By: Dr. John H Peacock, MD, PhD
The medical note in this issue of the Parkinson Press explores the potential benefits of ethanol in Parkinson’s disease with a focus on red wine. Red wine may provide a dual benefit for Parkinson’s disease. First the ethanol in wine is capable of direct stimulation of dopamine-containing nerve cells (dopaminergic neurons) in the substantia nigra. Second, as some of you may know, red wine contains resveratrol a plant product with several potential neuroprotective effects. Note that other foods such as peanuts also contain resveratrol.
Looking first at the direct effects of ethanol. Laboratory studies on the direct effect of ethanol on dopaminergic neurons has been examined. In this research, injection of ethanol into the substantia nigra of anesthetized rats caused a dose-related increase in locomotor activity once the anesthetic was removed (1). Enzymes such as catalase were evaluated in this regulation of ethanol-induced motor activity. Previously Gessa, et al. (2) found that low doses of ethanol induced a 30-80% increase in firing rate of dopaminergic neurons in experimental animals.
Focusing next on the effects of resveratrol. It is an antioxidant (4, 5), modulates inflammation (6, 7), and stimulates growth factors (8). Each of these properties is presented below for those who want to review them. The science itself is complex, but hopefully the summary paragraphs are clear.
What are the benefits of an antioxidant? By definition, “Antioxidants are man-made or natural substances that may prevent or delay some types of cell damage. Antioxidants are found in many foods, including fruits and vegetables” (3); many vitamins including Vitamin C are antioxidants. Ono and Yamada (4) found a direct antioxidant effect of wine related phenols such as resveratrol on formation of alphasynuclein. You will recall that alphasynuclein is the protein that aggregates in dopaminergic neurons adversely affecting their function and ultimately their survival. The authors speculated that this group of molecules could play a key role in “the development of preventatives
and therapeutics for LBD (Lewy Body disease) and MSA (Multiple System Atrophy) as well as Alzheimer’s disease”.
Albani, et al. (5) studied the neuroprotective effects of SIRT1, a protein that can protect against oxidation when activated. Such activation occurs with resveratrol. In these experiments cells that were growing in culture provided the experimental model, not experimental animals. The oxidative challenge for these cells was exposure to weak solutions of hydrogen peroxide or 6- hydroxydopamine, a chemical that can kill dopaminergic neurons. Ensuing detrimental effects were blocked by resveratrol through the SIRT1 pathway. In the same experiments, SIRT1 itself was unblocked by its inhibitor, sirtinol.
Why is resveratrol an anti-inflammatory agent? The inflammatory response in Parkinson’s disease is mediated by microglia. Glia are one of the non-neural cell types that are in the brain along with nerve cells. Proliferation of glial cells occurs after toxic insults to nerve cells in a way analogous to proliferation of scar forming cells outside of the brain following cuts and abrasions of the skin.
Zhang et al (6) examined the mechanisms underlying resveratrol-mediated neuroprotection in rat midbrain neuron-glia cultures. This region of the rat midbrain has dopamine neurons and provides a relevant model for Parkinson’s disease. Using this model, his group exposed dopamine nerve cells in culture to lipopolysaccharide, a molecule that triggers microglial proliferation and an accompanying proinflammatory factor release. Resveratrol inhibited the microglial cell formation and blocked the toxic effects of lipopolysaccharide. Biochemical details of that inhibition are provided in the report and beyond the scope of this news article.
Additional experimental work on the modulation of microglial proliferation by resveratrol was reported by Gordon et al. (7). These scientists also examined the positive modulation of apoptosis, perhaps the topic of a subsequent newsletter, by resveratrol.
Additionally, resveratrol stimulates the production and release of growth factors. You may recall that neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) are important for the development, maintenance and survival of neurons including dopaminergic neurons in the substantia nigra. Astroglia, another cell type in the brain are a source of neurotrophic factors. Zhang et al. (8) evaluated the possibility that resveratrol might stimulate the production and release of neurotrophic factors from astroglial enriched cultures. After cell cultures were exposed to low concentrations of resveratrol for 12–48 hours, BDNF and GDNF were measured in the culture medium. Following 24 hours of resveratrol exposure, the production of BDNF was increased five-fold over control levels and remained high 36 hours later. Meanwhile, the production of GDNF was initially increased by up to four-fold in 24 hours after resveratrol treatment and continued to increase to six-fold at 36 hours. The level remained high for 48 hours.
Ethanol and Multiple Sclerosis. It is notable that ethanol may be beneficial for other Neurological diseases such as MS. In January 2006, Hedstrom et al. (8) reported the results from their analysis of two epidemiological studies. They found a dose-dependent, inverse association between alcohol consumption and risk of developing MS that was statistically significant in both sexes.
Conclusion. This report has briefly reviewed evidence for a direct stimulatory effect of ethanol on dopaminergic neurons as well as potential neuroprotective effects of resveratrol found in wine and other foods. These neuroprotective properties include antioxidation (4, 5), anti-inflammatory modulation (6, 7), and stimulation of production of growth factors (8). So enjoy a glass of red wine and don’t let all this information about resveratrol spoil its magic for you. You may also purchase resveratrol in a capsule form at most health food stores.
1. Arizzi-LaFrance MN, Correa M, Aragon CMG and Salamone JD. Motor stimulant effects of ethanol injected into the substantia nigra pars reticulata: Importance of catalase-mediated metabolism and the role of acetaldehyde. Neuropsychopharmacology 2006; 31:997-1008.
2. Gessa GL, Muntoni F, Varglu MCL, and Mereu G. Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area. Brain Research 1985;348:201-203.
3. Antioxidants. Medline Plus. A service of the U.S. National Library of Medicine National Institutes of Health.
4. Ono, K, and Yamada, M. (2006), Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for a-synuclein fibrils in vitro. Journal of Neurochemistry, 97: 105–115.
5. Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro A and Forloni G. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by a-synuclein or amyloid-ß (1-42) peptide. Journal of Neurochemistry 2009;1109(5):1445–1456.
6. Zhang F, Shi J-S, Zhou H, Wilson B, Hong J-S, Gao H-M. Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Molecular Pharmacology 2010 vol. 78:466-477.
7. Gordon R, Hogan CE, Kanthasamy K, Vellareddy A, Vellreddy A, Kanthasamy A, and Kanthasamy AG Resveratrol protects dopaminergic neurons in Parkinson’s disease models by modulating the PKC-delta apoptotic signaling pathway & microgiial activation. Faseb J April 2010 24 (Meeting Abstract Supplement) 763.5.
8. Zhang F, Yuan-Fu L, Qin W, Jie L, Jing-Shan S. Resveratrol promotes neurotrophic release from astroglia. Exp Biol Med (Maywood) August 2012 237(8):943-948.
9. Hedstrom AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol. Published online January 06, 2014