Saturday, October 31, 2015

Apigenin for parkinson's

Honey, pollen, and propolis ("bee glue" resin from trees) appear to be MAO inhibitors in the test tube. 

Especially propolis.  The active ingredient in it appears to be APIGENIN, which is available as a supplement. It protects against a-syn aggregation, ROS, increases BDNF, is an MAO inhibitor, and increases dopamine uptake. 

But like Xanthumol (which may work by increasing activity of GM1 like nilotinib that affect Bcr/Acl inhibitor) it also stops excess glutamate which is key in many neurodegeneration like that caused by hypoxia.

Luteolin and apigenin are the main active ingredients in Chamomile (tea) and artichoke which can be bought as extracts.  Their molecular weights are less than 400 (270) so they might cross blood brain barrier, although luteolin was found to not be bioavailable in one study, although its metabolites might be the active ingredients.  200 mg for either is the dose needed to copy the work in mice, but that is a bit high.

Apigenin is about 0.005% in orange juice, which is a decent amount. Hesperidin is 10x higher. Naringin in grapefruit juice is also 10x higher.  400 g grapefruit juice contains 0.2 g naringin.

Parsley and celery have the highest amounts, about 2% in fresh wet parsley, but maybe only 1% seems to reach blood stream. So 10 grams of parsley should give 200 mg Apigenin.

luteolin and apigenin  "enhancing monoamine uptake" "monoamine transporter activators"

apigenin is an inhibitor of liver enzyme CYP2C9 so the list in the link below needs to be consulted if you're taking medication. It will amplify the effect of any drugs listed in the "substrate" column by not letting them be broken down.  Most notably NSAIDs.

"In conclusion, apigenin and luteolin protected the dopaminergic neurons probably by reducing oxidative damage, neuroinflammation and microglial activation along with enhanced neurotrophic potential. The above results propose both these flavonoids as promising molecules in the therapeutics of PD. "

apigenin promotes neurogenesis

Bee products are MAO inhibitors, propolis is stronger.

Apigenin is main active ingredient in propolis, targets the preferred MAO-B (less chees effect) strongest

"has been used as a sedative and tranquilizer in Brazilian folk medicine and as a natural anxiolytic agent. Flavonoids from Passiflora edulis and P. alata have been shown to improve behavioral performance in rats [95]. The phytochemicals that contribute most to the effects of Passiflora are flavonoids such as apigenin-8-C-β-digitoxopyranoside, apigenin-8-C-β-boivinopyranoside (Figure 6), and luteolin-8-C-β-boivinopyranoside [88]. Apigenin and its derivatives are known to have anticarcinogenic, antioxidant, and anti-inflammatory properties [96]. Subchronic treatment with apigenin in APP/PS1 mice model downregulates BACE, β-CTF, and β-amyloid deposition and restores BDNF expression leading to increased memory and synaptic plasticity by ERK1/2/CREB-mediated prevention of AD [97]. Recently, we studied apigenin and found that it also plays a vital role in neurodegenerative disease. It exerts its anti-inflammatory effect on LPS-activated microglia and inhibits NO and PGE2 production by scavenging free radicals. Moreover, apigenin suppresses ERK1/2, p38 MAPK, and JNK and modulates NGF-induced neurite outgrowth in PC12 cells [88]. Additionally, apigenin has an apparent permeability coefficient in the BBB, and thus it serves as an effective phytochemical for the treatment of neurodegenerative diseases "

Thursday, October 29, 2015

parkinson's, alcohol, complex 1, and personality

I'm curious if it's a diabetic-like effect (insulin insensitivity, syndrome x) or if alcohol is assisting the impaired cells by a different mechanism. Does it get into the cells more easily? Does alcohol not need the mal-functioning complex 1 in the mitochondria of the injured cells whereas sugar needs complex 1 in order to be turned into ATP energy?

In looking at genetic disorders that have complex 1 not functioning, alcoholism is very common. This indicates that alcohol helps their condition, but I have not been able to confirm it. Alcohol is associated with decreased incidence of PD, especially beer, which increases uric acid which is also associated with decreased incidence of PD. So a beer a day, or maybe once in the morning and one at night, might be a good idea. Once every 4 hours might show short term benefit, but very likely not long term benefit.

PD patients are well-known to be "serious" personality types for most of their life. So it is possibly no coincidence that cigarrattes, coffee, alcohol, gluttony (uric acid diet leading to gout) and weed all help prevent PD. But as one researcher said, whatever is causing the serious personality might be the cause of PD, not necessarily that avoid fun stuff is what caused their PD.

Alcohol and marijuana reduce cerebral pressure and release dopamine, which are more likely the reasons they reduce tremors.

parkinson's, alcohol, and complex 1

Wednesday, October 21, 2015

parkinson's: nilotinib, PP2A, AMPK, c-Abl tyrosine kinase inhibitors for parkinson's

Protocol to amplify nilotinib: take with 2 grapefruit, naringin, pepper/peperine, and curcumin, all to inhibit CYP3A enzyme that degrades it. Grapefruit by itself, about 30% more. The low pH (1.5) helps absorption, maybe 50%.  Take with food, about 50% more exposure. All in all, I might hope for a double or triple increase.  I need to take 50 mg twice a day to hopefully get 200 mg equivalent. Headache and nausea are most common symptoms.  Also maybe alcohol to increase capability of cells to remove a-Syn, along with other compounds that can remove a-Syn..

Posts to healthunlocked:

Concerning nilotinib in 12 PD patients: This work says they gave it at 1/5 to 1/3 normal doses, and in looking at the animal studies that led to this research, I see they were giving only 1/50 in human-equivalent doses. It looks like it should have noticeable benefit at only 15 mg instead of 150 mg.

Here's the work in mice:

They are saying not just Nilotinib (generic form of Tasigna) but also Bosutinib. 
The method of action is c-Abl inhibition. The connection with Parkinson's was discovered 5 years ago by John Hopkins. There have been 14 papers since then with on "c-Abl parkinson's" in the abstract or title, and none before.
Two years ago, this group tried this drug in mice. 
Any nutrient or drug capable of c-Abl inhibition probably works.
The two research groups that previously published on the c-Abl connection have jumped on this treatment, testing it in mice.  Here's their research papers:
The John Hopkins group was first to discover the c-Abl inhibition benefits:
The Japan group soon followed:
Then this group identified the existing drug that does it.
I'll be researching if any natural nutrients can also do it.  Yes, metacognito, there is a bioavailable form of fake-curcumin that does it.
These are the c-Abl inhibitors, most used for leukemia. Blocking c-Abl may help get rid of the bad a-syn, but c-Abl is also used for "neuronal plasticity, neurite outgrowth, and neurogenesis" and "required for optimal synaptic function"  so taking too much of it is not good for the brain.
 Keep in mind that lower doses are needed for PD, so the toxicity dangers are not as great as the ones I've pointed out.  
Switching from one to the other may be important as the body develops protection mechanisms against them.  So if you have 3 choices, you would try to alternate them every 3 months or something like that.

Nilotinib seems to be the one of choice due to less toxicity.  Price might be in the $100,000 a year range.  PD patients should not expect it to be less because the Pharmaceutical might require off-label use to charge 10x more even if you use 10x less.  They charge based on patient desperation and ability to pay, not based on cost to develop.  It does not matter if all their costs were paid by taxpayers through research grants.  Grapefruit "interferes" with it as it is a substrate of the protein CYP3A4 that grapefruit blocks.   I believe this means grapefruit will make a lower dose more powerful (more bioavailable for its benefits as well as its toxicity).  I did not know if the others are also affected by grapefruit.  There are "competing" pharmaceuticals, but it seems they all want $100,000 to take these drugs.  Be "thankful": I know a baby who had brain-damaging seizures and it was costing $50,000 a WEEK and was known to probably not work.  "Dude, get this $50,000 glass vial (1 teaspoon) out of my hand before I drop it. That's not funny putting something like that in my hand and then telling me what it is."

imatinib, the original, not as good as the others.  $100,000 a year for leukemia patients. Does not efficiently cross blood-brain barrier in humans.

Ponatinib (Ariad pharmaceuticals), works good, but was halted in U.S. due to toxicity (blood clots). Still available in U.K. to leukemia cancer patients.  Cost would have been about $100,000.

Bosutinib, may not be good because it stops the bad-protein removal mechanisms, even as it dissolves a-syn. Maybe at lower doses it is OK.  But it worked in mice when it was being compared to nilotinib.

Bafetinib (INNO-406) newer, looks good, may not be available.  Efficiently crosses blood brain barrier.  Molecular weight is 576.  Tested in PD mice:

Dasatinib (Bristol-Meyers).  looks good except can have several fluid on lung build up in 20% of patients on the high doses needed for leukemia. 15% lower molecular weight than bafetinib (488), so may cross blood-brain barrier. It has a lot of studies on it for PD, but I noticed one seems to claim it did not work as well as bafetinib.  U.S. gov is trying to stop indian manufacturers from making it in order to maintain Bristol-Meyers patent rights.  $133,000 a year for leukemia patients.  $1,500 a year in India if they are getting around the patents.  Same situation for rasagiline, $50 a year in india, several thousand here.   Almost all of Bristol-Meyers cost in developing it came from tax payers through NIH research grants and a 50% tax CREDIT (which can lead to tax REFUNDS). 
Green tea extract, olive oil, and fake-curcumins are so far the only compounds I can find that also inhibit c-Abl. 
If you've read my posts you know I believe there is a connection between PD and cancer.  Viruses and mitochondria dysfunction are two connections. This c-Abl connection is another:  "The c-Abl kinase protein is one of the most studied targets in the fight against cancer and is a hotspot for drug development because it participates in several solid tumors and is the hallmark of chronic myelogenous leukemia."
I keep repeating the lack of oxygen increases PD progression.  It turns out intermittent hypoxia (as may occur every night when we sleep) increases c-Abl.
Several of us use a stationary bicycle.  I have found that I need at least an hour a day of > 120 beats per minute heart rate to see improvement. At 30 minutes per day, it appears that I get worse.  At 1 hour per day I start getting better in every way.  My impression is that if I were able to do 2 hours per day, my PD symptoms would disappear and not return.  No exercise leads to a decline in everyway. 
Switching from 30 minutes to 1 hour has immediate benefits such as better mood and more energy, but then it is easy to digress back to zero exercise because skipping a day has no noticeable detriment.  Continuing with 1 hour per day for more than a few days becomes boring and I do not notice I feel better afterwards, but that is because I feel better BEFORE the exercise already because of the previous days' exercise.  After about 1 month of 1 hour per day, I suddenly realize I had not thought about PD for the past few days because no symptoms were bothering me.
Exercise increases AMPK which helps break down proteins like a-Syn.  Exercise also increases heat shock proteins that carry the broken pieces of the a-Syn out of the cell. 
Nilotinib also increases AMPK (also decreases PP2A which increases activity of AMPK and thereby slows cancers) and is almost assuredly how it appears to reverse symptoms. In other words, nilotinib may be a way to get the benefits of exercise (in regards to PD) without exercising, which is crucial in severe cases. 
EHT in coffee methylates PP2A which increases its activity and this appears to be why coffee reduces Alzheimer's and PD.  

So nilotinib decreases PP2A and coffee increases.  PP2A blocks nilotinib's effects on AMPK. So taking coffee with nilotinib may decrease its benefits.

So activation or deactivation of PP2A could help PD by stopping a-Syn aggregation.  This confusion was mentioned in wiki article on PP2A that referenced these articles

=========== from a patent forum:
As a physician and also a patient with advanced Parkinson disease (PD), I recognized the originality and merit of Dr. Charbel Moussa's proposal to treat PD with nilotinib, or a similar tyrosine kinase inhibitor (TKI), by employing low-level cellular autophagy to clear out the accumulated toxic alpha-synuclein (ASN) protein which is the pathological cause of death in affected neurons. Dr. Moussa published a paper in 2013 which related his theories regarding the therapeutic potential of TKI's in PD and similar neurodegenerative diseases, and which documented dramatic reversal of PD in mice he treated with nilotinib. This paper was not his first on this topic, but it was the first time I was aware of his work and it convinced me that, if he could repeat those results in humans, he would be the first scientist to reverse the underlying course of PD in humans. This development, when fully proven in humans, will be one of the most significant advances in medical history and will certainly be awarded the Nobel prize in medicine. I would probably be taking nilotinib now, off label and self-prescribed based on Dr. Moussa's work, were it not for a rare but often fatal side-effect of nilotinib known as torsade de pointes (or just torsade), a cardiac arrhythmia that can strike suddenly and with little symptomatic warning.
Torsade, though, is predictably associated with a finding on the patient's electrocardiogram (ECG) called QT interval prolongation. Drugs that increase the risk of torsade do so by prolonging the QT interval, in a dose-dependent manner. Dr. Moussa addressed this concern by stating in his paper that the dose of nilotinib required to stimulate therapeutic autophagy in the brain of a PD patient would be substantially lower than the dose used to treat cancer patients, and that even at the full anti-cancer dose, torsade was a rare event. However, PD is known to cause the loss of autonomic sympathetic innervation to the heart, which contributes to the dangerous drops in blood pressure in advanced PD. Loss of sympathetic innervation might, in turn, result in the increased production of catecholamine receptors in denervated cardiac myocytes, thus potentially increasing their susceptibility to torsade, triggered by circulating catecholamines.
So, my specific question regarding patent WO2013166295A1 is this: what is the effect of nilotinib treatment on the QT interval (and thus, the likelihood of torsade) in PD patients treated with the reduced dose? The answer can be found by calculating the change in the QT interval in advanced PD patients treated with nilotinib. This calculation consists simply of subtracting the measured QT interval before administration of nilotinib from the measured QT interval during steady-state therapeutic dosing for each patient treated for advanced PD. The larger this increase in the QT interval, the greater the increased risk of torsade. Ideally, there would be no increase in the QT interval, but if so, the patient can be monitored more carefully and treated with medications to reduce the risk of torsade, such supplemental magnesium, potassium and beta-blockers if indicated.
Thank you for the opportunity to post this question, and I wish much continued success to Dr. Moussa and his research group at Georgetown University.

Friday, October 16, 2015

neurogensis notes from ted talk

Notes from this ted talk

Here's her list for improving neurogenesis in the hippocampus for improving mood and memory:

good sleep
calorie restriction
intermittent fasting
(she left out heat baths)

omega-3 oils (fish oil, canola)
low sugar
food that needs more chewing
vit A, vit D, vit B's, vit E, zinc, folic acid, caffeine, no saturated fat
She mentioned also resveratrol and curcumin, but these are only in animal models. These do not make it to the brain in humans in any formulation, certainly not in the concentrations that have been found to work in animals.

hurts it:
sleep deprevation

Tuesday, October 13, 2015

diabetes and parkinson's

Has anyone noticed their resting tremor reduces with a good dose of sugar or alcohol?  Like a soda (11 teaspoons of sugar) or a full beer (4 teaspoons of alcohol).   The idea is that cells which are not able to produce much energy from compromised mitochondria can function better on a sugar or alcohol high.  I seem to see a reduction. 

This made me think diabetes is a possible cause of PD and possibly treating undiagnosed diabetes could stop PD progression, so I did a pubmed search and low and behold:

"there are already randomized trials evaluating several established treatments for insulin resistance (pioglitazone and exenatide) as possible disease modifying drugs in Parkinson's disease...which may be effective in both disease processes through an action on mitochondrial function. "
"There are also reports of varying associations between diabetes or abnormal glucose tolerance and sporadic forms of Parkinson's disease from both cross-sectional and cohort studies. Survey data reveal that diabetes is established in 8–30% of patients with Parkinson's disease, consistently in excess of the prevalence found in non-Parkinson's disease individuals"
"up to 50–80% of patients with Parkinson's disease have abnormal glucose tolerance when tested" (1960's and 1970's studies)
"in a series of 800 patients with Parkinson's disease, concurrent diabetes was indeed shown to accelerate progression of both motor and cognitive symptoms " (1960 study)
"reduced insulin-mediated glucose uptake "  (1971)
"Nevertheless, a recent cohort study could not replicate an association between either type 2 diabetes mellitus or obesity and Parkinson's disease risk although the authors acknowledge that diagnosis of type 2 diabetes mellitus was entirely based on self-report" (2011)

L-dopa increases both blood glucose and insulin, but I don't know enough about diabetes to know what that means.  They're saying high blood glucose after a meal reduces dopamine production, which is the opposite of what I was thinking.  But I think the increased blood sugar and insulin from L-dopa should be like a good shot of sugar for the compromised neurons to work better, but long term this would make the neurons more dependent on the L-dopa, not to mention the increased oxidative damage from the shot of sugar.

I haven't looked at the other risk factors, but both PD and diabetes are connected to pesticide exposure, and protection can be seen for both in exercise, green tea, and caffeine.
So a good shot of sugar or alcohol might reduce symptoms, but long term it may not be good.

Wednesday, October 7, 2015

heat shock protiens and parkinson's

HSP70 reduced a-syn, helping neurons survive. 

HSP70 reduced the larger oligomer's of a-syn in the extracellular space.
"αsyn between ∼440 and ∼65 kDa in size may be toxic αsyn species"
" Regardless, our data identify Hsp70 as one critical component in the defense against the toxic effects of extracellular misfolded αsyn in neurons."
"we cannot distinguish whether the observed actions of Hsp70 are mediated intracellularly, where an abundant supply of ATP exists, or extracellularly where ATP has been found following cellular stress (). It is also possible that Hsp70 works extracellularly and that ATP is not required, as was recently described"

Blocking HSP90 increased expression of HSP70. HSP104 also helps.

"Hsp104 has only limited ability to eliminate disordered aggregates and amyloid fibers implicated in human disease. Thus, we aim to engineer Hsp104 variants to reverse the protein misfolding implicated in neurodegenerative disorders."

HSPS can be up-regulated by heat and dehydration.  How to target HSP70 specifically?

Competitive exercise and work outdoors were better than other types of exercise, indicating maybe the extra heat was helping.

HSPS bind to ATP for some reason and are key to preventing misfolding.  The heat helps unbind proteins to reform.  Without heat stress, HSPS form 1 to 2% of total cellular proteins, and 4 to 6% when stressed.

torsinA acts like HSPs and is protective in flies, and its absence via mutation causes dystonia without neurodegeneration. 

Notes on heat bath:  105 F was about as high as I could stand. 20 minutes at 105 dropping to 100 F raised body temp to 101 F in 5 to 10 minutes. Heart rate would increase up to 120 BPM and more than this was not tolerable.  Lost 1 pound fluid in the 20 minutes (in 10 minutes is possible) and an  extra 0.3 pounds during cool down.  Have done baths and halogen-light bed to lose 6 pounds of water in 1 morning.

Saturday, October 3, 2015

11 traits of irresistible people

It's all over the internet, but I find it useful and interesting. It's not just about being irresistible in a way that means finding a mate or getting what you want, but how to be happy *with* others.

They think about other people more than they think about themselves, and they make other people feel liked, respected, understood, and seen.

1) They Treat Everyone With Respect

2) The Platinum Rule—treat others as they want to be treated.

3) Irresistible people are great at reading others and they adjust their behavior and style to make them feel comfortable.

4) Irresistible people possess an authentic interest in those around them. As a result, they don’t spend much time thinking about themselves. They don’t obsess over how well they’re liked.

5) Irresistible people don’t dominate the conversation with stories about how smart and successful they are.

6) Irresistible people handle controversial topics and touchy subjects with grace and poise.

7) People gravitate toward authentic individuals because they know they can trust them. It’s easy to resist someone when you don’t know who they really are and how they really feel.

8) People with high integrity are irresistible because they walk their talk, plain and simple.

9) Irresistible people are positive and passionate...they see life as an amazing and joyful adventure and approach it with a joy that other people want to be a part of.

10) There’s a massive difference between being presentable and being vain.

other nutrients in PD for mitochondria, melatonin

Melatonin doesn't just improve sleep, but has a lot of neuroprotective effects.  They say it may be that P does not reduce ability to produce melatonin, but PD decreases the number of melatonin receptors.

Melatonin  helps  mitochondria complex 1
Here's another article on melatonin, but also has a list of chemicals that work in animal models of PD. This list aimed at better mitochondrial function, but also most of them have other effects like iron-chelating, antioxidant, and preventing protein misfolding.

(acetylsalicylic acid)
(–)-Epigallocatechin gallate
(R)-Lipoic acid

Friday, October 2, 2015

Terry Wahls diet, eating for mitochondria

3 cups sulfur-containing foods: 1 cup mushrooms / turnips-cruciferous-onion family (for organic sulphur), and seaweed for iodine and trace minerals.

3  cups dark greens (vit A, C, K) Kale, parsley best. Dehydrated kale chips.

3 cups intensely coloured: 1 cup red vegetables / fruit, 1 cup blue black vegetables / fruits, 1 cup yellow/orange vegetable / fruits

protein with omega 3 (for straight teeth) and grass fed meat each day.  Organ meats(once a week).

iodine for removing heavy metals and mylin, from seaweed.

No grain, potatoes, dairy (casein problem), or legumes

(Note: 1 cup = raw vegetables chopped = 1/2 cup cooked, an apple sized fruit, or 2 cups leafy greens)
Include spices and herbs.

Regular bone broth
Fermented foods or a probiotic