Neuroprotective effect of rapamycin again... - Cure Parkinson's

Cure Parkinson's

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Neuroprotective effect of rapamycin against Parkinson's disease in mice - 2018 pubmed.ncbi.nlm.nih.gov/306...

Bolt_Upright profile image

Conclusions: Rapamycin inhibits the activation of mTOR pathway, which contributes to protect against the loss of dopaminergic neurons and provide behavioral improvements in mice with Parkinson's disease. These results are partially related to the ability of rapamycin in inducing autophagy and reducing oxidative stress.

Is there a natural alternative to rapamycin?

In particular, they identified allantoin and ginsenoside as strong mimetics of metformin, epigallocatechin gallate and isoliquiritigenin as strong mimetics of rapamycin, and withaferin A as a strong mimetic of both.

Withaferin A is in Ashwagandha, and I have some arriving today!

33 Replies

epigallocatechin gallate is in the green Matcha tea I am drinking.

Isoliquiritigenin is a phenolic chemical compound found in licorice.

Allantoin is a byproduct of uric acid that can be extracted from urea and is the result of metabolic processes that occur in most organisms – among them animals (including humans) and bacteria. It can also be extracted from comfrey (taken from the roots and leaves) and is proven safe and effective because it does not contain the potentially irritating alkaloid compounds that occur in the comfrey plant.

Why was comfrey banned?

The pyrrolizidine alkaloids in comfrey can cause severe liver damage, liver cancer, mutagenicity, and even death. [8,9] For this reason, the U.S. Food and Drug Administration has banned the sale of oral comfrey products in the United States.

Allantoin is available in some skin care products and can be absorbed from topical application. Have not tried it myself (yet).sciencedirect.com/science/a...

The ginsenosides are the major active pharmacological components of ginseng.

sciencedirect.com/science/a...

Treating mice with rapamycin has been shown to increase lifespan when started early in life [12], late in life [13], when provided intermittently [14], or when given transiently during middle-age [15]. Along with increased lifespan, improvements from rapamycin or rapalog treatment have been reported for age-related cancers [16,17] and age-related declines in cognitive function [18], kidney function [19], heart function [[20], [21], [22]], immune function [23], intestinal function and gut dysbiosis [[15], [25]], ovarian function [26], and oral health [27,28], among others. This large body of literature has suggested multiple potential indications for clinical evaluation of the geroscience hypothesis via treatment with rapamycin or other mTOR inhibitors.

rapamycintherapy.com/

This page is by a doctor who seems to specialize in Rapamycin to treat aging and age related disease. This is not an endorsement.

How good is Rapamycin

Rapamycin is a true miracle drug. For persons over 50, it it most the important drug in the world today. Rapamycin does not reverse aging. It does not make you 25 again; but it may buy you an extra decade or more of good health.

Rapamycin is a generic drug. For Big Pharma, Rapamycin is worthless. There is no money to be made from Rapamycin for the anti-aging industry. You can't sell Rapamycin on the internet. If want a prescription for Rapamycin you must go to a physicians office, become a medical patient etc. And since the medical world does not recognize Aging as a disease; no insurance coverage. For the patient, all out of pocket.

JAS9 profile image
JAS9 in reply to Bolt_Upright

Small world. I was in contact with this doctor, Alan Green, back in 2017. I talked with him about giving me a prescription for it and he was open to the idea as long as I could get to his office in New York. I couldn't do it, so I dropped it.

Six or so years ago, I bought some sirolimus (brand of rapamycin) from someone in India over on reddit. I bought 100 pills for about $300 as I recall. There were a few of us on Longecity who tried it out. Everyone had a different idea of what dosage should be. I just found the last four I have. Tried looking up the seller a few years ago but no luck.

It looks like that Dr Green in the link I shared will prescribe it if you wanted to try again. It is generic.

Found a newer report:

More Mouse Trials - 2021 - Effects and potential mechanisms of rapamycin on MPTP-induced acute Parkinson’s disease in mice

Results: Rapamycin can effectively alleviate symptoms of PD. The levels of key protein p-4EBP1 in the striatum and substantia nigra were both significantly higher in PD group compared with control group (P<0.01), while being pretreated with rapamycin, the expression of p-4EBP1 in the striatum and substantia nigra were both decreased obviously (P<0.01).

Conclusions: p-4EBP1 protein may be involved in the pathogenesis of PD via mTOR signaling pathway. Inhibited mTOR-4EBP1 pathways could make a certain protective effect for the acute attack of PD induced by MPTP.

apm.amegroups.com/article/v...

JAS9 profile image
JAS9 in reply to Bolt_Upright

There's actually a lot of useful information on Longecity for Rapamycin. For example, here's a link to using Metformin to avoid developing diabetes:

kurzweilai.net/added-drug-a...

"However, rapamycin has some drawbacks, including an increase in insulin resistance that could set the stage for diabetes, observed in both humans and laboratory animals. The new findings, published in the Journals of Gerontology: Biological Sciences, help to explain why that happens, and what could be done to address it.

It found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy. Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which in humans can lead to diabetes.

However, the drug metformin can address that concern and is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.

“If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible,” the researchers wrote in their conclusion.

' Is there a natural alternative to rapamycin? '

Yes, it is called melatonin and has a hugely better safety profile than rapamycin. The side effects list may be the longest I have ever seen and some are very serious. Look at the side effects for Sirolimus/rapamycin :

drugs.com/sfx/sirolimus-sid...

Side effects requiring immediate medical attention

Along with its needed effects, sirolimus may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking sirolimus:

More common

Abdominal or stomach cramps or pain

accumulation of pus

anxiousness, unexplained

backache

black or red, tarry stools

bleeding from the gums or nose

blurred vision

body aches or pain

bone pain

bruising

burning or stinging of the skin

burning while urinating

burning, dry, or itching eyes

burning, tingling, numbness, or pain in the hands, arms, feet, or legs

change in mental status

changes in skin color

chest pain

chills

confusion

convulsions (seizures)

cough

dark or bloody urine

deafness

decreased urine output

decreased vision

difficulty with breathing or swallowing

dilated neck veins

discharge from the eyes

dizziness

drowsiness

dry mouth

earache

excessive tearing

extreme fatigue

eye pain

facial hair growth in females

faintness or lightheadedness when getting up from lying or sitting position

fast, slow, or irregular heartbeat

fever

flushing or redness of the skin, especially on the face and neck

general feeling of discomfort or illness

increased hunger

increased menstrual flow or vaginal bleeding

itching, pain, redness, swelling, tenderness, or warmth on the skin

lack or loss of appetite

large, flat, blue, or purplish patches in the skin

loss of sexual ability, desire, drive, or performance

loss of voice

muscle pain

nasal congestion

nausea or vomiting

numbness or tingling around the lips, hands, or feet

pain in the chest, groin, or legs, especially the calves

painful cold sores or blisters on the lips, nose, eyes, or genitals

pale skin

prolonged bleeding from cuts

rapid heartbeat

rash

red or dark brown urine

redness or swelling in the ear

redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid

ringing in the ears

runny nose

sensation of pins and needles

severe constipation

severe vomiting

severe, sudden headache

slurred speech

sore throat

sores or white spots on the lips or in the mouth

stomach pain or upset

sudden decrease in the amount of urine

sudden loss of coordination

sudden, severe weakness or numbness in the arm or leg

sudden, unexplained shortness of breath

sweating

swollen, painful, or tender lymph glands in the neck, armpit, or groin

tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over affected area

tremor

ulcers on the lips or in the mouth

unusual tiredness or weakness

vision changes

weakness or heaviness of the legs

white patches in the mouth or on the tongue

yellow skin and eyes

Less common

Bloating

change in size, shape, or color of existing mole

hoarseness

mole that leaks fluid or bleeds

new mole

pains in the stomach, side or abdomen, possibly radiating to the back

skin ulcer or sores

Incidence not known

Abnormal wound healing

headache

hives or itching

large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs

nails loose or detached

puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

swelling of the arms or legs

yellow nails lacking a cuticle

Side effects not requiring immediate medical attention

Some side effects of sirolimus may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Abnormal vision

acne

belching

blistering, crusting, irritation, itching, or reddening of the skin

burning feeling in the chest or stomach

burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feeling

constipation

continuing ringing or buzzing or other unexplained noise in the ears

cracked, dry, or scaly skin

crying

decrease in frequency of urination

degenerative disease of the joint

depersonalization

diarrhea

difficulty with moving

difficulty with passing urine (dribbling)

dysphoria

ear pain

enlarged abdomen or stomach

euphoria

excess air or gas in the stomach or intestines

excessive muscle tone, muscle tension or tightness

fear

feeling sad or empty

hearing loss

heartburn

inability to have or keep an erection

increase in heart rate

increased hair growth, especially on the face

increased urge to urinate during the night

indigestion

irritation in the mouth

joint pain or swelling

leg cramps

loss of bladder control

loss of energy or weakness

loss of interest or pleasure

loss of strength

lower abdominal or stomach pain

muscle aches, pain, stiffness, or weakness

nervousness

pain in the back, ribs, arms, or legs

pain or burning in the throat

pain or tenderness around the eyes and cheekbones

paranoia

pelvic pain

quick to react or overreact emotionally

rapid breathing

rapidly changing moods

inflammation, redness, or swelling of the gums or mouth

shaking or trembling

shivering

sleepiness

sunken eyes

swelling

swelling of the scrotum

tender or enlarged gums

tenderness in the stomach area

thickening of the skin

trouble concentrating

trouble sleeping

waking to urinate at night

Managing side effects (general information)

For Healthcare Professionals

Applies to sirolimus: oral solution, oral tablet

Respiratory

Very common (10% or more): Dyspnea (up to 30%), upper respiratory infection (up to 26%), pharyngitis (up to 21%)

Common (1% to 10%): Pneumonia, epistaxis, pleural effusion, epistaxis

Uncommon (0.1% to 1%): Pulmonary hemorrhage

Rare (less than 0.1%): Alveolar proteinosis

Frequency not reported: Pleural effusion, alveolar proteinosis[Ref]

Metabolic

Very common (10% or more): Hypertriglyceridemia (up to 58%), hypercholesterolemia (up to 46%), hypokalemia, hypophosphatemia, hyperglycemia

Common (1% to 10%): Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes mellitus[Ref]

Cardiovascular

Very common (10% or more): Peripheral edema (up to 58%), hypertension (up to 49%), chest pain (up to 24%), edema (up to 18%), lymphocele

Common (1% to 10%): Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia

Uncommon (0.1% to 1%): Pericardial effusion (including hemodynamically significant effusions in children and adults), lymphedema

Rare (less than 0.1%): Pericardial effusion[Ref]

Gastrointestinal

Very common (10% or more): Constipation (up to 38%), abdominal pain (up to 36%), diarrhea (up to 35%), nausea (up to 31%), vomiting (up to 25%), dyspepsia (up to 25%)

Common (1% to 10%): Stomatitis[Ref]

General

The most common adverse reactions associated with this drug are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.[Ref]

Hematologic

Very common (10% or more): Anemia (up to 33%), thrombocytopenia (up to 30%), blood lactate dehydrogenase increased, blood creatinine increased

Common (1% to 10%): Thrombocytopenic purpura/hemolytic uremic syndrome, leukopenia, neutropenia, aspartate aminotransferase increased, alanine aminotransferase increased

Uncommon (0.1% to 1%): Pancytopenia

Frequency not reported: Capillary leak syndrome[Ref]

Genitourinary

Very common (10% or more): Urinary tract infection (up to 33%)

Common (1% to 10%): Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with this drug, ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia), proteinuria

Postmarketing reports: Azoospermia[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (up to 31%)

Common (1% to 10%): Bone necrosis[Ref]

Nervous system

Very common (10% or more): Headache (up to 34%)

Common (1% to 10%): Osteonecrosis, tremor, insomnia[Ref]

Dermatologic

Very common (10% or more): Acne (up to 22%), rash (up to 20%)

Common (1% to 10%): Herpes zoster, herpes simplex

Uncommon (0.1% to 1%): Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia, melanoma, squamous cell carcinoma, basal cell carcinoma[Ref]

Renal

Very common (10% or more): Creatinine increased (up to 40%)

Uncommon (0.1% to 1%): Nephrotic syndrome

Frequency not reported: Focal segmental glomerulo-sclerosis, BK virus associated nephropathy, nephrotic syndrome, higher serum creatinine levels, lower glomerular filtration rates[Ref]

Ocular

Frequency not reported: Eyelid edema[Ref]

Hepatic

Common (1% to 10%): Liver function tests abnormal

Frequency not reported: Hepatic failure, hepatic artery thrombosis[Ref]

Hypersensitivity

Rare (less than 0.1%): Hypersensitivity reactions, including anaphylactic/ anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis[Ref]

Other

Very common (10% or more): Fever (up to 34%), pain (up to 29%)

Common (1% to 10%): Impaired healing[Ref]

Oncologic

Common (1% to 10%): Skin cancer, lymphoma/post-transplant lymphoproliferative disorder

Frequency not reported: Hepatocellular adenoma and carcinoma, testicular adenoma[Ref]

Immunologic

Common (1% to 10%): Sepsis, pneumonia, pyelonephritis, herpes simplex, fungal, viral, and bacterial infections (such as mycobacterial infections, including tuberculosis, Epstein-Barr virus, CMV, and Herpes zoster), mycobacterial infections (including M tuberculosis), cytomegalovirus (CMV), Epstein-Barr virus

Frequency not reported: Clostridium difficile enterocolitis[Ref]

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What is Sirolimus :

en.wikipedia.org/wiki/Sirol....

::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::

No thank you!

Art

eschneid profile image
eschneid in reply to chartist

Thanks for the warning list...my hand is tired from scrolling!! Lucky mice, maybe not.

JAS9 profile image
JAS9 in reply to chartist

That is one heckava list! To add a little context, though, Sirolimus is used in very high dosages in order to suppress the patient's immune system, in order to keep them from rejecting their organ transplants. What drugs WOULDN'T have a long list of side effects if you increased the dosage 10x? When you're dealing with saving someone who is obviously very close to dying (or they wouldn't have had the organ transplant) I think you'd accept a lot of side effects. With that said, one good question would be: is there a safe dose that is effective at slowing aging?

chartist profile image
chartist in reply to JAS9

That is a very good question, Jas and your point is well taken!

Another question would be what dose of melatonin would have a similar effect, since to date, melatonin has maintained an excellent safety profile at every dose that has been tested in studies in humans, animals and plants and melatonin also offers many other potential health benefits with limited side effects based on human and animal studies?

Art

Rhyothemis profile image
Rhyothemis in reply to chartist

Momo is taking rapamycin:cnn.com/videos/health/2016/...

chartist profile image
chartist in reply to Rhyothemis

I'm not good with dog breeds, but Momo looks like a Westie to me and if Momo is 13 in that video, that is a high activity level since Westies have a life expectancy of 12~16 years. On the other hand, my sister had two Westies with one living to 16 1/2 years and the other to 17 1/4 years and they were both very active up to the 14~15 year area.

It would have been helpful if they had mentioned the dose they were using on Momo.

Melatonin is also thought to have antiaging effects, but I doubt they are as fast acting as they appeared to be in Momo. A before video of Momo would have been useful in the linked to video.

Art

Rhyothemis profile image
Rhyothemis in reply to chartist

The pilot study used either 0.05 mg or 0.1 mg / kg 3x per week (Mon-Wed-Fri) ; this was for dogs weighing at least 18 kg (40 lbs) - so Momo was not part of the pilot study. It concluded that low-dose rapa was safe and effective, so I'm guessing Momo was on the low dose.

ncbi.nlm.nih.gov/labs/pmc/a...

One potential issue with rapamycin is that it can shrink testicles, something Momo (most likely) and most of the other male dogs in the Dog Aging Project don't need to worry about. Don't know if this particular dosing regimen has that effect on intact males.

chartist profile image
chartist in reply to Rhyothemis

This gives a whole new meaning to the phrase, "traveling light"! That's a side effect I would definitely like to avoid!

The low dose for me would be approximately 7.5 mg each dose and the high dose would be 15 mg. It is a prescription med with very specific uses, so the uses being discussed would be off label usage. Not many, if any doctors are going to be willing to prescribe this drug for this off label use, so are we spinning our wheels with this discussion or is there a way forward for off label use?

Art

Rhyothemis profile image
Rhyothemis in reply to chartist

There are doctors who prescribe rapa off-label for general anti-aging. If you can afford it, you can get it.

The PEARL trial is recruiting, but it is for relatively healthy people, age 50-85

clinicaltrials.gov/ct2/show...

chartist profile image
chartist in reply to Rhyothemis

What are they charging their patients for this service? Doesn't sound like anything insurance will be covering any time soon. Btw, it appears that melatonin is synergistic with rapamycin as an mTOR inhibitor.

Art

Rhyothemis profile image
Rhyothemis in reply to chartist

I'm afraid to ask ... There needs to be regular blood work, so that expense is a necessary part of treatment. There are doctors who are well-known in big urban centers (e.g., Alan Green, NY) and presumably it costs a lot just to see them, but there are probably concierge medicine doctors who charge less, but still a lot for someone on a budget. Good Rx says the rapa itself costs around $150 per 30 x 1 mg - so $75 or $150 / month at the PEARL trial dosing levels.

When I looked at Alan Green's web pages I noticed another drawback - the instructions for fever - stop taking rapa (okay) and take z-pack (not good) - I guess to reduce risk of bacterial pneumonia? Overall the treatment should improve immune function but I suppose even at low dose they are assuming some immunosuppression. Hopefully the PEARL trial will find this is not necessary.

chartist profile image
chartist in reply to Rhyothemis

Rhyothemis,

Constant and potent inhibition of mTOR may increase life span, but mTOR has a useful purpose at times and activation of that pathway may actually have beneficial effects in specific instances that may be critical. The "smart molecule", melatonin, seems to have the dual ability to activate or suppress mTOR as the situation dictates.

Here is a study that shows the usefulness of melatonin in activating the mTOR pathway when needed as one step to offset high glucose induced apoptosis of Schwann cells.

ncbi.nlm.nih.gov/labs/pmc/a...

In this next study, melatonin shows benefit by inhibiting the mTOR pathway.

docwirenews.com/abstracts/m...

In this study, melatonin shows synergy with Rapamycin to inhibit the mTOR pathway and melatonin also protected healthy cells from the damaging effects of mTOR.

onlinelibrary.wiley.com/doi...

Unfortunately for us, melatonin production declines with age as depicted in the chart below. Fortunately, melatonin is inexpensively available otc.

Art

Melatonin Decline With Age

If Rapamycin inhibits activation of the mTOR pathway, and according to what you just wrote the mTOR pathway contributes to protect against loss of dopaminergic neurons, why in the world would you want to take Rapamycin?

GioCas profile image
GioCas in reply to MarionP

I agree. 🤔

pubmed.ncbi.nlm.nih.gov/222...

Quote:”We observed that niacin pretreatment enhances UV induced activation of AKT (Ser473 phosphorylation) as well as that of the downstream signal mTOR (S6 and 4E-BP1 phosphorylation). The PI3K/AKT inhibitor, LY294002, and the mTOR inhibitor, rapamycin, largely neutralized the protective effects of niacin, suggesting that AKT and downstream signaling mTOR/S6 activation are necessary for the niacin-induced protective effects against UV-induced cell death and cell apoptosis.”

Rhyothemis profile image
Rhyothemis in reply to GioCas

Neurons are not subject to UV damage, like keratinocytes. The damage in neurons in PD comes from accumulation of protein aggregates. Inhibiting mTOR increases autophagy which clears protein aggregates.

Another potential mechanism of action for rapamycin in PD could be increase in Treg function. There was an SoP blog post on immune function and PD and the potential for treatments based on ex vivo expansion of Tregs using rapamycin and IL-10. It seems possible that rapamycin might do so in vivo also (i.e. , mouse or human takes rapamycin orally and their Treg function increases), but I have not found any studies reporting this.

Below is link to my comment on the blog post (scroll up for the post, which explains in detail about Tregs, etc.) : scienceofparkinsons.com/202...

Anyone know if a source for Rapamycin?

TIA

Not an endorsement, but you could start here: rapamycintherapy.com/

JAS9 profile image
JAS9 in reply to MarionP

From what I understand, you don't want to have mTOR activated all the time, as is the case with most people especially as we get older. You want to switch between the two states periodically. So, I think the best application of rapamycin would be, maybe a week on and then a week off. That way, you get the digest/repair state AND the remove-garbage/grow- new-cells state (these "programs" can't run at the same time). If you don't periodically turn off mTOR you end up with damaged cells that are full of garbage and malfunctioning mitochondria, which is where we are right now. If you don't clear out the damaged cells, more inflammation builds up as the body keeps signaling that something's wrong, protein plaque builds up, and our stem cells never get a chance to be new neurons.

This mimics the way our ancestors lived; sometimes they had plenty of food, so they spent energy digesting and storing as much fat as possible. But sometimes food was scarce, so their bodies used that stored fat, cleaned up their damaged cells, and used them for fuel too. That's autophagy ("self eating") for you.

This phaze 1/2 clinical trial on RAPA in healthy elderly subjects showed no significant changes in cognitive or physical function. ncbi.nlm.nih.gov/pmc/articl.... But a larger PHASE 2 clinical trial is in progress. clinicaltrials.gov/ct2/show...

You just opened a door to greater understanding for me - thank you!

Can you share the link to the article you referenced?

SE

pubmed.ncbi.nlm.nih.gov/306...

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