http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845822/
Excellent review.
Rikkunshito (Bu Zhong Yi Qi Wan, which contains aged mandarin orange peel, and is a mixture of herbs given at 7.5 grams/day for 10 days to critically ill patients) doubled acylated (active, acyl) and deacyl ghrelin. Hesperedin (hesperitin?) is in this herb mixture increase ghrelin by blocking serotonin 5HT 2B and 2C receptors and nobiletin and tangeretin (tangeritin) blocks the 2B receptor.Tangeretin is about 100 ppm in tangerine and mandarin. About 10x less in orange and grapefruit.
The major PMFs, i.e. sinensetin, nobiletin, tangeretin, heptamethoxyflavone, tetramethylscutellarein and hexamethyl-o-quercetagetin
Citrus = Flavanones
broccoli, kale, onion, chocolate = FlavOnols (can't find an extract)
teas = FlavAnols (and chocolate)
parsley, thyme, celery = Flavones
blueberries, strawberry, grapes = Anthocyanins, Proanthocyanidins ,
apples, chocolate = Proanthocyanidins
Grapefruit juice can make more flavonoids more bioavailable. Naringin is not the cause as previously believed. "It has now been established that the bioactive chemical compounds (furanocoumarins: bergamottin and 6′, 7′-dihydroxybergamottin [they interact]) present in grapefruit inhibit intestinal CYP3A4 activity through a mechanism-based reaction, which causes degradation of the enzyme, hence reducing its levels by as much as 47% within four hours after grapefruit juice ingestion."
bitter orange from which my 10% nobiletin comes may contain a weight-loss stimulant.
1 kg of the peel consumed converts the ppm values below into mg. So if 1 kg is safe, then the ppm values below when read as mg should be safe. The bitter orange values are direct whereas the pellets might be 10:1. If 1kg/day is safe, then 100 g of the 10:1 powders should be safe.
Hamlin orange pellets:
hesperidin 14,000 ppm
nobiletin 400 ppm (35x)
HMF 300 ppm (45x)
tangeretin 75 ppm ( 200x)
These are half the values I have seen elsewhere, but the same ratio.
Mandarin peel oil:
tangeretin 2000 ppm, 1500 tangerine, 600 hamlin orange
nobiletin 700 to 2000 ppm, 1500 tangerine, 1000 ppm hamlin orange
HMF 800 ppm mandarin, 200 ppm tangerine, 700 ppm hamlin orange
Citrus aurantium (bitter orange) from korea, fresh peel
naringin 450 ppm (400 g grapefruit juice has 0.2 g)
hesperidin 1800 ppm
nobiletin 50 ppm (but many companies sell 98% of this, so this does not make sense)
HMF: 6 ppm
Tangeretin 35 ppm
Tangeretine was $7000 per kg.Nobiletin was $1000 per kg.
10:1 extracts of apple, tangerine, and bitter orange were $100 per kg.
nobiletin compares favorably between oranges and mandarines, and if the 10:1 extract is of the same type of pellet as with the orange, then 250 g is needed to give me 100 mg per day which is 10 mg/kg in mice. This would be 3x more hesperidin than in the 100 mg/kg rat study. The common mandarin was the best source
Mandarins had wildly varying HMF.
A 98% hesperidin concentration will have lost a lot of the others. 95% might be OK.
Heptamethoxyflavone (HMF) and hesperedin were given to mice at 33 to 100 mg/kg
Hesperidin has been shown to help in a PD model. (100 mg/kg)
Nobiletin has been shown to help in 2 models of PD (at 10 mg/day but not at 1 or 20, but 50 mg/day work with a different PD model.)
tangeretin helped in 2 PD models (10 and 20 mg/kg/day for 28 days, and crossed the blood brain barrier in rat)
The citrus flavonoids include a class of glycosides, namely, hesperidin and naringin, and another class of O-methylated aglycones of flavones such as nobiletin and tangeretin, which are relatively common two polymethoxylated flavones (PMFs)
Citrus Aurantium extract profile seems ideal and contains naringin ... but naringin is not,bioavailable...but another study says they are bioavailable..."The flavonoids naringenin and hesperetin, which form the aglycones of naringin and hesperidin..."
flavonoid protection from PD was 40% lower risk in men in the highest quintile of intake, adjusted for smoking, age, etc. No effect in women.
"These anti-inflammatory actions of nobiletin are very similar to those of anti-inflammatory steroids such as dexamethasone, and the upregulation of TIMP-1 production is a unique action of nobiletin. Therefore, these results further support the notion that nobiletin is likely to be a candidate for characterization as a novel immunomodulatory and anti-inflammatory drug. "
Prolonged fasting, lighter meals, green tea extract, marijuana, and coconut oil all increase it. It works when taken orally. The MCT's in coconut oil increase its utilization in the brain. So it seems ending a long fast with coconut oil is a good idea, as well as marijuana and green tea extract during the fast.
It seems many if not most cases of PD begin in the gut and stomach where 500 million neurons make up the enteric nervous system. Other cases start in the nose and heart. The Lewy-bodies caused by a-syn misfolding travel up to the brain over the course of years. These neurons are only 0.5% of your total neurons, but they produce 50% of the dopamine. But it seems the ghrelin they produce is more relevant to PD. PD patients produce less of it which causes PD to worsen more quickly and worsen anxiety, depression, memory, and lack of sleep. It also increases dopamine in the SN and protects the SN from future damage. Prolonged fasting produces more ghrelin and calorie restriction has been shown to slow PD progression and especially in this article. Marijuana increases ghrelin which might be why it often causes hunger and sleep. Not giving in to that crave will repair damaged neurons and slow PD progression. Green tea extract also increases it. Chin-shin oolong tea is a special tea that a researcher noticed had similar effects as ghrelin as it is reputed to relieve constipation and something else I can't remember. So they tested it and it has a ghrelin-like compound that appears to activate the needed receptor, so it might work as well, so I spent the $64 on amazon to get 10 oz. It does not decrease as much if you consume fats instead of proteins or carbs. It appears that you could take it orally (if you can find it). More likely to be easily available (since ghrelin is natural and therefore not patentable) are similar synthetic compounds that are more likely to not work right and be toxic. Medium-chain triglycerides like coconut oil increase GOAT activity that converts ghrelin to its useful forms. Believing you are not going to get a good meal anytime soon, or believing the current meal is less calories, increases ghrelin.
It increases insulin activity and improves muscle tone and bone density, in addition to memory benefits. It increases just before a meal. A large meal makes it decrease. It is used to sense fats, signaling to the brain a lot of calories were consumed, even as they prevent as much ghrelin decrease afterwards compared to carbs and esp protein.
A ketogenic diet did not increase ghrelin when the subjects were non-hungry (in ketosis). A high protein diet did not increase it much over more carbohydrates.
High fat diet increases ghrelin secretion cells.
It increases HDL and promotes fat storage and fat burning. Best to exercise when hungry (when ghrelin is higher).
Circulating MCFAs did not alter ghrelin, but gastro MCFAs did increase acylation mediated by GOAT (goat attaches a lipid to ghrelin to make it active)
"As ghrelin circulates naturally, it is possible to pharmacologically increase the plasma concentration with minimal adverse effects. Patients who have been diagnosed with PD already exhibit reduced levels of circulating ghrelin as well as a reduced postprandial ghrelin response [Unger et al. 2011]. Ghrelin may also help to minimize nonmotor effects of PD such as gastrointestinal dysfunction, weight loss and depression, as well as learning and memory deficits [Diano et al. 2006; Edwards et al. 1992; Starkstein et al. 1991]. Nearly all patients diagnosed with PD suffer from selective cognitive impairments, including problems with attention, concentration and memory [Zgaljardic et al. 2004] and studies have shown that ghrelin enhances both learning and memory via an increase in synaptic plasticity in the hippocampus [Diano et al. 2006]. To date, ghrelin agonists have been successful for the treatment of cachexia to increase food intake and decrease energy expenditure in cancer patients [Neary et al. 2004]. These studies indicate that the ghrelin system is a potential therapeutic target to reduce multiple nonmotor symptoms of PD, as well as playing an active role in reducing further neurodegeneration."
post to PD forum
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The way to convert doses from animal studies to humans is to do it based on relative caloric or water intake. Water consumption is based on calorie consumption due to respiration, except humans that work enough to sweat can throw the water conversion off. Most nutrients are studied at a level of 0.2% to 0.5% of daily water or food intake. In humans this works out to be about 0.2% to 0.5% of 1 kg of food or 1 liter of water per day which is 2.5 to 10 grams of the nutrient. (1 liter per non-sweating person is closer to normal than eight 8 oz glasses per day which they finally realized was absurd after 30 years of the 8 of 8oz nonsense. )
But usually you see data in mg nutrient per kg body weight of rat or mice. Mice are about 30 grams and rats about 300 grams. You can find many studies giving 10 mg/kg/day to mice or rats for many nutrients. (It can range from 1 to 200 mg/kg/day.) You would think that to convert this to a human dose you would multiply 10 mg/kg times 70 kg person which gives 700 mg/day. But there is an adjustment: for mice you divide this by 7, and for rats divide by 4. So it's 100 mg/day for a 70 kg person if it was a mouse study and 175 mg/day if it was a rat study. The reason for the reducing it is because larger animals have a slower metabolic rate per kg body weight. The reducing factor is found by (human kg)/(animal kg) raised to the 0.25 power. EPA and FDA still use 0.33 power which was found to be wrong about 50 years ago, but they stick with it because they are normally investigating the toxicity of pollutants and pharmaceuticals and the 0.33 factor gives a margin of safety. But for nutrition comparison, 0.25 power should be used because it is more accurate and the safety of plant compounds is about 100,000 times better than pharmaceuticals. At least that's the ratio of the number of people killed each year from each, 100,000 pharmaceutical deaths when taken as directed verses 1 nutritional supplement death. The 0.25 factor results in slightly higher doses than FDA's 0.33. Study trials use these considerations to determine how much of a nutritional supplement to give to people for the first time, using animal data as the starting point.
To convert rat to 65 kg, multiply mg/kg by 16. To convert mice, multiply by 10.
To demonstrate how closely animals and humans compare: RDA's or RDI's for mammals are consistent, having roughly 1/3 of the RDA's 3x lower in other mammals than in humans, 1/3 are about 3x higher, and 1/3 about the same. The list of RDA/RDI's for all mammal is nearly the same. The macronutrients compare more closely. Specific compounds might be further off than the RDI's. But if they are similar to RDI errors, then if I conclude I need 100 mg of a nutrient to compare to the mice or rat study, it might be that I need closer to 300 mg or 30 mg. As with RDI's, being in the ballpark is a major step forward, and 100 mg is definitely in the ball park. But PD is very much like cancer, spreading to adjoining cells and compromising mitochondria, causing it to burn sugars anaerobically. It is no coincidence that green tea extract and grape seed extract work great in mice and rats for both cancer and PD. And in cancer, dose is everything: for example, with green tea extract and grape seed extract, cancer grows 50% slower instead of 25% slower if you double the amount of green tea or grape seed extract mouse or rat is getting, like a grandmother drinking 20 cups of green tea instead of 10, or eating 1/2 pound of grape seeds per day instead of 1/4 pound. So thank goodness for the extracts. So I might conclude 100 mg is enough, but 300 mg might be twice as healthy, if it doesn't rot my stomach from too many bitter powders, as you'll see from my list below.
Yesterday and today I worked on flavonoid extracts. To figure the dose I need, I needed to see what dose was used in mice models of PD, then see what concentration of each compound is found in tangerine peel, then look at what is available for sale, and adjust for human body weight. The mice studies used about 10 mg/kg for several of these flavonoids, so I want about 100 mg/day as I detailed above. I am talking about the compounds that specifically raise ghrelin and work in mouse models of PD: tangeretin, hesperidin, and nobiletin. Hesperidin was used at much higher levels than the other two in the PD models, but it is also in much higher concentrations in the tangerine peel. So if I get enough of the others, I get about the right amount of it. Tangerine peel has about 500 mg/kg (500 ppm) nobiletin which is 0.05%. Extracts are sold with 10% nobiletin or 10:1 concentration. The 10:1 will be only 0.5% nobiletin and cost $50/kg. The 10% has 20x more and cost twice as much. But I do not know the effects of their 10% extraction process on the other compounds. Tangerine peel extract standardized to 10% nobiletin could have anywhere from 10% tangeretin to 1% based on tangerine peel data I've seen, but it could be have a lot less because they may be selling a separate 10% tangeretin product, or otherwise neglecting the tangeretin due to concentrating the nobiletin. But typically pick only 1 component to measure because of the expense and complexity of trying to measure the others, not because the ratio of the others has been reduced.
ANYWAY, I got the 10:1 product, having 0.5% of my nobletin and since tangeretin is probably about 0.15%, I'll shoot for 200 mg/day of nobiletin which would be about 60 mg/day tangeretin and plenty of hesperidin. 200 mg/0.5% = 40 grams/day of 10:1 tangerine peel extract. This means the $50 for 1 kg will last 25 days. Will it mix in a blueberry smoothie? I'll find out. But the 10% nobiletin product looks a LOT more doable, requiring only 2 grams a day, about 2 large pills.
The bitter orange extract powder product can be found standardized to 10% naringin, but then I found a grapefruit extract can do 10% naringin at 1/2 the cost. It has shown major promise in PD animal models, and in many other things. This is the grapefruit compound that amplifies the effects of some drugs and is believed by some to help weight loss. It's strange how "stimulants" keep popping up for PD.
Dried blueberries are about 0.4% anthocyanins and the available extracts are 25% (62x concentration), so to get the 2 cups (300 g) per day human equivalent found very useful to the balance and cognition in mice, I will need 300/62 = 5 g. Therefore the $200 I spent on 1 kg will last 200 days. Other studies put 0.2% to 0.3% anthocyanins in water or food, which works out to 2 to 3 grams for 1 kg food or 1 L water for a human, so 5 g is about right.
If you found the above too painful, here is the summary (and for my future reference):
tangerine extract 10:1, 40 g/day, or more preferable:
50% tangeretin: 400 mg/day $1/day (20 mg/kg/day mice in treatments before toxin adminstered)
10% nobiletin: 2 g/day $0.20/day (20 mg/kg/day mice, but this is short term)
tangerine extract 10% nobiletin, 2 g/day ($150/kg, $0.30/day)
blueberry extract 25% antho's: 5 g/day ($1/day)
green tea extract 1 to 2 g/day (two to four 500 mg pills, lot of caffeine)
black tea extract, 0.5 to 1 g/day (2 to 4 pills, not cheap)
apple extract 80% polyphenols 3 g/day (to simulate 200 mg/kg in mice) $200/kg, $0.75/day
naringin 98% 1.4 grams/day (to simulate 80 mg/kg in rats but 4 days) $120/kg, $0.17/day
conclusions for my products, using 1/4 formula for this short term tests and 16x for rats and 10x for mice:
tangeretin: 100 mg/day $0.25
nobiletin: 500 mg/day $0.05
naringin: 300 mg/day $0.04
98% tangeretin looked great, but it is $7000/kg.
Broccoli and strawberries are two other good foods to eat. All of the extracts above might be combined with their whole fruit to be more palatable, and to help in absorption and correct metabolism. For example, more sugars in the blood stream might help them cross the blood brain barrier better.
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I have been putting together a really strong drink. I guess it's about $15 a day, with most of the cost being in the powder extracts, $2 to $3 per day each, straight from China in bulk.
12 oz pomegranate juice from Hispanic store (not the expensive POM)
added sweet concentrates:
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black cherry concentrate 12 g
black molasses 12 g (sugar cane juice after most of the white sugar is removed)
Jallab 12 g (Arabic grape skin extract plus others)
powder 10:1 extracts:
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blueberry extract 12 g (my eyesight sharpened enough to not need my barely-needed glasses in 4 days)
strawberry extract 12 g
apple peel extract 12 g
tangerine peel extract 12 g
Citrus flavonoids with animal studies in PD, bought from china in bulk.
These doses are 1/4 the human-equivalent doses because the studies are "shock" studies on the animals by which I mean they are very short term to see how the chemicals work in response to PD-like toxin challenges.
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nobiletin 500 mg
naringin 300 mg
tangeretin 100 mg
Other stuff in pills with strong animal and epidemiological evidence for PD and ability to absorb and cross blood brain barrier (pills not in the drink):
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black tea extract
green tea extract
grape seed extract
fisetin
(inosine to be added)
The American producer of patented fisetin is not clear that it is pure fisetin and the brand is hiding details about what it is, exactly, so I'll spend 1/3 as much to get pure fisetin from China and then sell the excess on ebay. Inosine in bulk is also 1/3 the cost from china.
Canola mayonnaise, the bomb!
Broccoli, Sardines, home-made very yeasty beer, olive oil
1 hour exercise, then drink it to absorb the sugar.
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