BDNF increased by boron, N-acetyl-carnitine (ALCAR), magnesium, & pomegranate peel extract.

Pomegranate peel extract dosing - 200-800 mg/kg ~ 1 1/2 teaspoons - 2 tablespoons; atherosclerosis (200mg/Kg) and an Alzheimer's dementia (800mg/Kg) mouse-based model.

Pomegranate peel affects similar pathways as brain-derived neurotrophic factor (BDNF), which suggests why pomegranate peel is so helpful. EGCG was mentioned as promoting BDNF in the first post of this series. Inhibiting TNF alpha is a mechanism of action by EGCG and other phytonutrients found in pomegranate peel, and by niacin and butyrate. Inhibiting it would also help keep tryptophan being converted into serotonin (and a better mood) instead of sending it down the kynurenine pathway. (Part 3 post)

Series on BDNF: (Part 1 niacin, butyrate, EGCG and BDNF) (Part 2 exercise & butyrate producing microbes) (Part 3 kynurenine pathway, tryptophan, butyrate producing microbes and peaceful thinking) (This post, Pomegranate peel, ALCAR & BDNF, Part 4)

This post doesn’t get into boron and magnesium in detail - but a list is included at the end.

A reply had suggested I look up ALCAR, boron and magnesium and the ALCAR link set me off on a pomegranate peel tangent. At the very end of this post is a link to a nice blog article which lists 31 research-based things that promote BDNF and magnesium is included in that article. I list the items at the end of this post and I added a reference with some dosing guidance regarding boron and ALCAR.

No speculation is needed about the use of pomegranate peel for increasing BDNF.

Levels of BDNF increased in a study on Alzheimer’s dementia risk. The experimental group of mice were given “PPE, 800 mg/kg/day,” as the experimental treatment against amyloid beta infusion. The PPE treated group and the control group of mice were able to find their way out of an escape box, while the amyloid beta treated mice that didn’t receive Pomegranate peel extract didn’t find their way out. (Morzelle, et al., 2016)

How much pomegranate peel extract to use per day?

~ 1 1/2 teaspoons to 1 or 2 tablespoons in divided doses possibly - drink extra water and have it earlier in the day rather than at bedtime (it’s a diuretic).

Later in this post I do the math for an approximate human dosing equivalent and the results ~ about 2 tablespoons might provide 800 mg/70kg average human/day. I also discuss the edibility and cautions and link to some How-to prepare pages.

“To this end, here we demonstrate the effects of pomegranate (Punica granatum) peel extract (PPE) regarding spatial memory, biomarkers of neuroplasticity, oxidative stress and inflammation in a mouse model of neurodegeneration. Male C57Bl/6 mice were chronically infused for 35 days with amyloid-β peptide 1–42 (Aβ) or vehicle (control) using mini-osmotic pumps. Another group, also infused with Aβ, was treated with PPE (p.o.– βA+PPE, 800 mg/kg/day). Spatial memory was evaluated in the Barnes maze. Animals treated with PPE and in the control group exhibited a reduction in failure to find the escape box, a finding that was not observed in the Aβ group. The consumption of PPE reduced amyloid plaque density, increased the expression of neurotrophin BDNF and reduced the activity of acetylcholinesterase enzyme. A reduction in lipid peroxidation and in the concentration of the pro-inflammatory cytokine TNF-α was also observed in the PPE group. No hepatic lesions were observed in animals treated with PPE.” (Morzelle, et al., 2016)

What is neurotrophin BDNF and what are its functions?

- brain cell support & it activates tyrosine receptor kinase B.

“The second discovered neurotrophin in CNS, brain-derived neurotrophic factor (BDNF) is highly expressed and widely distributed in the brain [17], [18]. It provides trophic support to neurons and plays a crucial role in various neurodevelopmental processes, such as development, maintenance and survival of the nervous system, synaptic plasticity and cognitive function [17], [18], [19], [20], [21]. (Kazak and Yarim, 2017)

What pathways are activated by TRKb? - MAPK, PLC gamma, and PI3K.

Brain-derived neurotrophic factor demonstrates these functions by binding its receptor (tyrosine receptor kinase B), [(TrkB)],

• and activating the mitogen-activated protein kinase, [(MAPK)],

• the phospholipase C gamma, [(PLC gamma)].

• and the phosphatidylinositol 3-kinase pathways [(PI3K)] (19).

Based on these functions, researchers have proposed that dysregulation of BDNF signaling leads to the onset of neurodegenerative diseases and neuropsychiatric disorders [22], [23], [24], [25].” (Kazak and Yarim, 2017)

Pomegranate peel extract also helps those pathways. In the following animal model of atherosclerosis, TNF alpha levels were reduced and IL-10 increased in the PPE treated group.

Pomegranate peel extract (200 mg/kg dose) studied in an atherosclerosis animal-based model was found to decrease levels of TNF-alpha (G in the Figure below) and increase levels of cytokine IL-10 quite a bit [*IL-10 is beneficial for T-cell immunity and is generally anti-inflammatory (Gorby, et al., 2020)] (the H is missing in the graphic excerpted below). Blood lipid levels improved (D and E) and body weight decreased in the graphic below (F), click through to see the other lab values that were measured. (FIGURE 1, Manickam, et al., 2022)

FIGURE 1 10 male and 10 female Apoe ^-/- mice were randomized into two groups of 5 mice each, one receiving vehicle and another receiving pomegranate peel extract (200 mg/kg body weight) per oral daily during the entire duration of 12 weeks when they were fed western-type diet. At the end of 12 weeks of treatment, the following parameters were measured (A) fasting blood glucose (B) intraperitoneal glucose tolerance test (C) plasma insulin (D) plasma total cholesterol (E) plasma triglyceride (F) body weight (G) plasma TNF and IL-10 levels by ELISA (H) plasma AST levels (I) plasma ALT levels (J) plasma creatinine, and (K) differential leukocyte count. All data were tested for statistical significance using Mann–Whitney test. ns, no significant difference; *, p < 0.05; **, p < 0.01. TNF and IL-10 ELISA were conducted on 5 control and 4 PPE-treated female mice due to insufficient sample volume in one PPE-treated female mouse. (Manickam, et al., 2022)

Inhibition of NMDA receptors has also been found to improve BDNF levels in the brain, (Tanqueiro, et al., 2018), which adds further support to my pomegranate, niacin/butyrate graphic - inhibiting NFkB (and TNF alpha) helps prevent degranulation of mast cells, prevent over activation of NMDA receptors and prevent the gradual destruction of the hippocampus.

Hyperinflammation - a positive feedback loop. Don’t get stuck in this loop... use niacin, butyrate, pomegranate peel and other phytonutrients to help block the escalating spiral of inflammation and chronic damage. (Graphical Abstract)

Pomegranate peel extract Dosing math

For dietary equivalents, let’s do the math from that second mouse study: 200 mg/kg body weight of pomegranate peel extract (Manickam, et al., 2022) would be 0.2 grams times ~ 70 Kg human = 14 grams of pomegranate peel extract per day (about 3 teaspoons) - to greatly improve atherosclerosis risk, blood lipids and reduce weight (in rodents). That would be approximately three teaspoons, which divided over the day would not be an unreasonable amount to take, BUT it would be at a diuretic level. So, have it earlier in the day and drink some extra non-caffeinated beverage too (like water or herbal tea - non-calorie is generally a better beverage choice).

This dosing info supports my premise that we should view pomegranate peel as a functional food, rather than as a 200 mg capsule product.

The dosing math as a percent of total daily food intake:

Two hundred milligrams per kilogram for a mouse sized mammal… is more of a macro-food dose, rather than a trace nutrient. An average lab mouse weighs ~ 30 grams, one ounce. (Kinaneh, et al., 2018) 200/1000 = x/30 200 = 1000x/30 200*30/1000 = x x = 6 mg, the amount the mice received. Lab mice tend to eat about 23 grams of food per day, or almost double that during early rapid growth weeks. (Kinaneh, et al., 2018) That means they were given 0.26% of their daily intake as pomegranate peel extract.

Humans vary in the nutrient density of their food choices - celery provides bulk without calories compared to dried nuts or a marbled cut of beef. Salad with low calorie salad dressing would add bulk without calories. But … we might average an intake of 3-6 pounds of food per day (Brave AI Summary) - multiplied by 0.26% we arrive at 7 grams of pomegranate peel extract as a potentially comparable dose - about two teaspoons per day.

The first mouse study on Alzheimer’s dementia risk used four times as much - 800 mg/kg, which would be 4 times ~ 7-14 grams, or 28-56 grams, and that is a lot - 1 to 2 ounces, which I probably have used - one or two tablespoons a couple times a day would provide that amount. But I think we need some human trials for tolerance in addition to measuring lab values.

*And/or plan on a dietary and nursing care plan for dehydration prevention or treatment. Drinking extra fluids and having adequate potassium and salt and magnesium is important with a diuretic. It can help with detox and lymphatic flow. Detox benefits for smog and lung health too: later in the post there is a section on nanoparticles and the benefits of pomegranate for clearing particulate matter smaller than 10 micromoles (PM10).

Bonus: Pomegranate peel extract also tends to reduce appetite and improve leptin and insulin resistance.

Why I recommend buying pomegranate and processing your own peel - cost and ability to separate the outer and inner peel.

People ask me about good ‘supplement products’ to buy and I hesitate to support any versus buying the whole fruit in season (but I have mentioned that Dr. Mercola has one that I have heard is helpful).

Any capsule product is likely going to be a minimal dose, or a dose to use several times a day if you are actively trying to treat something rather than just for preventive health goals. And taking several capsules per day of a product that can easily cost $1 per capsule is going to add up fast compared to buying pomegranate in season and freezing or drying the peel. I strongly encourage that method as you can separate the outer and inner peel to use in different ways. The outer rind is too high in tannins to use as a functional food as the diuretic potential and bitter taste are so great. The inner pith is higher in pectin which provides additional health benefits and the tannin concentration is lower.

Several house mice and I agree - the inner pith of pomegranate is edible, the outer rind is an insect proof barrier to the good stuff within. House mice will also choose pomegranate over other available fruit (but they eat most anything ;-).

Inner pith dosing - about 1/4 to 1/2 teaspoon fresh, minced is what I have come to consider a single serving, and I might have that 1-3 times a day or slightly more, but too much more is a negative. I have learned that cookies are not a good choice for a functional food ingredient - too likely to overeat compared to bean soup. I use about 2 tablespoons minced inner pith in a two-to-three-quart batch of soup or 24 muffin batch of quick bread. See effectivecare.info for a few recipes on page G13. Pomegranate and G10. Nrf2 Promoting Foods. (*Which are basically the same foods and spices as SIRT1 promoting foods which had become part of a trendy “SIRT food” weight loss diet, a few years back - Brave AI gives it a not well-researched and may be low protein and other nutrients - I would agree based on a knockoff diet book I saw. Also high oxalate would be likely.)

Tangent into benefits of Pomegranate peel extract (PPE) for nanoparticulates in air.

Use of pomegranate peel extract helps monocytes to clean up the nanoparticles, otherwise nanoparticles are ignored due to being too small. Pomegranate phytonutrients helps clump nano-sized things (PM10 < 10 micrometers) into a larger cluster including heavy metals and other toxins found in smog or smoke.

*TNF alpha was also reduced - leading to my finding the search result.

In the image below, compare the dots on black images - the first is the Control, second is exposure to PM10 particulate matter, third is the same PM10 particulate exposure but with Pomegranate peel extract too. It visibly helped a lot - but it was still better to not be exposed to the equivalent of smog though (control image). (Park, et al., 2016)

Figure 4 Effects of PPE on the adhesion of PM10-treated THP-1 monocytes to cells to EA.hy926 endothelial cells. THP-1 cells were treated with PM10 in the absence or presence of PPE, followed by incubation for 24 h. The treated monocytes were fluorescence-labeled and coincubated with EA.hy926 endothelial cells to monitor cell-cell adhesion. Fluorescing monocytes adhered on the endothelial cells were observed under a microscope (a) and quantified fluorometrically (b). Data are expressed as percentages of the control value. Data are means ± SEs (n = 3). ^∗ p < 0.05. (Park, et al., 2016)

PM10 = particulate matter smaller than 10 micrometers

“Particulate matter is known to cause airway epithelium injury and endothelial dysfunction [4, 5]. Larger particles can be filtered in the nose and throat via cilia and mucus, but particulate matter smaller than 10 micrometers (PM10) can enter the deepest parts of the lungs, such as the bronchioles and alveoli [6]. PM10 may cause severe effects on human health due to the broad range of miscellaneous toxic compounds present in this particulate matter fraction, such as transition metals, endotoxins, and ultrafine components. The mechanism of action of PM10 may include the induction of oxidative stress and activation of nuclear factor kappa B (NF-κB) pathway, leading to inflammation [7]. PM10 increases the production of reactive oxygen species (ROS) and cytokines in human and rat alveolar macrophages [8]. In addition, PM10-induced inflammation is attenuated by antioxidants from plant sources [9–11].” (Park, et al., 2016)

Pomegranate peel is a censored topic because it is not bannable, inexpensive, and quite effective with minimal risk. Cautions: salicylate/phenols, oxalate, and the diuretic tannins may lead to side effect symptoms if pomegranate peel/extract is used in excess or by people with increased sensitivity. As someone with genetically poor clearance of phenols, I can use too much if I am not watching portion sizes but the 1/4-1/2 teaspoon dose once or a few times a day generally is not too much for me.

Skullcap, a source of baicalin, has become a tea herb that I use regularly. It also increases BDNF levels. (Li, et al., 2021)

Nutshell: basically, my entire list of Nrf2 promoting phytonutrients/foods, is also a list of substances that help increase BDNF and they would also help tryptophan to be made into serotonin instead of it being directed down the kynurenine pathway. I’m late to the BDNF party, but I had been in the neighborhood with my work on the inhibitors of NFkB and TNF alpha being the same things that promote Nrf2 - and BDNF.

See this helpful article for more herbs and nutrients that help increase levels of brain cell supporting BDNF, and yes, exercise is mentioned too:

• 31 Proven Ways to Increase BDNF, Your Brain's Growth Hormone,

  February 4, 2024, Jordan Fallis, (optimallivingdynamics.com) *Click through for his free downloadable grocery shopping guide.

1. Coffee fruit extract

2. Curcumin

3. Green Tea [and pomegranate peel/extract, powdered Sumac, or goji berries]

4. Omega 3 fatty acids

5. Resveratrol

6. Prebiotics and Resistant Starch

7. Magnesium

8. Lithium orotate [5 mg is a low dose used for health support rather than the higher dosing used in psychiatric care.]

9. Dark chocolate

10. N-acetyl-cysteine [600 mg is recommended as a preventive health dose - an excess may inhibit methylation cycles. If actively sick, take more frequent dosing to add more to the daily intake. It is plentiful in animal and plant protein foods, so getting adequate protein generally leads to having a good intake of cysteine too.]

11. Theanine

12. Adaptogenic herbs “Rhodiola, bacopa and ginseng are the three main herbs I have used to increase BDNF and support my brain function.

    But there are several other herbs that have been shown to increase BDNF, including baicalin (Skullcap), ashwagandha, gotu kola, and magnolia officinalis (81-84).”

13. Zinc

14. Blueberries

15. Progesterone

16. Dehydroepiandrosterone (DHEA) - [*Men can use a higher dose than females (25-75 mg maybe), females should stick to a lower dose (5-25 mg, or use 7-keto DHEA) as it can be turned into testosterone.]

17. Quercetin

18. Coffee and caffeine

19. Niacin [*The flush type is the one that helps the most. Niacinamide is a less bioactive form but is the standard form in mixed supplements now.]

20. Extra virgin olive oil

21. Taurine

22. Saffron

23. Exercise “Lift heavy weights 1-4 times per week
    •    High-intensity interval sprinting 1-2 times per week
    •    Walk as much as you can (ideally 30-60 minutes every day)”

24. Sunlight [Dawn or early morning light helps get our circadian cycle switched to day mode and then more sunshine later in the day helps us make vitamin D and other nutrients related to sunshine (sulfur compounds and vitamin A have sunshine related metabolism).]

25. Intermittent Fasting

26. Avoid Processed Food and Refined Sugar

27. Lose fat

28. Socialize

29. Deep sleep

30. Neurofeedback/meditation/reduce stress;

31. Ketogenic Diet/or occasional ketosis from intermittent fasting

    1. List by: Jordan Fallis, (optimallivingdynamics.com)

32. Boron - 160 mg/L helped ostrich chick brain development but 640 mg/L was too much and caused worse development. (Tang, et al., 2016) Boron has a narrow safety range. I have exceeded it with ~ 3 tbs of Borox in my bath weekly for one month. An excess causes hand cramping that just does not stop - disabling muscle cramping - you can’t move your hand normally. I switched to a trace mineral supplement with 3 mg/day which is the recommended intake goal.

33. ALCAR / N-acetyl-carnitine - 100 mg/kg/day was more helpful than a higher 300 mg/kg/day dose (animal based study); Abstract below. (Kazak and Yarim, 2017)

34. Butyrate

Abstract:

Neuroinflammation is the inflammation of nervous tissue that can lead to neurodegeneration. Brain-derived neurotrophic factor (BDNF) is a neurotrophin which affects growth, function and survival of neurons, enhances the stabilization of synapses, regulates synaptic function and branching of dendrites and axons. Brain-derived neurotrophic factor is believed to be involved in the pathophysiology of central nervous system (CNS) diseases associated with neuroinflamation.

The aim of this study was to investigate new protective and therapeutic effect of acetyl-l-carnitine (ALCAR) in neuroinflammation. Acetyl-l-carnitine was administered into Swiss Albino mice as 100mg/kg/day and 300mg/kg/day for 5days. Neuroinflammation was induced by lipopolysaccharide (LPS). Histopathological findings associated with ALCAR administration on neuroinflammation in the brain were determined. Moreover, the effects of ALCAR on BDNF concentration in the brain tissue was evaluated. The LPS administration showed higher microglial activation in the brain of LPS, 100A+LPS and 300A+LPS groups compared to that in the control (p<0.05). In the 100A+LPS group, microglial activation was lower and BDNF concentration was higher than in the 300A+LPS group (p>0.05).

The findings suggest that the dose of ALCAR at 100mg/kg/day i.p. may have a beneficial effect on LPS-induced neuroinflammation in mice. As a conclusion, ALCAR may be used as an optional neuroprotective and therapeutic agent to attenuate inflammatory damage in the CNS regarding BDNF, in a dose dependent manner. (Kazak and Yarim, 2017)

BDNF series links

1. (Part 1 niacin, butyrate, EGCG and BDNF)

2. (Part 2 exercise & butyrate producing microbes)

3. (Part 3 kynurenine pathway, tryptophan, butyrate producing microbes and peaceful thinking)

Disclaimer: This information is being shared for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.

Reference List

(Gorby, et al., 2020) Claire Gorby et al., Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses. Sci. Signal. 13, eabc0653(2020). DOI:10.1126/scisignal.abc0653 https://www.science.org/doi/10.1126/scisignal.abc0653

(Kazak and Yarim, 2017) Filiz Kazak, Gul Fatma Yarim, Neuroprotective effects of acetyl-l-carnitine on lipopolysaccharide-induced neuroinflammation in mice: Involvement of brain-derived neurotrophic factor, Neuroscience Letters, Vol 658, 2017, pp 32-36, ISSN 0304-3940, https://doi.org/10.1016/j.neulet.2017.07.059. https://www.sciencedirect.com/science/article/pii/S0304394017306353.

(Kinaneh, et al., 2018) Kinaneh S, Agbaria M, Abu-Saleh N, Hamoud S. Dataset on mice body weights and food intake following treatment with PG545. Data Brief. 2018 Sep 6;20:1305-1308. doi: 10.1016/j.dib.2018.08.179. PMID: 30238043; PMCID: PMC6143748. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143748/

(Li, et al., 2021) Li C, Sui C, Wang W, Yan J, Deng N, Du X, Cheng F, Ma X, Wang X, Wang Q. Baicalin Attenuates Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury by Modulating the BDNF-TrkB/PI3K/Akt and MAPK/Erk1/2 Signaling Axes in Neuron-Astrocyte Cocultures. Front Pharmacol. 2021 Jun 21;12:599543. doi: 10.3389/fphar.2021.599543. PMID: 34234667; PMCID: PMC8255628. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255628/

(Manickam, et al., 2022) Manickam V, Dhawan UK, Singh D, Gupta M, Subramanian M. Pomegranate Peel Extract Decreases Plaque Necrosis and Advanced Atherosclerosis Progression in Apoe^-/- Mice. Front Pharmacol. 2022 Jun 1;13:888300. doi: 10.3389/fphar.2022.888300. PMID: 35721222; PMCID: PMC9198482. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198482/

(Morzelle, et al., 2016) Morzelle MC, Salgado JM, Telles M, Mourelle D, Bachiega P, Buck HS, Viel TA. Neuroprotective Effects of Pomegranate Peel Extract after Chronic Infusion with Amyloid-β Peptide in Mice. PLoS One. 2016 Nov 9;11(11):e0166123. doi: 10.1371/journal.pone.0166123. PMID: 27829013; PMCID: PMC5102433. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102433/

(Park, et al., 2016) Park S, Seok JK, Kwak JY, Suh HJ, Kim YM, Boo YC. Anti-Inflammatory Effects of Pomegranate Peel Extract in THP-1 Cells Exposed to Particulate Matter PM10. Evid Based Complement Alternat Med. 2016;2016:6836080. doi: 10.1155/2016/6836080. Epub 2016 May 10. PMID: 27247608; PMCID: PMC4877489. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877489/

(Tang, et al., 2016) Tang J, Zheng XT, Xiao K, Wang KL, Wang J, Wang YX, Wang K, Wang W, Lu S, Yang KL, Sun PP, Khaliq H, Zhong J, Peng KM. Effect of Boric Acid Supplementation on the Expression of BDNF in African Ostrich Chick Brain. Biol Trace Elem Res. 2016 Mar;170(1):208-15. doi: 10.1007/s12011-015-0428-y. Epub 2015 Jul 31. PMID: 26226831. https://link.springer.com/article/10.1007/s12011-015-0428-y

(Tanqueiro, et al., 2018) Tanqueiro SR, Ramalho RM, Rodrigues TM, Lopes LV, Sebastião AM, Diógenes MJ. Inhibition of NMDA Receptors Prevents the Loss of BDNF Function Induced by Amyloid β. Front Pharmacol. 2018 Apr 11;9:237. doi: 10.3389/fphar.2018.00237. PMID: 29695962; PMCID: PMC5904251. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904251/