Tag: brain

Posted on

Glymphatic system – yes- sleep helps protect against Alzheimer’s dementia

Following up on Friday’s easy answer day (previous post) – yes, the glymphatic system of the brain does help protect against Alzheimer’s dementia, (7, 8, 14, 17), and sleep, especially one of the deeper stages of sleep (low-delta), is important. (10, 11, 13) Sleeping on your right side may help promote better fluid drainage through the glymphatic system of the brain (sleeping on your right side puts the left side of your body with your heart farther up above the rest of your body, a pillow between your knees and a neck support may also help). (Social media link, reference source: Neurology Reviews, 2) (12) *I had trouble finding anything very specific about whether right or left side was better for glymphatic and lymphatic drainage – this article from an Ayurveda specialist describes how the anatomy is better suited to sleeping on the left side than the right side – the aorta leaves the heart on the left so laying on the left side allows the flow to go downhill with the aid of gravity. (https://lifespa.com/amazing-benefits-of-sleeping-on-your-left-side/ )

The circulation by the heart can help move fluid through the brain but only indirectly due to the on/off pressure of the arterial pulse. The regular lymphatic system of the body is a drainage system for the brain fluid system but the blood brain barrier prevents direct interaction. Specialized water pumps in some types of brain glial cells help provide circulation within the brain by pumping water in two directions within the second layer of thick membranes that separate the soft brain tissue from the bony skull. (3)(4)(15)(16)

Overall the fluid within the brain does circulate and there is a visible, small, pulsing movement that has been amplified and can be observed in a video: (5). The spread of a dye within the brain can be observed in a different type of brain scan, the fluid diffusion is not rapid taking 24 hours to reach a maximal point, and the movement of the dye was most prevalent (see color chart) near the skull: (6). The glymphatic system as defined as the specialized glial cells with water pump channels is located in the area near the skull. (4) Diffusion of fluid throughout deeper areas of the brain where the blood brain barrier is not found can occur to a small extent through membranes. (9)

Exercise may also help the glymphatic system function better. (18) The lymphatic vessels and lymph nodes in the neck are the initial drainage route for the glymphatic system cleansing of the various fluid filled areas of the brain. Stretching exercises and rhythmic walking type exercise can help move lymphatic fluid from farther areas of the body to the torso and urinary system for eventual excretion.

Small amounts of alcohol – one third of a serving; to moderate – one or two servings per day (too much may not be helpful); may help the detoxification of the brain fluid by mechanisms that are not well understood yet but which seem to involve the glymphatic system. (19, 20) The mechanism may involve the effect of alcohol on GABA receptors, it can activate them which in general would have a calming/inhibitory effect, (23), however GABA receptors also are involved in promoting more production of the water pump Aqaporin 4 channels in neural stem cells within the subependymal zone. (24) The subependymal zone is in the lateral part of the lateral ventricle which is a cerebrospinal fluid filled area near the center of the brain, (27), which is involved in fluid balance and drainage of the glymphatic system. (25) GABA receptors are also involved with flow of chloride ions across membranes (for an inhibitory effect on nerve signaling, (pp 126-131, 1), and affect fluid balance in areas of the brain without the blood brain barrier which makes diffusion of water across the brain membranes more possible. (26)

Alcohol also inhibits the action of the excitatory neurotransmitter glutamate, particularly at the NMDA receptor, (23), which is an excitatory ion channel and also allows calcium to enter the cell where the mineral can activate many functions within the cell. (pp 120-126, 1) If drinking alcohol is not preferred or legal due to age or advised due to pregnancy or possibility of becoming pregnant then GABA (gamma-aminobutyric acid) is available as an over the counter supplement, typically in a form that melts in the mouth to promote more direct absorption. While it is not typically referred to as an amino acid due to its role as a neurotransmitter, it is simply an amino acid, a smaller molecule from which proteins can be formed. The level of GABA a has been found to be reduced in the brains of patients with severe Alzheimer’s Disease and its use as a treatment has been studied, (29), levels in other abnormal brain cells were found to be elevated in a specific area of the brain of patients with Alzheimer’s Disease and treatment to increase transport of GABA has also been studied. (30)

Or sleep, in the form of a short nap, may also help promote GABA. Naps may benefit our health in part because of a beneficial effect on GABA promotion by increased glymphatic action in the brain – twenty minutes of sleep may be adequate. (28)

An overview of the glymphatic system and lifestyle and dietary tactics that might improve its function are described in a video by a nutritionist: (21); and also in a self-help style article by a different person: (22).

Some types of magnesium supplements including magnesium threonate may also help. Magnesium within the brain has many functions including inhibiting the NMDA glutamate receptor which would prevent excess calcium from entering the cell. (pp 120-126, 1)

We tend to hear about neurotransmitters such as serotonin for depression or dopamine and Parkinson’s disease, yet we rarely hear that calcium is the mineral that signals the release of both of those and over one hundred other neurotransmitters that are involved in nerve signals within the brain or throughout the body (page 85, 1.Neuroscience, 6th Ed.). Neurotransmitters include excitatory and inhibitory chemicals and they activate or inhibit the firing of a nerve signal. GABA can be a calming/inhibitory neurotransmitter that may be low when anxiety is a problem. Magnesium is the mineral inside cells which helps control how much calcium will be allowed to enter. Excess calcium can cause excess release of neurotransmitters. Magnesium deficiency can also be involved when anxiety is a symptom.

Adequate fluid is also likely important for adequate cleansing of waste from the brain by the glymphatic system. Problems with edema/swelling in other areas of the body or problems with hypertension may indicate problems with the lymphatic system in general. Moderate exercise helps the muscle power of movement also move extracellular fluid and lymphatic fluid through the lymphatic vessels to lymph nodes to be filtered by blood cells. Waste is removed into blood vessels for later excretion by the kidneys.

Additional note – adenosine was mentioned in the series on demyelination as a chemical that may lead to more breakdown of cells or myelin. It is produced as a metabolite of normal energy production and increased levels seem to be involved in our beginning to feel sleepy, signaling a need for rest – which would then give the brain clean up glymphatic system a chance to work on decreasing levels — so feeling sleepy? Your brain may be trying to tell you it is time to clean up after a strenuous workout whether physical or mental.  (See the What Makes You Sleep? section in the NHLBI article about Sleep Deprivation and Deficiency)

For more general information about promoting sleep and coping with insomnia see the post “Sleep and Health.”

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326841/Reference: pp 85-112, “Synaptic Transmission,” Neuroscience, 6th Edition, Editors D. Purves, G.J. Augustine, D. Fitzpatrick, W.C. Hall, A.S. LaMantia, R.D. Mooney, ML. Platt, L.E. White, (Sinauer Associates, Oxford University Press, 2018, New York) (Barnes&Noble)
  2. Glymphatic System May Play Key Role in Removing Brain Waste, Neurology Reviews, 2016 October;24(10):13   https://www.mdedge.com/neurologyreviews/article/114150/alzheimers-cognition/glymphatic-system-may-play-key-role-removing
  3. Understanding the Glymphatic System, Neuronline, adapted from the SfN Short Course The Glymphatic System by Nadia Aalling, MSc, Anne Sofie Finmann Munk, BSc, Iben Lundgaard, PhD, and Maiken Nedergaard, MD, DMSc http://neuronline.sfn.org/Articles/Scientific-Research/2018/Understanding-the-Glymphatic-System
  4. Tsutomu Nakada, Ingrid L. Kwee, Fluid Dynamics Inside the Brain Barrier: Current Concept of Interstitial Flow, Glymphatic Flow, and Cerebrospinal Fluid Circulation in the Brain. The Neuroscientist, May 24, 2018, http://journals.sagepub.com/doi/10.1177/1073858418775027#articleCitationDownloadContainer
  5. Bruce Goldman, The beating brain: A video captures the organ’s rhythmic pulsations. Scope, Stanford Medicine, July 5, 2018, https://scopeblog.stanford.edu/2018/07/05/the-beating-brain-a-video-captures-the-organs-rhythmic-pulsations/?linkId=53912604
  6. Geir Ringstad, Lars M. Valnes, Anders M. Dale, et al., Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight. 2018;3(13):e121537 https://insight.jci.org/articles/view/121537?utm_content=buffer13f62&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer
  7. Brain discovery could block aging’s terrible toll on the mind. University of Virginia Health System, EurekAlert! Science News, July 25, 2018, https://www.eurekalert.org/pub_releases/2018-07/uovh-bdc072518.php
  8. Da Mesquita S., Louveau A., Vaccari A., et al., Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease, Nature, 185,191, Vol 560, Issue 7717, 2018/08/01. https://www.nature.com/articles/s41586-018-0368-8
  9. Albargothy N. J., Johnston D. A., MacGregor‑Sharp M., Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathologica (2018) 136:139–152 https://link.springer.com/epdf/10.1007/s00401-018-1862-7?shared_access_token=oYhOYaeYOAlkFhECIjAc6Pe4RwlQNchNByi7wbcMAY7lrBk-VqU01OilsaKMVR9FXaHRKmFQ1tkD03g-Q04DmsYSxRC_gucPZRYlFW0xfyU2pYNfhmwcokVbMCreuzU3wBLsjKpRasKo-6HXTJLMHNXMqFbaSsQVIB34EgzIUsc%3D
  10. Tamara Bhandari, Lack of Sleep Boosts Levels of Alzheimer’s Proteins, The Source, Washington University in St. Louis, Dec. 27, 2017, https://source.wustl.edu/2017/12/lack-sleep-boosts-levels-alzheimers-proteins/
  11. Yo-El S Ju, Sharon J Ooms, Courtney Sutphen, et al., Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain, Vol 140, Issue 8, 1 August 2017, Pages 2104–2111, Oxford Academic, https://academic.oup.com/brain/article/140/8/2104/3933862
  12. Krista Burns, American Posture Institute: Proper Sleeping Posture for ‘Brain Drain,’ April 5, 2017, https://americanpostureinstitute.com/proper-sleeping-posture-for-brain-drain/
  13. Patricia Farrell, Sleep: Everyone Needs It and So Do You, March 16, 2017, https://www.amazon.com/dp/152061294X
  14. Melanie D. Sweeney, Berislav V. Zlokovic, A lymphatic waste-disposal system implicated in Alzheimer’s disease. July 25, 2018, https://www.nature.com/articles/d41586-018-05763-0?utm_source=twt_na&utm_medium=social&utm_campaign=NNPnature
  15. Nadia Aalling Jessen, Anne Sofie Finmann Munk, Iben Lundgaard, Maiken Nedergaard, The Glymphatic System – A Beginners Guide, Neurochem Res. 2015 Dec; 40(12): 2583–2599. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636982/
  16. Maiken Nedergaard, Steven A. Goldman, Brain Drain, Sci Am. 2016 Mar; 314(3): 44–49. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347443/
  17. Rainey-Smith S. R., Mazzucchelli G. N., Villimagne V. L., et al. Genetic Variation in Aquaporin-4 Moderates the Relationship Between Sleep and Brain Aβ-amyloid burden. Translational  Psychiatry, (2018) 8:47 https://www.nature.com/articles/s41398-018-0094-x.epdf?author_access_token=iK09AkugOzYXUjXJCpGfIdRgN0jAjWel9jnR3ZoTv0P4SU0l7P8A1C64dg2xJ-HX7jlpuvyMeHzBYm6I5D0yMRBsx023MtG5Y3KNpj4EoNEqA4ELFuByqeysfTCRKZdGegxohMN9WLBb_S6H0UZYpw%3D%3D
  18. Brown B., Rainey-Smith S. R., Dore V., et al., Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. Journal of Alzheimer’s Disease, vol. 63, no. 4, pp. 1299-1305, May 30, 2018 https://content.iospress.com/articles/journal-of-alzheimers-disease/jad170998
  19. Chloe Chaplain, Drinking wine every day could help prevent Alzheimer’s, experts say. London Evening Standard, June 6, 2018, https://www.standard.co.uk/news/health/drinking-wine-every-day-could-help-prevent-alzheimers-experts-say-a3856646.html
  20. In Wine, There’s Health: Low Levels of Alcohol Good for the Brain. Feb. 2, 2018, University of Rochester Medical Center, https://www.urmc.rochester.edu/news/story/5268/in-wine-theres-health-low-levels-of-alcohol-good-for-the-brain.aspx
  21. Brianna Diorio, Glymphatic System 101, video,August 8, 2018,  https://vimeo.com/283708099?ref=tw-share
  22. Sydney, How To Detox Your Brain By Hacking Your Glymphatic System. A Healthy Body, May 18, 2018, http://www.a-healthy-body.com/how-to-detox-your-brain-by-hacking-your-glymphatic-system/
  23. The Effects of Alcohol on the Brain, The Scripps Research Institute, https://www.scripps.edu/newsandviews/e_20020225/koob2.html
  24. Li Y, Schmidt-Edelkraut U, Poetz F, et al. γ-Aminobutyric A Receptor (GABAAR) Regulates Aquaporin 4 Expression in the Subependymal Zone: RELEVANCE TO NEURAL PRECURSORS AND WATER EXCHANGE. The Journal of Biological Chemistry. 2015;290(7):4343-4355. doi:10.1074/jbc.M114.618686. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326841/ (24)
  25. Plog BA, Nedergaard M. The glymphatic system in CNS health and disease: past, present and future. Annual review of pathology. 2018;13:379-394. doi:10.1146/annurev-pathol-051217-111018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803388/ (25)
  26. Cesetti Tiziana, Ciccolini Francesca, Li Yuting, GABA Not Only a Neurotransmitter: Osmotic Regulation by GABAAR Signaling. Frontiers in Cellular Neuroscience, Vol. 6, 2012, https://www.frontiersin.org/article/10.3389/fncel.2012.00003 DOI=10.3389/fncel.2012.00003 ISSN=1662-5102 (26)
  27. Kazanis I. The subependymal zone neurogenic niche: a beating heart in the centre of the brain: How plastic is adult neurogenesis? Opportunities for therapy and questions to be addressed. Brain. 2009;132(11):2909-2921. doi:10.1093/brain/awp237. (27)
  28. Robert I Henkin, Mona Abdelmeguid, Sleep, glymphatic activation and phantosmia inhibition. The FASEB Journal, Vol 31, No. 1_supplement, April 2017, https://www.fasebj.org/doi/abs/10.1096/fasebj.31.1_supplement.749.4  (28)
  29. Solas M, Puerta E, Ramirez MJ. Treatment Options in Alzheimer’s Disease: The GABA Story., Curr Pharm Des. 2015;21(34):4960-71. https://www.ncbi.nlm.nih.gov/pubmed/26365140 (29)
  30. Zheng Wu, Ziyuan Guo, Marla Gearing, Gong Chen, Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model. Nature Communications, 5,  Article number: 4159 (2014) https://www.nature.com/articles/ncomms5159 (30)
Posted on

Ginger slows prostate cancer growth

In a study at Georgia State University whole ginger extract was found to slow growth rate and to cause the death of pancreas cancer cells (PC-3 line) in petri dish type studies and in live mice. [1]

Two grams of ginger per day for one month time periods was found successful at reducing inflammation of the intestinal lining in human studies. [5,6] Free arachidonic acid levels were reduced. Arachidonic acid levels are typically increased in inflammation and it has been found to be a precursor for 5-HETE, a main energy source for stimulating prostate cancer cell growth. [8-12] The prostate cancer cells seem to have the ability to increase production of  an enzyme that converts arachidonic acid (half of the endogenous cannabinoid, anandamide) into 5-HETE which is a form needed by the cancer cells.

Conjugated linolenic acid (CLA) was used successfully to reduce breast tumor growth in a study regarding the same enzyme from the prostate cancer cells, 5-lipoxygenase (5-LO). The CLA, an essential fatty acid, was not found to be inhibiting the 5-LO enzyme but instead it was reducing the enzyme’s activating protein and possibly competing with arachidonic acid (also an essential fatty acid). It might be able to stand in for the 5-LO enzyme but less 5-HETE was being produced and breast tumor cell growth was “attenuated” (sounds like a good thing).

Attenuation can be defined as the process by which a virus, bacterium, etc., changes under laboratory conditions to become harmless or less virulent.

So I think this research shows:

  1. Prostate and breast cancer cells have learned how to make the 5-LO enzyme or more likely how to make 5-LO’s activating protein
  2. In humans, mice, and in petri dish studies, ginger has been found to inhibit the action of 5-LO from converting as much arachidonic acid into 5-HETE and slowing prostate cancer cell growth.
  3. Conjugated linolenic acid may also help slow the conversion by taking the place of the arachidonic acid and/or by inhibiting the activating protein.
  4. If a patient has breast or prostate cancer currently then do eat at least two grams of ginger extract per day. I aim for a 5 gram per day arthritis research-pain killing intake – which is about a teaspoon of the powder. I sprinkle on a variety of foods or beverages throughout the day or I eat the crystallized ginger or cook with the raw root as well. Easy bruising, blood thinning properties, are the only side effect that I’ve noticed and only when I’m eating the candied ginger as well as the powder.
  5. Avoiding excess amounts of foods rich in arachidonic acid [livestrong.com AA food sources], while fighting prostate or breast cancer and increasing CLA and omega 3 fatty acids might help reduce the 5-HETE availability to cancer cells.
  6. Increasing intake of the other endogenous cannabinoid building blocks, the essential phospholipids could help rebuild stronger membranes. Loss of the arachidonic acid as a membrane building block leaves weakened defenses against other infections. Anandamide, the endogenous cannabinoid that contains arachidonic acid, isn’t the only one, so medical marijuana – an external source of cannabinoids,  might not be the only solution to rebuilding strong membranes without also feeding the cancer cells. – Flaw in that plan is that the foods high in arachidonic acid also tend to be good sources of phospholipids – not really a surprise –  half the brain weight is made up of phospholipids.

________________________________________________________________________
Addition Dec. 15, 2011:  [drdavidbrownstein.blogspot.com]  has info about iodine levels in association with breast and prostate cancer rates.

*This list of articles was tacked on the eicosanoid article but it became apparent that more discoveries had been made regarding ginger itself.

1. [ncbi.nlm.nih.gov/pubmed/21849094] 2011 Aug 18:1-12. [Epub ahead of print] Benefits of whole ginger extract in prostate cancer. Karna P, Chagani S, Gundala SR, Rida PC, Asif G, Sharma V, Gupta MV, Aneja R. Source: Dept. of Biology, Georgia State U., Atlanta, GA 30303, USA.

*These articles were tacked on the bottom of the eicosanoid article but it became apparent that more discoveries had been made regarding ginger itself.

4. “Nutritional Sources of Arachidonic Acid, Livestrong.com [livestrong.com]

5. [mdnews.com]
Colon Inflammation Markers Lower With Ginger Extract

*** Two grams of ginger was given daily for 30 days and intestinal lining inflammation seemed improved based on reduced free arachidonic acid (which is released from breakdown of the endogenous cannabinoids after they are released from their membrane storage in response to elevated intracellular calcium or glutamate levels – just to review from a few blogs ago).

6. [ncbi.nlm.nih.gov/] 
Zick SM, Turgeon DK, Vareed SK, Ruffin MT, Litzinger AJ, Wright BD, Alrawi S, Normolle DP, Djuric Z, Brenner DE. Phase II Study of the Effects of Ginger Root Extract on Eicosanoids in Colon Mucosa in People at Normal Risk for Colorectal Cancer.Cancer Prev Res (Phila). 2011 Oct 11.

7. [ncbi.nlm.nih.gov/]

Prostaglandins Leukot Med. 1986 Dec;25(2-3):187-98. Isolation and effects of some ginger components of platelet aggregation and eicosanoid biosynthesis. Srivastava KC.

“Interestingly the incorporation of AA into platelet phospholipids increased in platelets treated with aqueous ginger extract.”

***** Swish and score – ginger helped the body to rebuild endogenous cannabinoids – AA plus phospholipid = healthy rebuilt membranes and endogenous cannabinoids reloaded ready for the next stress signal to fire them off where they can be messengers or be transformed into eicosanoids or other metabolites.

8.  [/i4cmwo.com.au/ginger.html]

** I should have just read this one first. It seems that prostate cancer eats only a metabolite of arachidonic acid – which itself is a building block of endogenous cannabinoids and strong membranes. It would be to the cancer cell’s advantage to have learned how to use the body’s own system to mobilize resources as a way to get nutrients for themselves. The cancer cell can make the enzyme that activates vitamin 25-D to hormone 1,25-D; hormone 1,25-D signals the bones to release calcium; increased intracellular levels of calcium signal the release of endogenous cannabinoids from membrane storage – arachidonic acid and free phospholipids – cancer food. In the placenta they would have become nutrients for the fetus.

9. [ncbi.nlm.nih.gov]
Jagadananda Ghosh and Charles E. Myers, Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells Proc Natl Acad Sci U S A. 1998 October 27; 95(22): 13182–13187.    ***I think this might be the research mentioned in the previous link.

10. [ncbi.nlm.nih.gov]
Cancer. 2001 Feb 15;91(4):737-43. Lipoxygenase-5 is overexpressed in prostate adenocarcinoma. Gupta S, Srivastava M, Ahmad N, Sakamoto K, Bostwick DG, Mukhtar H.

***Aha, the problem – the prostate cancer cells have learned how to signal the body to make the 5-Lipoxygenase so more ginger for men as a preventative and if prostate cancer is already present then excess intake of arachidonic acid foods may not be good.

11.  [ncbi.nlm.nih.gov] Myers CE, Ghosh J Lipoxygenase inhibition in prostate cancer.. Eur Urol. 1999;35(5-6):395-8.
12. [ncbi.nlm.nih] Carcinogenesis. 2011 Jun;32(6):822-8. Epub 2011 Mar 10. Enhanced formation of 5-oxo-6,8,11,14-eicosatetraenoic acid by cancer cells in response to oxidative stress, docosahexaenoic acid and neutrophil-derived 5-hydroxy-6,8,11,14-eicosatetraenoic acid. Grant GE, Rubino S, Gravel S, Wang X, Patel P, Rokach J, Powell WS.

***Did anyone besides me notice that they stimulated those cancer cells with calcium? Might simply not over stimulating cancer with excess calcium be an attractive target for cancer therapy? and cheap? – less calcium intake – more health output? /speculation/

13. [ncbi.nlm.nih.gov] Biochim Biophys Acta. 2005 Oct 1;1736(3):244-50. Attenuation of breast tumor cell growth by conjugated linoleic acid via inhibition of 5-lipoxygenase activating protein. Kim JH, Hubbard NE, Ziboh V, Erickson KL.

***Take home point – if you already have breast cancer (and probably similar for prostate cancer) then consuming more CLA type of good fats may help reduce the over-conversion of arachidonic acid into the cancer friendly type, 5-HETE.
Disclaimer: This is provided for informational purposes. Please see a health professional for the purposes of individual health care.