up to 30 mg/kg/day). As with the previous Sinclair study,¹ the resveratrol-supplemented mice in the high-calorie group did not lose weight, but lived longer than the untreated high-calorie group. The researchers speculated that an improvement in several markers for heart health and a reduction both in aortic stiffness and the severity of albuminuria may have contributed to animals’ increased life span.⁶

They also found that even in mice in the standard diet group, resveratrol improved cardiovascular function, bone density, and motor function, and delayed cataracts.⁶

The team also performed a gene-expression analysis in liver, skeletal muscle, fat, and heart tissue to see if resveratrol mimicked the physiological effects of dietary restriction in terms of gene activity. They found that resveratrol induced transcriptional changes in key metabolic tissues that closely resembled those induced by dietary restriction in the group fed every other day. However, they were unable to confirm SIRT1’s role in the anti-aging effects seen in this study. The team concluded, “long-term resveratrol treatment of mice can mimic transcriptional changes induced by dietary restriction and allow them to live healthier, more vigorous lives.”⁶

It may be that resveratrol alters not just SIRT1, but multiple proteins involved in the cellular stress response. A recent study focused on another target—an enzyme called AMPK (adenosine monophosphate-activated kinase), which is a sensor of cellular energy levels and is thought to be activated in brain neurons during calorie restriction. Using neuronal cell cultures and mice, the researchers found that many of resveratrol’s effects including energy expenditure do indeed depend on AMPK.⁷ Resveratrol activated AMPK in primary neurons in vitro as well as in the brain. It also stimulated mitochondrial biogenesis (the formation of increased numbers of mitochondria) in an AMPK-dependent manner, which plays an important part in neuronal energy homeostasis and contributes to the neuroprotective effects of resveratrol.⁷

While research into gene-expression changes induced by resveratrol continues, another study published this year builds on evidence that alcohol inhibits SIRT1 and AMPK. This study of alcoholic fatty liver showed that the accumulation of fat in the livers of mice fed alcohol and a low-fat diet could be prevented with resveratrol through its upregulation of both SIRT1 and AMPK.⁸

Cardiovascular Protection

Results from the groundbreaking studies mentioned earlier revealed that mice in high-calorie groups given resveratrol had healthier hearts, essentially helping them to live normal, active lives despite becoming obese.¹

A new study confirms that resveratrol confers special protection to the heart.⁹ Researchers divided two groups of middle-aged mice (14 months) to receive resveratrol (4.9 mg/kg/day) or a calorie-restricted diet (reduction of daily energy intake by 40 percent) and followed them until old age (30 months). They found that while aging altered gene-expression profiles in the heart, calorie restriction and resveratrol mitigated these changes by 90 and 92 percent, respectively, thus preventing the decline in cardiovascular function associated with aging. The researchers stated that “resveratrol at doses that can be readily achieved through dietary supplementation in humans is as effective as calorie restriction in opposing the majority of age-related transcriptional alterations in the aging heart.”⁹

They also measured an indicator of cardiac function called the myocardial performance index, which normally increases with declining function and age. Both calorie restriction and resveratrol almost completely protected against this increase, unlike the control group, in which the index increased as expected. They concluded, “resveratrol mimics the effects of calorie restriction to prevent cardiac aging at both the transcriptional and functional levels.”⁹

Many studies have found that resveratrol acts through several mechanisms to protect against acute and chronic heart disease. In an experimental study of cardiac hypertrophy, resveratrol helped improve blood flow by increasing the production of nitric oxide, the universal vasodilator, by 90 percent,¹⁰ while reducing levels of the artery-constricting angiotensin 2.¹⁰

In another experimental study, resveratrol showed a direct cardioprotective effect on diabetic myocardium in rats with streptozotocin-induced diabetes. Resveratrol also significantly reduced glucose levels in this study, improved left ventricular function, reduced the size of myocardial infarcts, and increased levels of superoxide dismutase, a powerful antioxidant.¹¹ Another study showed that resveratrol has potent cardioprotective properties following a reduction in oxygen and blood supply in ischemia-reperfused hearts.¹²

In addition, resveratrol inhibits platelet aggregation in high-risk cardiac patients,¹³ which lowers the risk of deadly blood clots that can cause heart attacks. It also reduces the expression of endothelin (a potent vasoconstrictor) and cardiac apoptosis in ischemic-reperfused hearts,¹⁴ and increases endothelial progenitor cells in patients with hypercholesterolemia (which helps repair arteries damaged by atherosclerosis).¹⁵ In addition, resveratrol protects heart muscle by reducing the effects of cardiac fibrosis (stiffening of heart tissue).¹⁶

Osteoarthritis and Neurodegenerative Diseases

Resveratrol may also hold promise in osteoarthritis following studies that it inhibits the expression of proinflammatory mediators such as COX-217 and that it has a cartilage-protecting effect.¹⁸

Resveratrol also offers neuroprotective benefits. It has been shown to help degrade the destructive amyloid-beta protein implicated in Alzheimer’s disease¹⁹ and protect dopaminergic neurons against a neurotoxic compound that causes brain lesions in Parkinson’s disease.²⁰

Conclusion

Resveratrol can harness the anti-aging benefits of calorie restriction without food deprivation by activating genes that influence a variety of aging-related metabolic functions. Resveratrol is metabolized very rapidly when ingested, but its bioavailability can be increased with substances such as quercetin (as found in Extension Resveratrol). In addition, resveratrol occurs naturally as two forms: cis and trans, but it is the trans form that is the most bioactive and clinically beneficial. Furthermore, the studies mentioned in this article used human equivalent doses of resveratrol of up to a few hundred milligrams per day. In fact, the leading resveratrol researcher, Dr. Sinclair, has been reported to take 5 mg/kg/day of resveratrol,²¹ which translates to 300 mg/day for a 60-kg (132-lb) person.

References

1. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-342.

2. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006 Dec 15;127(6):1109-1122.

3. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005 Mar 3;434(7029):113-118.

4. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschöp MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci USA. 2008;105(28):9793-9798.

5. Sun C, Zhang F, Ge X, et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 2007;6:307-319.

6. Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008 Aug;8(2):157-168.

7. Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 2007;104(17):7217-7222.

8. Ajmo JM, Liang X, Rogers CQ, Pennock B, You M. Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G833-G842.

9. Barger JL, Kayo T, Vann JM, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE. 2008 Jun 4;3(6):e2264.

10. Liu Z, Song Y, Zhang X, et al. Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model. Clin Exp Pharmacol Physiol. 2005 Dec;32(12):1049-1054.

11. Thirunavukkarasu M, Penumathsa SV, Koneru S, et al. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med. 2007 Sep 1;43(5):720-729.

12. Dernek S, Ikizler M, Erkasap N, et al. Cardioprotection with resveratrol pretreatment: improved beneficial effects over standard treatment in rat hearts after global ischemia. Scand Cardiovasc J. 2004 Aug;38(4):245-254.

13. Stef G, Csiszar A, Lerea K, Ungvari Z, Veress G. Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance. J Cardiovasc Pharmacol 2006;48:1-5.

14. Lekli I, Szabo G, Juhasz B, et al. Protective mechanisms of resveratrol against ischemia-reperfusion induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin. Am J Physiol Heart Circ Physiol. 2008;294:H859-H866.

15. Wang XB, Huang J, Zou JG, et al. Effects of resveratrol on number and activity of endothelial progenitor cells from human peripheral blood. Clin Exp Pharmacol Physiol. 2007 Nov;34(11):1109-1115.

16. Olson ER, Naugle JE, Zhang X, Bomser JA, Meszaros JG. Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1131-H1138.

17. Martinez J, Moreno JJ. Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem Pharmacol. 2000;59:865-870.

18. Elmali N, Baysal O, Harma A, Esenkaya I, Mizrak B. Effects of resveratrol in inflammatory arthritis. Inflammation. 2007;30:1-6.

19. Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem. 2005 Nov 11;280(45):37377-37382.

20. Blanchet J, Longpré F, Bureau G, et al. Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jul 1;32(5):1243-1250.

21. Wade N. Yes, red wine holds answer. The New York Times. 2006, Nov 2.

Galantamine is a natural plant product used for neurological conditions. It is also a popular nootropic agent, used for better memory retention, concentration and better “dream recall.”¹ This plant-derived substance supports better living by providing clearer memory to anyone seeking cognitive enhancement including students, teachers, seniors, and individuals who want to improve their job-related attention skills (for example, airline pilots). It also may help individuals who are seeking to give up cigarettes.

Galantamine is isolated from daffodil bulbs, the Caucasian snowdrop, and Leucojum aestivum (snowflake). The active ingredient in daffodil extracts were used as popular home remedies in Europe and re-discovered during ethnobotany driven drug exploration.²

Galantamine as a supplement is a reversible acetylcholinesterase inhibitor, which results in higher brain acetylcholine levels in animals and humans.^2-3 Acetylcholinesterase inhibitors such as galantamine suppress acetylcholinesterase to prevent it from degrading acetylcholine, which allows the neurotransmitter to persist in the synaptic cleft for longer, enhancing cognitive function.

In addition to acetylcholine, dopamine also is an important thought transmitter in the brain, and galantamine increases brain dopamine levels in experimental animals and humans.¹ Poorly functioning animal and human brains have much lower levels of acetylcholine than normal brains and lower levels of dopamine than normal brains.^{4-5, 7}

A Cochrane Database Systematic Review of all galantamine studies that fit its review criteria showed that galantamine above 8 mg per day over 3- to 6-month study periods showed statistically significant improvements in cognitive performance in mildly cognitively impaired people.⁶

Powerful Cognitive Enhancer

Numerous studies have investigated galantamine’s role in memory improvement. The safety and efficacy of galantamine has been demonstrated in multiple randomized, Phase III trials of greater than 2,600 patients with mild-to-moderate Alzheimer’s disease (AD). Studies have found that galantamine improved or maintained performance in all domains of AD (cognition, function, behavior, and caregiver burden).⁸

Many of the studies on galantamine were designed to study its effects in the short-term (3 to 12) months, so in 2004, researchers decided to conduct a 36-month trial to investigate its effectiveness over the long-term. In the trial, 194 subjects with mild to moderate Alzheimer’s were randomized to receive galantamine hydrobromide or a placebo. Subjects subsequently received open-label continuous galantamine therapy for up to 36 months. Cognitive decline in galantamine-treated subjects was compared with that in a clinically similar historical control sample of AD patients who had received placebo for 12 months and with the mathematically predicted decline of untreated patients over 36 months. The rate of cognitive decline of the 119 patients who completed the entire 36-month trial was compared with that of the 75 patients who withdrew for any reason during the long-term open-label extension.

Patients treated continuously with galantamine for 36 months experienced a substantially smaller cognitive decline (approximately 50 percent) than that predicted for untreated patients. Almost 80 percent of patients who received galantamine continuously for up to 36 months seemed to demonstrate cognitive benefits compared with the rate that would be predicted for untreated patients.⁹

According to the study authors, “Cognitive decline over 36 months of continuous galantamine treatment was substantially less than the predicted cognitive decline of untreated patients with mild to moderate dementia. Thus, the cognitive benefits of galantamine seemed to be sustained for at least 36 months. These findings suggest that galantamine slows the clinical progression of AD.”

Galantamine appears to increase oxygenated blood hemoglobin in elderly people’s brains, as measured by near-infrared spectroscopy, compared to older people with dementia, who had less oxygenated hemoglobin when both groups were compared performing a verbal fluency task (VFT). Healthy female subjects show more oxygenated brain hemoglobin than their male counterparts.¹⁰

Animal studies have reinforced the fact that galantamine possesses strong cognitive-enhancing properties.

In a study using 60 younger rabbits (4-month-old) and 60 older rabbits (27-month-old), galantamine-treated old and young rabbits were better learners than untreated old or young rabbits.¹¹

Actual physical changes occurred in the brains of the galantamine-treated rabbits because their brains had higher levels of brain nicotinic receptor binding sites (memory binding sites). The memory changes to the treated rabbits were permanent and structural during their growth and development.¹¹

Glutamate induced toxicity is believed to be one of the central mechanisms that result in Alzheimer’s and Parkinson’s disease by attacking and killing cortical neurons. Galantamine protected from both high dose and lower dose glutamate toxicity in rat cortical neurons. The protective effect of galantamine was, again, mediated through nicotinic acetylcholine receptors. The authors of this study concluded, “These findings unveiled the hitherto unknown neuroprotective effects of therapeutic AChe inhibitors and provided valuable insights into its neuroprotective mechanisms.”¹²

Early postnatal maternal deprivation causes memory deficits in adult life regardless of species, including primates and man. A 2008 study with pregnant rats set about to prove the theory that these memory deficits in later life were linked to a disruption of the cholinergic system. Complete maternal deprivation affects social learning in rats, primates and humans. In this study, the rat mothers were separated from their pups for 3 hours from postnatal day 1 to postnatal day 10. The grown pups showed a clear impairment in memory of two recognition tasks measured 24 hours after training, but treatment (with oral galantamine) reversed the memory impairments caused by maternal deprivation.¹³

Several studies have revealed that galantamine, both in brain cell cultures and in transgenic mice, has the ability to regulate amyloid precursor protein processing. APP, or amyloid precursor protein, forms brain beta amyloid found in animal and human Alzheimer brains in significant quantities. Galantamine interferes with APP formation through multiple complex mechanisms involving its cholinergic agonist effect and other signaling pathways.¹⁴

In three studies with rabbits that were intentionally surgically brain damaged by cutting certain hippocampal areas of the brain, galantamine later completely restored the rabbits’ eye blink reflex.¹⁵ In the author’s words: “These findings suggest that galantamine may provide benefit in the reversal of cognitive dysfunction following certain types of brain damage, especially damage involving hippocampal structures.”

APP23 mice as they grow older develop a cognitive deficit similar to Alzheimer’s disease seen in higher mammals. At 6 weeks of age half of the mice were implanted with an osmotic pump delivering a steady amount of galantamine to the brain. After two months the pumps were removed and the animals were given a cognitive evaluation called the Morris water maze. Low-dose galantamine significantly improved their spatial accuracy compared to the control mice not receiving galantamine. The author’s concluded, “This is the first study reporting disease-modifying efficacy of galantamine and memantine in transgenic mice modeling Alzheimer’s disease.”¹⁶

AD11 mice that could not produce nerve growth factor also develop an early form of neurodegeneration resembling Alzheimer’s disease found in higher mammals. In an earlier study, scientists divided the mice into two groups, one group receiving galantamine, the other a placebo. The brains of the mice receiving galantamine for two months showed a greatly reduced amount of APP (amyloid precursor protein) compared to the untreated controls. This study again demonstrates that a mouse model of neurodegeneration can be prevented by giving galantamine at an early enough age.¹⁷

Going to Bat Against Inflammation

Recent (2009) research with galantamine is revealing how the brain, and, in particular, the vagus nerve, controls the release of inflammatory cytokines that are the fundamental backbone of all inflammatory conditions throughout the body. The vagus nerve is the central regulator keeping inflammation down by controlling brain acetylcholinestrase activity. The authors concluded, “inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central…vagal…dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor (galantamine) can be utilized to suppress abnormal inflammation to therapeutic advantage.”¹⁸

Other Uses for Galantamine

Beyond its effects on memory and inflammation, galantamine appears to have other fascinating uses.

Galantamine can help individuals who are undergoing smoking cessation. In one study conducted with detoxified alcohol-dependent patients who smoked, galantamine reduced smoking rates 20 percent in a 24-week randomized multi-center clinical trial. One hundred fourteen smokers received galantamine or placebo without any other intervention and the results were positively confirmed by measuring the patients’ blood cotinine levels.¹⁹

Pesticides and nerve gas agents greatly increase the action of acetylcholine at all its receptor sites in the human body. Overstimulation of acetylcholine can lead to incapacitation, muscle paralysis and even death. The PNAS Albuquerque study investigated galantamine as a treatment for pesticide and nerve gas exposure.²⁰

Galantamine protected guinea pigs against sarin and soman, the two most common nerve gas agents, along with parathion, used in most bug sprays, lawn sprays and used as a crop pesticide. Galantamine in combination with atropine gives complete protection against these man-made toxins. This would be especially useful knowledge to farmers, people handling pesticides and lawn-spraying personnel as well as the general public, who are often exposed to these chemicals through the environment.²⁰

Galantamine also is a potent antioxidant, a property that was demonstrated in one study using brain cell cultures. Identical brain cell batches were exposed to hydrogen peroxide, with one of the batches containing galantamine. In the brain cell batch without galantamine present, oxygen free radical levels rose 54 percent and nitrogen free radical levels rose 52 percent. Galantamine reduced the release of oxygen free radicals by 50 percent, and kept nitrogen free radicals at control levels no matter what concentration of hydrogen peroxide was added to the brain cell cultures.²¹

Conclusion

As an acetylcholinesterase inhibitor, galantamine has shown itself to have memory improvement effects in various animal and human studies. The galantamine available here provides the original, naturally derived plant extract, rather than the higher cost synthetic product sold by others and is therefore a good choice for individuals seeking cognitive enhancement with additional benefits.

References

1. Hornick A, Schwaiger S, Rollinger JM, Stuppner H. Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: brain ACh increasing and memory improving properties. Biochem Pharmacol. 2008 Jul 15; 76(2):236-48.

2. Heinrich, M., Teoh, H.L. Galanthamine from snowdrop—the development of a modern drug…from local Caucasian knowledge. Journal of Ethnopharmacology, 2004; 92:147-162.

3. Schilström B, Ivanov VB, Wiker C, Svensson TH. Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology. 2007 Jan; 32(1):43-53.

4. Houghton PJ, Howes MJ. Natural products and derivatives affecting neurotransmission relevant to Alzheimer’s and Parkinson’s disease. Neurosignals. 2005; 14 (1-2):6-22.

5. Nagatsu T, Sawada M. Biochemistry of postmortem brains in Parkinson’s disease: historical overview and future prospects. J Neural Transm Suppl. 2007; (72):113-20.

6. Olin J, Shneider L. Galantamine for Alzheimer’s disease (Cochrane Review) Cochrane Database Syst. Rev. 2001;4:CD001747.National Institute of Mental Health, Bethesda, Maryland.

7. Goldstein DS, Holmes C, Sato T , Bernson M, Mizrahi N, Imrich R, Carmona G, Sharabi Y, Vortmeyer AO. Central dopamine deficiency in pure autonomic failure. Clin Auton Res. 2008 Apr; 18(2):58-65.

8. Dengiz AN, Kershaw P. The clinical efficacy and safety of galantamine in the treatment of Alzheimer’s disease. CNS Spectr. 2004 May;9(5):377-92.

9. Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol. 2004 Feb;61(2):252-6.

10. Richter, M.M., Herrmann, MJ, Ehlis, AC, Plichta, M. M., Brain activation in elderly people with and without dementia: Influences of gender and medication. World J. Biol. Psychiatry.2007; 8(1): 23-9.

11. Woodruff-Pak, D.S., Lehr, MA, Li, JG, Liu-Chen, LY. Young and old good learners have higher levels of brain nicotinic receptor binding. Neurobiol. Aging, 2008; Oct 22.

12. Takatori, Y. Mechanisms of neuroprotective effects of therapeutic acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease. Yakugaku Zasshi 2006 Aug; 126 (8): 607-16.

13. Benetti, F., Mello, PB, Bonini, JS, Monteiro, S, Cammarota, M. Early postnatal deprivation in rats induces memory deficits in adult life that can be reversed by donezepil and galantamine. Int. J. Dev. Neurosci.2008 Oct 2. PMID 189481.

14. Racchi, M, Mazzucchelli, M, Porello, E, Lanni, C, Govoni, S. Acetylcholinesterase inhibitors: novel activities of old molecules. Pharmacol Res. 2004 Oct; 50(4): 441-51.

15. Oswald, BB, Maddox, SA, Powell, DA. Impairments in trace EB conditioning by knife-cut lesions to the fornix in rabbits: reversal by galantamine. Neurobiol Learn. Mem. 2007 Oct: 88(3): 369-80.

16. Van Dam, D, De Devn, PP. Cognitive evaluation of disease-modifying efficacy of galantamine and memantine in the APP23 model. Eur. Neuropsychpharmacol. 2006 Jan; 16(1): 59-69.

17. Capsoni, S, Gionetta, S, Cattaneo, A. Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad Sci USA. 2002 Sep 17; 99(19): 12432-7.

18. Pavlov, VA, Parrish, WR, Rosas-ballina, M, Ochani, M, et al. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav. Immun. 2009 Jan (1): 41-5.

19. Diehl, A., Nakovica, H., Croissant, B. Galantamine reduces smoking in alcohol-dependent patients: a randomized, placebo-controlled trial. Int J Clin Pharmacol Ther. 2006 Dec.; 44(12): 614-22.

20. Albuqerque, E.X., Pereira, E.F.R., Ancava, Y., Fawcett, W.P., et al. Proc. Natl. Acad. Sci. USA.2006; 103:13220-13225.

21. Ezoulin, MJ, Ombetta, JE, Dutertre-Catella, H, et al. Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK-N-SH cells. Neurotoxicology. 2008 Mar; 29(2):270-7.

Leaky bowel syndrome is a problem that arises from the small and large bowel losing its ability to keep bacteria and/or their toxins from migrating into the vascular system. When we look at the human experimental model, we can translate some of those findings across into the pet patient.

There are quite a number of research articles that link chronic fatigue syndrome in people to leaky bowel syndrome.^1-6 There are findings that show that chronic fatigue syndrome and major depression are accompanied by an increased gut permeability due to a compromised epithelial barrier (the gut wall).² Leaky bowel syndrome also has been linked to chronic heart failure, which is a multi-organ disease with increasing evidence for the involvement of the gastrointestinal system. Furthermore, intestinal ischemia may play an important role in bacterial translocation by increasing bowel permeability.⁷

Moving away from this human experimental model, I will now discuss our pets. We have known about leaky bowel syndrome in our pets, especially dogs, for many years without really understanding some of the ramifications. Areas of potential concern, instead of chronic fatigue syndrome and major depression, may be food allergies accompanied with pruritis (itching) or it may be involved with some of the immune disease issues that show up. Thankfully, we see more allergies than known immune problems, so we will spend more time discussing these. I will only be discussing food borne allergies here and contact allergies will be addressed another time.

While the leaky bowel is not likely the only causative problem in allergies, it may cause quite an increase in the problem. It has been known for some time that probiotics (the “good” kind of bacteria) make a real difference in the gut to be able to respond to negative stimuli. The local immune areas of the gut are called peyers patches and have a better immune response when a probiotic such as BioPro™ is given on a consistent basis.

The second approach to helping pets with leaky bowel and allergy issues is to use Digestive Enzymes (available from VRP), which are helpful in reducing the food to its smallest parts. This means the proteins are broken down to even more reducing antigens. This may be protective to stressed bowels that are leaking toxins. The use of Digestive Enzymes in excess of digestive needs provides systemic absorption allowing the enzymes to assist in removal of material that is trapped or excreted into intercellular space. The Digestive Enzymes may be very helpful in the healing process and including Bromelain Extract between meals may help reduce inflammation.

Part three to this approach to protect against leaky bowel is the inclusion of GI Cell Support (also available from VRP). This product includes a variety of materials shown to be supportive of the healing process for leaky bowel. L-glutamine, contained in GI Cell Support, has been shown to have healing properties in the human gut. A much larger dose can be given when L-glutamine is administered by itself. Deglycyrrhizinated licorice, also contained in GI Cell Support, has a settling effect on the stomach and bowel. Each ingredient is helpful in its own way and works better when together and synergism occurs.

Part four in strengthening our dogs’ intestinal health may be to try a true organic food such as Wenaewe. Because of the cost of the raw product and the fact they only use meat as their protein ingredient as opposed to meat by products or meat meal, the cost of the food is higher. However, the food does not contain any fertilizer or pesticide, substances which may also contribute to food allergies. I have had some excellent results with dogs that have chronic GI problems that have cleared up when fed Wenaewe.

Trying this four-part approach can be very helpful in pets who suffer from leaky bowel syndrome and food allergies.

References:

1. Maes M, Coucke F, Leunis JC. Neuro Endocrinol Lett. 2007 Dec;28(6):739-44.

2. Maes M, Mihaylova I, Kubera M, Leunis JC. Neuro Endocrinol Lett. 2008 Jun;29(3):313-9.

3. Maes M. Curr Opin Psychiatry. 2009 Jan;22(1):75-83.

4. Maes M. Neuro Endocrinol Lett. 2008 Jun;29(3):287-91.

5. Singh A, Naidu PS, Gupta S, Kulkarni SK. J Med Food. 2002 Winter;5(4):211-20.

6. Singal A, Kaur S, Tirkey N, Chopra K. J Med Food. 2005 Spring;8(1):47-52.

7. Krack A, Sharma R, Figulla HR, Anker SD. Eur Heart J. 2005 Nov;26(22):2368-74.

Depression and other mood disorders are some of the most common and debilitating conditions experienced by patients. In the U.S. alone, an estimated 26.2 percent of Americans suffer from mental disorders—including depression and bipolar disorder.¹ Applied to the 2004 United States Census, this equates to roughly 57.7 million people.² In other words, 1 in 4 people we encounter during the day (friends, family members, co-workers) have some form of depression. Furthermore, nearly half of those with mental disorders suffer from more than just one condition at any given time.¹

Some of the more prevalent mental disorders include conditions that are classified as mood disorders, such as major depressive disorder (depression) and bipolar disorder. Depression is considered the leading cause of disability in the U.S. for people aged 14 to 44,³ affecting a total of 14.8 million adults, or 6.7 percent of the adult (age 18 and above) population in the U.S.¹ The median age of onset for depression is 32,⁴ and is more common in women than men–however, it can develop at any time and can occur in men as well.⁵

Depression

Depression is a mental illness that affects both the mind and the body, influencing the way a person eats, sleeps and how he or she views the world and themselves. It is not simply an extended “bad” mood or a lack of personal or mental strength; nor is it laziness. Left untreated, depression exerts a profound crippling effect and symptoms can last a lifetime. Depression and other mental conditions are diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).⁶

Bipolar disorder

Bipolar disorder, also known as manic depression, is a condition that is punctuated by wide changes in mood, thought, energy levels, and behavior. Although different from clinical depression, the depressive episodes in bipolar disorder are similar. Bipolar disorder affects roughly 5.7 million American adults, or about 2.6 percent of the adult population1; the median age of onset is 25 years for this condition.⁴

People with bipolar disorder experience moods that can alternate between excessive highs (mania) and excessive lows (depression). Changes can be apparent for as little as a few hours to days, weeks, and even months. The cyclical or episodic occurrences of depression and mania can be solitary in nature, and episodes of mixed mania and depression can appear as well, becoming increasingly frequent leading to disruptions in all aspects of the person’s life.

Seasonal Affective Disorder

Another related condition to depression and bipolar disorder is Seasonal Affective Disorder (SAD), which is generally caused by bodily rhythms that are out of synch with the sun due to the late dawn and early dusk of wintertime. Symptoms of SAD are similar to those of clinical depression, including lack of energy.⁷ In the U.S., it is thought that SAD affects roughly 9 percent of the population in the Northern U.S. and about 1.5 percent of the population in Florida.⁸ Additionally, a milder form of SAD known as Subsyndromal SAD is thought to affect 14.3 percent (northern) to 6.4 percent (Southern) of the population in the U.S.⁹ The majority of people with SAD will also experience depression, and up to 20 percent of people with SAD may also suffer from bipolar disorder.⁹ Such people will be depressed in the winter and manic in the summer.

Clinically, many patients present with these conditions that are often not extreme nor frequent enough for them to have been “officially” diagnosed according to DSM-IV standards. This population is perhaps at greater risk of not obtaining proper treatment, as they may fall through the proverbial diagnostic criteria gap, resulting in their symptoms either being downplayed or completely unaddressed as a result. In my practice based in the Pacific Northwest, where sunlight is often scarce, I tend to see many patients who did not receive proper treatment and happen to mention mood symptoms. Other patients wait until they can no longer stand the emotional pain to finally speak out about their condition. In these cases, if the patients’ symptoms are worse in winter, I suspect SAD as a possible cause.

Lithium’s Mood-Elevating Properties

The mineral lithium orotate is used by doctors to help stabilize and equilibrate mood swings and is therefore of particular interest to people with mood disorders. It is helpful in making the highs and lows of bipolar less dramatic, and for lifting depressive symptoms. It also works to stop mood swings and depressive lows, as long as it is taken regularly. The exact mechanism of action of lithium is not well understood; it is thought to regulate how the brain communicates messages within itself.

Lithium is available in several forms; most often it is prescribed in a form known as lithium carbonate or lithium citrate. Both of these types of lithium have a very narrow therapeutic range, meaning that the most effective dose is very close to a toxic dose as well. However, because of the side effects that are often encountered due to the large amounts typically prescribed, people taking lithium often suffer from several medication side effects.

Prescription strength lithium must be used in high amounts to achieve therapeutic efficacy, because the cells of the body generally poorly absorb it. Lithium and many other drugs must be absorbed into the cells where they affect the internal cellular chemistry to cause physiologic changes. Because lithium does not readily enter the cells, patients must take very high doses to “force” lithium into the cells. At the same time, these high doses are extremely close to toxic levels; prescription strength lithium must be used with extreme caution, as the difference between therapeutic and toxic levels are extremely small. Because of this, people taking lithium must maintain strict dosing schedules and be diligent about obtaining blood tests every 3 months to ensure they stay within optimal, non-toxic dose ranges. Symptoms of lithium overdose include tremors, diarrhea, thirst and frequent urination, nausea and a feeling of detachedness.

Lithium in any of its forms is not a pharmaceutical drug in the strictest sense; rather the different forms are simply minerals (very similar to salt) with significant effects on conditions of the mind. Lithium occurs naturally in the environment and it is found in very small amounts in the food and water supply.

Lithium Orotate – The Safe Lithium

Another form of lithium, known as lithium orotate, is much safer than its prescription strength counterparts yet at the same time it maintains a similar degree of efficacy. Because of this, much lower doses can be used, and toxic side effects are avoided, but clinical improvements are similar.

Lithium orotate differs chiefly from prescription strength lithium based on the ion it is bound to. This seemingly insignificant change makes all the difference in the world in the realm of safety. The original scientific study looking at lithium orotate theorized that this form of lithium was specifically released within cells at the critical sites where cellular transmission occurs, and that this form of lithium is able to cross the blood brain barrier with greater efficacy than standard lithium.¹⁰

It is theorized that the cells can absorb lithium orotate more effectively than the prescription form.¹¹ This study looked at lithium orotate absorption in animals and showed that the brain and blood serum concentrations of lithium orotate remained stable in the serum up to 24 hours post-administration, and brain concentrations were 3 times higher than that found with prescription lithium carbonate – leading to greater therapeutic efficacy.

Other Uses of Lithium

People with mood disorders (especially depression) are at a much higher risk of suicide than the general population.¹² Lithium has been shown to lessen the incidence of suicide in patients with depression who are taking it compared to those who do not. And, suicide is also lower among those taking lithium compared to other types of antidepressant medications.^13-14 Lithium has been used with success in a variety of conditions other than mood disorders, including alcoholism, anemia, migraine and cluster headache¹⁵, as well as nearsightedness and glaucoma.¹⁰

Conclusion

Lithium orotate is a simple mineral available as a safe nutritional preparation that has significant effects on conditions such as depression, bipolar disorder, and Seasonal Affective Disorder. Lithium orotate is available as a safer alternative to prescription strength lithium, which has a high risk of several dangerous side effects. Lithium orotate is uniquely designed to provide the same positive effects on mood as prescription lithium, but at a much lower and thus safer dose. Lithium can be used in clinically diagnosed mood disorders as well as for subclinical mood conditions that are not always readily diagnosed by clinicians. Lithium orotate should always be used under the discretion of a physician.

References

1. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry. 2005 Jun;62(6):617-27.

2. U.S. Census Bureau Population Estimates by Demographic Characteristics. Table 2: Annual Estimates of the Population by Selected Age Groups and Sex for the United States: April 1, 2000 to July 1, 2004 (NC-EST2004-02) Source: Population Division, U.S. Census Bureau Release Date: June 9, 2005. http://www.census.gov/popest/national/asrh/

3. The World Health Organization. The World Health Report 2004: Changing History, Annex Table 3: Burden of disease in DALYs by cause, sex, and mortality stratum in WHO regions, estimates for 2002. Geneva: WHO, 2004.

4. Kessler RC, Berglund PA, Demler O, Jin R, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry. 2005 Jun;62(6):593-602.

5. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Journal of the American Medical Association. 2003; Jun 18;289(23):3095-105.

6. American Psychiatric Association. Diagnostic and Statistical Manual on Mental Disorders, fourth edition (DSM-IV). Washington, DC: American Psychiatric Press, 1994.

7. Lam RW, Levitt AJ, Levitan RD, Enns MW, Morehouse R, Michalak EE, Tam EM. “The Can-SAD Study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder.” American Journal of Psychiatry. 2006;163(5):805-12.

8. Modell J,  Rosenthal NE, Harriett AE, Krishen A, Asgharian A, Foster VJ, Metz A, Rockett CB, Wightman DS. Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL Biological Psychiatry. 2005;58(8): 658-667.

9. Avery DH, Kizer D, Bolte MA, Hellekson C. Bright light therapy of subsyndromal seasonal affective disorder in the workplace: morning vs. afternoon exposure. Acta Psychiatrica Scandinavica. 2001;103 (4): 267-274.

10. Nieper HA. The clinical applications of lithium orotate. A two years study. Agressologie. 1973;14(6):407-11.

11. Kling MA, Manowitz P, Pollack IW. Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate. J Pharm Pharmacol. 1978 Jun;30(6):368-70.

12. Moscicki EK. Epidemiology of completed and attempted suicide: toward a framework for prevention. Clinical Neuroscience Research. 2001; 1: 310-23.

13. McElroy SL, Kotwal R, Kaneria R, Keck PE Jr.  Antidepressants and suicidal behavior in bipolar disorder. Bipolar Disord. 2006 Oct;8(5 Pt 2):596-617.

14. Howland RH. Lithium: underappreciated and underused?

J Psychosoc Nurs Ment Health Serv. 2007 Aug;45(8):13-7.

15. Sartori HE. Lithium orotate in the treatment of alcoholism and related conditions. Alcohol. 1986 Mar; 3 (2): 97-100.

Grape Seed Extract Triggers Leukemia Cell Death

In a new in vitro experiment, grape seed extract caused human leukemia cells to commit cell suicide (a process known as apoptosis).

In past studies, grape seed extract has shown activity in a number of laboratory cancer cell lines, including skin, breast, colon, lung, stomach and prostate cancers. However, until now, the extract had not been tested in hematological cancers such as leukemia. In addition, the precise mechanism of action by which it has demonstrated activity against other cancer lines has never been revealed. Consequently, researchers undertook a new study on grape seed extract to determine what effects grape seed extract has on leukemia cells.

The scientists, who report their findings in Clinical Cancer Research, treated human leukemia cells with varying doses of grape seed extract. Their findings indicated that within 24 hours, 76 percent of leukemia cells had died after being exposed to the higher dose of the extract. The extract did not affect normal cells.

The researchers also investigated the cell signaling pathway associated with use of grape seed extract that led the cancer cells to commit suicide. They found that the extract activates JNK, a protein that regulates the apoptosis pathway. To confirm this finding, they used an agent to inhibit JNK and found that the grape seed was then ineffective. Additionally, they silenced the JNK gene and found that this too canceled out grape seed extract’s ability to cause cell suicide in the leukemia cells, confirming that the extract does indeed work by activating JNK.

“These results could have implications for the incorporation of agents such as grape seed extract into prevention or treatment of hematological malignancies and possibly other cancers,” said the study’s lead author, Xianglin Shi, Ph.D., in a press release issued by the American Association for Cancer Research. “What everyone seeks is an agent that has an effect on cancer cells but leaves normal cells alone, and this shows that grape seed extract fits into this category.”

After calling for more studies to confirm the results of the findings, Shi said, “This is a natural compound that appears to have relatively important properties.”

Reference:

Gao N, Budhraja A, Cheng S, Yao H, Zhang Z, Shi X. Induction of Apoptosis in Human Leukemia Cells by Grape Seed Extract Occurs via Activation of c-Jun NH2-Terminal Kinase. Clinical Cancer Research. January 1, 2009. 15:140-149.

Vitamin C May Support Healthy Blood Pressure

Young women with the highest levels of vitamin C have the lowest blood pressure, a new study indicates, an important finding because lower blood pressure in young adulthood often means improved cardiovascular health when those same subjects become older adults.

The study authors decided to investigate vitamin C’s role in blood pressure because “the prevalence of hypertension and its contribution to cardiovascular disease risk makes it imperative to identify factors that may help prevent this disorder,” they wrote. “Extensive biological and biochemical data suggest that plasma ascorbic acid may be such a factor.”

Consequently, researchers studied 242 women aged 18-21 years from the cohort of the National Heart, Lung and Blood Institute Growth and Health Study. After following the subjects for 10 years, the scientists examined the associations of plasma ascorbic acid with blood pressure levels.

The results indicated that the higher the plasma vitamin C levels at year 10, the lower the systolic and diastolic blood pressure after adjusting for race, body mass index, education, and dietary intake of fat and sodium. The systolic blood pressure in persons with the highest one-fourth of plasma ascorbic acid levels was 4.66 mmHg lower and the diastolic blood pressure was 6.04 mmHg lower compared to those in the lowest one-fourth of vitamin C levels.

The researchers also noted that individuals with the higher vitamin C levels did not experience an increase in blood pressure levels during the last year of the study, whereas the subjects with the lowest vitamin C levels did experience an increase. While diastolic blood pressure among persons with the lowest plasma ascorbic acid increased by 5.97 mmHg from year 9 to year 10, those with the highest levels of plasma vitamin C experienced an increase in their diastolic blood pressure of only 0.23 mmHg. A similar effect was seen for change in systolic blood pressure.

The researchers concluded, “Plasma ascorbic acid was found to be inversely associated with BP and change in BP during the prior year. The findings suggest the possibility that vitamin C may influence blood pressure in healthy young adults. Since lower blood pressure in young adulthood may lead to lower BP and decreased incidence of age-associated vascular events in older adults, further investigation of treatment effects of vitamin C on BP regulation in young adults is warranted.”

Reference:

Block G, Jensen CD, Norkus EP, Hudes M, Crawford PB. Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women. Nutr J. 2008 Dec 17;7(1):35.

Rhodiola Rosea Reduced Stress-Related Fatigue in New Human Study

In a randomized, placebo-controlled, double-blind study, the adaptogenic botanical rhodiola rosea reduced the symptoms of stress-related fatigue in a group of human subjects.

In the clinical trial, participants (males and females aged between 20 and 55 years) were selected according to the Swedish National Board of Health and Welfare diagnostic criteria for fatigue syndrome. A total of 60 individuals were randomized into two groups: 30 subjects received four tablets daily of rhodiola rosea extract (576 mg extract per day), while a second group of 30 subjects received four placebo tablets daily. The effects of the rhodiola rosea with respect to quality of life (measured by a questionnaire), symptoms of fatigue, depression, attention span and saliva cortisol response during awakening were assessed on day 1 and after 28 days of using the extract.

Post-treatment improvements were observed in the rhodiola group compared to the placebo. Specifically, participants given rhodiola experienced significant improvements in symptoms of fatigue and in attention span. Furthermore, cortisol responses during awakening improved in the group taking rhodiola compared to the placebo group. No serious side effects that could be attributed to the extract were reported.

The study authors wrote, “It is concluded that repeated administration of R. ROSEA extract… exerts an anti-fatigue effect that increases mental performance, particularly the ability to concentrate, and decreases cortisol response to awakening stress in burnout patients with fatigue syndrome.”

Reference:

Olsson EM, von Schéele B, Panossian AG. A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Standardised Extract SHR-5 of the Roots of Rhodiola rosea in the Treatment of Subjects with Stress-Related Fatigue. Planta Med. 2008 Nov 18. Published Online Ahead of Print.

Turmeric-Derived Compound May Improve Digestive Health

Supplementation with curcumin, a compound derived from turmeric, resulted in a complete resolution of diarrhea in patients with HIV, researchers report in a new study.

Because curcumin possesses anti-inflammatory properties, the researchers investigated whether the use of curcumin in patients with HIV-associated diarrhea would have any beneficial effects. The scientists gave eight patients with HIV-associated diarrhea an average daily dose of 1,862 mg of curcumin and followed the subjects for about 41 weeks.

The results indicated that all subjects had resolution of diarrhea and normalization of stool quality in an average of 13 days. The mean number of bowel movements per day dropped from 7 to 1.7. Seven of eight patients taking the turmeric-derived compound gained back a considerable amount of the weight they had lost from the diarrhea. Five of six patients had resolution of bloating and abdominal pain. While taking curcumin, patients on anti-retroviral therapy experienced no discernible drug interactions, changes in CD(4) count, or changes in HIV viral load.

According to the researchers, “Curcumin therapy was associated with rapid and complete resolution of diarrhea, substantial weight gain, [and] improvement in the reduction of bloating and abdominal pain.”

Reference:

Conteas CN, Panossian AM, Tran TT, Singh HM. Treatment of HIV-Associated Diarrhea with Curcumin. Dig Dis Sci. 2008 Dec 3. Published Online Ahead of Print.

Cranberry Extracts May Strengthen Urinary Tract

A report in the Journal of Antimicrobial Chemotherapy indicates that cranberry extract can reduce the recurrence of chronic urinary tract infections (UTIs) in older women.

A large number of previous studies have shown that cranberry extract can stop E. coli, a common cause of UTIs, from adhering to the walls of the urinary tract. Because the bacteria are unable to stick to the walls, they are flushed out of the body.

In the current study, researchers compared the effectiveness of cranberry extract with a low-dose antibiotic commonly used to prevent the recurrence of chronic urinary tract infections in women who are predisposed to developing this condition. One hundred and thirty-seven women with two or more antibiotic-treated UTIs in the previous 12 months were randomized to receive either 500 mg of cranberry extract or 100 mg of the antibiotic trimethoprim for 6 months.

The researchers found that the time to first recurrence of a UTI was not significantly different between the cranberry and antibiotic groups. The median time to recurrence of UTI was 84.5 days for the cranberry group and 91 days for the antibiotic group. There were 17/137 (12 percent) withdrawals from the study, 6/69 (9 percent) from the cranberry group and 11/68 (16 percent) from the antibiotic group.

According to the researchers, “Trimethoprim had a very limited advantage over cranberry extract in the prevention of recurrent UTIs in older women and had more adverse effects. Our findings will allow older women with recurrent UTIs to weigh up with their clinicians the inherent attractions of a cheap, natural product like cranberry extract whose use does not carry the risk of antimicrobial resistance or super-infection with Clostridium difficile or fungi.”

Reference:

McMurdo ME, Argo I, Phillips G, Daly F, Davey P. Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother. 2008 Nov 28. Published Online Ahead of Print.

Cranberry Concentrate is available here as a stand-alone supplement and is also available in D-Mannose Plus, which combines cranberry with D-Mannose, another substance shown to support urinary health.

CoQ10-H₂^™ Found to Be Better Absorbed in Heart Patients

Congestive heart failure patients who consume a special bioavailable form of Coenzyme Q10 known as CoQ10-H₂^™ (ubiquinol) have higher levels of this antioxidant in their blood and have a greater degree of clinical improvement than patients receiving the standard form of CoQ10 (ubiquinone), researchers report in the December issue of the journal BioFactors.

New York Heart Association (NYHA) Class IV congestive heart failure patients are often unable to reach adequate plasma CoQ10 levels even after consuming up to 900 mg per day of standard CoQ10 (ubiquinone) supplements. These patients often have plasma total CoQ10 levels of less than 2.5 µg/ml and have limited clinical improvement. Researchers believe these low levels are the result of the intestinal edema that occurs in these patients, which may impair CoQ10 absorption.

In the current study, researchers investigated seven patients with advanced congestive heart failure (mean ejection fraction 22 percent) with sub-therapeutic plasma CoQ10 levels (mean level of 1.6 µg/ml on an average dose of 450 mg of ubiquinone daily). Ejection fraction refers to the fraction of blood pumped out of a ventricle with each heartbeat. All seven of these patients were switched to an average of 580 mg per day of CoQ10-H₂ (450–900 mg/day) with follow-up plasma CoQ10 levels, clinical status, and ejection fraction measurements by echocardiography.

After the subjects were switched to the CoQ10-H₂, mean plasma CoQ10 levels increased from 1.6 µg/ml (0.9–2.0 µg/ml) up to 6.5 µg/ml (2.6–9.3 µg/ml). Mean ejection fraction improved from 22 percent (10–35 percent) up to 39 percent (10–60 percent). Clinical improvement in the CoQ10-H₂ group was what the researchers termed as “remarkable” with the NYHA class improving from a mean of IV to a mean of II. The prognosis for patients with NYHA class IV heart failure is very poor with mortality as high as 74 percent at 6 months and 94 percent at 12 months, but six of the seven patients receiving CoQ10-H₂ survived longer than expected and remained stable throughout the 12-month study. The one patient in this study that did not survive stopped taking the CoQ10-H₂ after three months, even after experiencing an improvement in heart function.

The study authors concluded, “Ubiquinol has dramatically improved absorption in patients with severe heart failure and the improvement in plasma CoQ10 levels is correlated with both clinical improvement and improvement in measurement of left ventricular function.”

The results are interesting in light of an earlier study by another group of researchers, which found that in 236 patients with chronic heart failure, plasma CoQ10 concentration was an independent predictor of mortality.

References:

Langsjoen PH, Langsjoen AM. Supplemental ubiquinol in patients with advanced congestive heart failure. BioFactors. December 2008;32:119-128.

Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M, Richards AM. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008 Oct 28;52(18):1435-41.

Selenium and N-Acetyl Cysteine May Improve Fertility in Men

In a new double-blind, placebo-controlled, randomized study, selenium and N-acetyl cysteine (NAC) improved sperm quality in men.

The study included 468 infertile men who had poor sperm quality. The men (116 subjects) were randomized to receive 200 mcg selenium orally per day, 600 mg N-acetyl-cysteine orally per day (118 subjects), 200 mcg selenium plus 600 mg N-acetyl-cysteine orally daily (116 subjects) or a placebo (118 subjects). The subjects were given the supplements for 26 weeks, followed by a 30-week treatment-free period, and provided blood samples for the measurement of serum testosterone, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone, prolactin, inhibin B (a hormone that inhibits FSH production), selenium and N-acetyl-cysteine. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body. In males FSH is critical in spermatogenesis. Luteinizing hormone (LH) also is essential for reproduction in males. LH acts upon the Leydig cells of the testes to trigger the production of testosterone, which in turns helps produce spermatogenesis.

In addition to measuring the above factors, researchers obtained semen samples from the subjects for routine semen analysis, and the measurement of seminal plasma selenium and N-acetyl-cysteine. In analyzing these samples, the scientists discovered that selenium and N-acetyl-cysteine appeared to balance the levels of serum follicle-stimulating hormone, serum testosterone and inhibin B. All semen parameters significantly improved with selenium and N-acetyl-cysteine treatment. Administering selenium plus N-acetyl-cysteine resulted in additive beneficial effects. A strong correlation was observed between the administration of combined selenium and N-acetyl-cysteine and mean sperm concentration, sperm motility and percent of the sperm that had normal structure and form.

According to the researchers, “These results indicate that supplemental selenium and N-acetyl-cysteine improve semen quality. We advocate their use for male infertility treatment.”

Reference:

Safarinejad MR, Safarinejad S. Efficacy of Selenium and/or N-Acetyl-Cysteine for Improving Semen Parameters in Infertile Men: A Double-Blind, Placebo Controlled, Randomized Study. J Urol. 2008 Dec 15. Published Online Ahead of Print.

Alpha-Lipoic Acid Studied For Possible Neuroprotective Properties

In a new study, researchers have found a possible explanation for the mechanism of action behind alpha-lipoic acid’s ability to protect neurons.

Neurodegenerative disorders include Alzheimer’s disease, dementia, Parkinson’s disease, and amyotrophic lateral sclerosis (Lou Gehrig’s disease, ALS). Neurodegeneration occurs when neurons in the brain and spinal cord fail to function. Because these cells do not easily regenerate en masse, excessive damage can occur in the brain.

Alpha-lipoic acid has recently been reported to afford protection against neurodegenerative disorders in humans and experimental animals. However, the mechanism by which lipoic acid accomplishes this neuroprotection has not been determined. Consequently, researchers in the current study decided to test lipoic acid’s effect on brain cells treated with peroxynitrite, a compound known to be involved in various neurodegenerative diseases. Researchers induced DNA strand breaks in the cells by stimulating the production of peroxynitrite.

When the cells were treated with lipoic acid, DNA strand breaks were significantly inhibited in a concentration-dependent manner. The lipoic acid appeared to stop the DNA breaks by reducing the generation of peroxynitrite.

In a second experiment, the lipoic acid also dramatically inhibited the DNA strand breaks when the DNA was treated directly with peroxynitrite.

Finally, in a third experiment, lipoic acid was able to stop the formation of hydroxyl radicals, harmful compounds that can damage nearly all types of macromolecules including carbohydrates, nucleic acids, lipids and amino acids.

“Taken together,” the researchers wrote, “these studies demonstrate for the first time that LA [lipoic acid] can potently inhibit peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation. In view of the critical involvement of peroxynitrite in the pathogenesis of various neurodegenerative diseases, the inhibition of peroxynitrite-mediated DNA damage by LA may be responsible, at least partially, for its neuroprotective activities.”

Reference:

Jia Z, Zhu H, Vitto MJ, Misra BR, Li Y, Misra HP. Alpha-lipoic acid potently inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation: implications for the neuroprotective effects of alpha-lipoic acid. Mol Cell Biochem. 2008 Dec 11. Published Online Ahead of Print.

CLA May Play a Role in Bone Health

In a new study, researchers report that conjugated linoleic acid (CLA) may increase bone mineral content and reduce some of the side effects associated with taking corticosteroids.

Past studies have found that CLA may play a role in weight management and newer evidence has suggested that it also is involved in bone health.

In the current study, researchers investigated whether CLA could build bone in rodents given corticosteroids, which are commonly used in human patients with rheumatoid arthritis and numerous other diseases. Corticosteroids are known to destroy bone.

To determine whether CLA can attenuate the bone-weakening side effects of 8 weeks of corticosteroid administration, researchers randomized 24, 5-week-old male rats into 1 of 4 groups. One group served as a control, another received the corticosteroid drug methylprednisolone, a third group received CLA alone while a fourth group received CLA plus methylprednisolone. The researchers then assessed body composition, bone mineral content, and bone mineral density at the onset and at the end of the 8-week intervention.

Administration of the corticosteroid drug methylprednisolone resulted in a reduction in body mass and lean mass over the 8 weeks. CLA, however, prevented the methylprednisolone-induced reduction of body mass and lean mass accumulation. CLA also resulted in a greater increase in bone mineral content in the lumbar spine and improved the health of the femurs in corticosteroid-treated animals.

According to the researchers, “Dietary CLA prevents many of the growth- and bone-related side effects arising from 8 weeks of corticosteroid administration, results in greater increases in BMC [bone mineral content] and BMD [bone mineral density], and can contribute to an improvement in some of the mechanical properties of bone.”

Reference:

Roy BD, Bourgeois J, Rodriguez C, Payne E, Young K, Shaughnessy SG, Tarnopolosky MA. Conjugated linoleic acid prevents growth attenuation induced by corticosteroid administration and increases bone mineral content in young rats. Appl Physiol Nutr Metab. 2008 Dec;33(6):1096-104.