Long-Term Resveratrol Supplementation as a Secondary Prophylaxis for Stroke

1. Long-Term Resveratrol Supplementation as a Secondary Prophylaxis for Stroke Kaitin Fodor, Delia Mirela Tit, Bianca Pasca, Cristiana Bustea, Diana Uivarosan, Laura Endres, Ciprian Iovan, Mohamed Abdel-Daim, and Simona Bungau Oxidative Medicine and Cellular Longevity, 2018 Powerpoint by Marie Angela Gochangco, MD

2. Introduction

3. Stroke is a major health concern and continues to be one of the leading cause of death and disability worldwide.

4. According to the American Heart Association, central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury. • Central nervous system infarction includes ischemic stroke, which refers to central nervous system infarction accompanied by overt symptoms and silent infarction, which causes no known symptoms. • Stroke also broadly includes intracerebral hemorrhage and subarachnoid hemorrhage1.

5. The most common cause of stroke is ischemia caused by vascular obstruction in the cerebral circulation. • Increased microvascular permeability and intracerebral hemorrhage can also result in decreased perfusion. • High blood pressure, smoking, obesity, poor diet, sendentary lifestyle, diabetes mellitus, alcohol consumption, psychosocial stress and depression are risk factors associated with 90% of stroke episodes2. • These conditions decrease the release of nitric oxide hence leading to high production of reactive oxygen species (ROS).

6. In stroke, ROS are generated which play a critical role in the pathogenesis of myocardial infarction and stroke. • The production of ROS promotes cell death by damaging the neuronal membranes and cellular components3. • Resveratrol is a natural organic compound produced naturally by some plants and in red wine in response to several harmful factors such as attack by pathogens (bacteria or fungi), UV radiation, or increased oxidative stress. • Sources of resveratrol in food include skin of grapes, blueberries, raspberries, mulberries, and peanuts.

7. It is a naturally occurring polyphenol that has been shown to have beneficial effects in cardiovascular and metabolic disease. • Resveratrol is an effective scavenger of reactive oxygen (ROS) and nitrogen (RNS) species, and can neutralize free radicals4.

8. Treatment with resveratrol was shown to prevent the pathophysiologic mechanisms that mediates stroke. • These include oxidative stress, inflammation, ionic imbalance and apoptosis. • Resveratrol is a potent pharmacological agent that can prevent secondary damage after stroke and acute CNS injury5.

9. Espinoza, J., et al in 2017 assessed the effects of repeated doses of resveratrol (1000 mg/day for 28 days) on circulating immune cells in healthy Japanese individuals. • 9 healthy volunteers were enrolled in the phase 1 randomized trial. • Consumption of resveratrol resulted in increased antioxidant activities in the plasma of participating subjects. • An oxidative marker, 8-OHdG was significantly decreased after the administration of resveratrol.

10. A clinical trial was performed by Theodotou, M., et al in 2018 to investigate the effects of Evelor, a micronized formulation of resveratrol, in addition to standardized hypertension treatment in patients with primary hypertension. • The study showed that addition of resveratrol to standard antihypertensive therapy is sufficient to reduce blood pressure to normal levels, without the need for additional antihypertensive drugs. • Resveratrol is beneficial in the control of blood pressure by increasing the production of nitric oxide (NO), an endogenous and potent vasodilator. • Vasodilatation decreases peripheral resistance and hence lowers blood pressure.

11. The review of clinical trials by Berma, A., et al in 2017 showed that resveratrol was well tolerated and beneficial in neurological disorders, cardiovascular diseases, and diabetes. • Biomarkers associated with Alzheimer’s disease and ischemic stroke were reduced upon administration of resveratrol. • It has also shown to promote endothelial function and improve flow-mediated dilatation in atherosclerosis and coronary artery disease. • Resveratrol treatment for 3 months improved glycemic control, decreasing HbA1c levels, systolic blood pressure, total cholesterol, and total protein.

12. Relevance

13. Stroke remains to be one of the most prevalent cardiovascular disease and leading cause of mortality worldwide. • The production of ROS is generated in stroke, which then promotes oxidative damage and damage to the neuronal membrances. • Antioxidants are needed to neutralize these free radicals generated by ROS. • Resveratrol has been shown to have a promising effect in reducing the incidence of stroke by neutralizing free radicals in the human body and reducing cellular damage.

14. Objectives

15. The study aims to determine effects of resveratrol on blood pressure, weight status, glucose, and lipid profile in patients who had a stroke in the last 12 months. These parameters serve as major risk factors for stroke.

16. Highlights

17. Fodor, K., et al in 2018 conducted a study on the effects of resveratrol supplementation on blood pressure, weight status, glucose, and lipid profile in patients who had a stroke in the last 12 months. • Patients included were those who had first stroke in the last 12 months and hospitalized for recovery treatment during 2011-2015. • All patients were stabilized after stroke and were hospitalized and monitored in the Baile Felix Clinical Rehabilitation Hospital.

18. Two hundred and twenty-eight patients were included in the study and divided into three groups. • Group I, the control group, comprised of 92 patients who underwent allopathic (medical) treatment combined with medical physical rehabilitation. • Group II was comprised of 81 patients who received allopathic treatment and medical physical rehabilitation, combined with a 12-month supplementation with an oral daily dose of 100 mg/patient of resveratrol. • Group III was comprised of 55 patients who received allopathic treatment and medical physical rehabilitation, combined with a 12-month supplementation with an oral daily dose of 200 mg/patient of resveratrol.

19. The selection method was used to distribute the patients into groups. • The patients were divided into the groups based on the patient’s willingness to take either 100 or 200 mg resveratrol as week as their clinical history and characteristics. • No significant differences were noted between groups. • Individualization of treatment was done depending on their clinical condition.

20. All patients were evaluated initially, at 6 months, and at 12 months from the start of the treatment. • Blood pressure, weight status, lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides), and glucose profile were monitored in each patient. • Paired t test and Bravais-Pearson correlation coefficient were used for statistical analysis. • Those with a p value of <0.05 were considered to be statistically significant. • The effect size (ES) was measured to determine the extent of change in parameters at different time points.

21. Small ES was equal to 0.20, medium ES was equal to 0.50, and large ES was equal to 0.80. • There were no significant differences (p > 0.05) in the initial mean systolic and diastolic blood pressure values between the 3 groups. • There was a significant difference (p < 0.05) in the systolic pressure from the initial evaluation up to 12 months of treatment in the group receiving 100 mg resveratrol, which showed an ES of 0.53, and in the group receiving 200 mg resveratrol, which showed an ES of 0.65. • The control group had an ES of 0.20 (p > 0.05) which showed no significant difference in systolic pressure.

22. A significant difference (p < 0.05) in the diastolic pressure in the group receiving 100 mg resveratrol and 200 mg resveratrol were also noted (ES of 0.37 and 0.39 respectively). • The control group had an ES of 0.17 (p > 0.05) which showed no significant difference in diastolic pressure. • The initial BMI values between the two experimental groups showed no significant differences.

23. There was a significant difference (p < 0.05) in the BMI from the initial evaluation up to 12 months of treatment in the group receiving 100 mg resveratrol, which showed an ES of 0.64 and in the group receiving 200 mg resveratrol, which showed an ES of 0.87. • The control group had an ES of 0.20 (p > 0.05) which showed no significant difference in systolic pressure. • Resveratrol administration had a substantial effect on all lipid profile parameters after 12 months, especially on triglycerides (ES = 1.81 at 100 mg and ES = 1.95 at 200 mg) and serum cholesterol (ES = 1.51 at 100 mg and ES = 1.63 at 200 mg). • The control group had an ES of 1.39 and 1.07 in triglycerides and serum cholesterol respectively.

24. In HDL cholesterol, the effect of resveratrol 100 mg was 2.02 times greater (ES = 1.25 versus 0.62) compared to the control group. • The effect of resveratrol 200 mg was also 2.11 times greater (ES = 1.31 versus 0.62) compared to the control group. • In LDL cholesterol, the effect of resveratrol 100 mg was 2.34 times greater (ES = 1.24 versus 0.53) compared to the control group. • The effect of resveratrol 200 mg was also 2.42 times greater (ES = 1.28 versus 0.53) compared to the control group.

25. In diabetic patients, blood glucose levels decreased insignificantly (p > 0.05) after 12 months in the control group (ES = 0.12), in the group receiving 100 mg resveratrol (ES = 0.52), and in the group receiving 200 mg resveratrol (ES = 0.56). • In non-diabetic patients on the other hand, there were significant differences (p < 0.05) in blood glucose levels in the group receiving 100 mg resveratrol and in the group receiving 200 mg resveratrol (ES of 0.20 and 0.85 respectively). • There was no significant difference (p > 0.05) in the control group (ES = 0.20). • Glycated hemoglobin values decreased in the 3 groups but showed no significant differences (p > 0.05) in its decrease. • ES was 0.34 in the group receiving 100 mg resveratrol, 0.40 in the group receiving 200 mg resveratrol, and 0.03 in the control group.

26. Conclusion

27. The study showed that supplementation with resveratrol had a significant effect on blood pressure, body mass index, lipid profile, and glucose (in nondiabetic patients) in patients who had a stroke in the last 12 months compared to the control group. • Resveratrol, therefore has a beneficial effect in the secondary prevention of stroke. • Further reserach of supplementation of reservatrol are warranted to provide more treatment breakthroughs in field of medicine.

28. References • 1. Sacco, R., et al. An Updated Definition of Stroke for the 21st Century. AHA Journals. 2013. • 2. O’Donnell, M., et al. Risk Factors for Ischaemic and Intracerebral Hemorrhagic stroke in 22 countries (the Interstroke study): a case-control study. Lancet. 2010. • 3. Kalogeris, T., et al. Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs. preconditioning. Redox Biology. 2014. • 4. Gerszon, J., et al. Antioxidant Properties of Resveratrol and Its Protective Effects in Neurodegenerative Diseases. Advances in Cell Biology. 2014. • 5. Lopez, M., et al. Resveratrol Neuroprotection in Stroke and Traumatic CNS Injury. Neurochem Int. 2015. • 6. Espinoza, L. et al. The Repeated Administration of Resveratrol Has Measurable Effects on Circulating T-Cell Subsets in Humans. Oxidative Medicine and Cellular Longevity. 2017. • 7. Theodotou, M. et al. The Effect of Resveratrol on Hypertension: A Clinical Trial. Experimental and Therapeutic Medicine. 2017. • 8. Berma, A., et al. The therapeutic potential of resveratrol: a review of clinical trials. Precision Oncology. 2017.