Nobiletin: The ultimate brain flavonoid

[neuron]

Nobiletin




Nobiletin is a polymethoxylated flavonoid derived from the peels of certain citrus fruits. Due to its chemical structure, nobiletin does not suffer from rapid metabolism which may account for hydroxylated flavonoids poor en vivo results. More information can be found here, and the abstracts listed below.


* Positive NMDA allosteric modulator [1]
* Ameliorates beta-amyloid-induced memory impairment [2]
* Positive AMPA allosteric modulator via increased PKA phosphorylation [3]
* Neurotrophic [4]
* Ameliorates cholinergic neurodegeneration associated with chronic cognitive dysfunction [5]

-----
Non-Brain related benefits

* Interfers with gene expression of cartilage destroying enzymes [6]
* Exceptionally orally bioavailable anticancer agent [7,8,9, exc.]

[1]http://www.ncbi.nlm.nih.gov/pubmed/17289833?ordinalpos=32&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[2]http://www.ncbi.nlm.nih.gov/pubmed/18544674?ordinalpos=1&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[3]http://www.ncbi.nlm.nih.gov/pubmed/17976577?ordinalpos=12&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[4]http://www.ncbi.nlm.nih.gov/pubmed/16229458?ordinalpos=59&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[5]http://www.ncbi.nlm.nih.gov/pubmed/17895593?ordinalpos=23&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[6]http://www.ncbi.nlm.nih.gov/pubmed/18541144?ordinalpos=2&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[7]http://www.ncbi.nlm.nih.gov/pubmed/17574860?ordinalpos=20&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[8]http://www.ncbi.nlm.nih.gov/pubmed/18053806?ordinalpos=10&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[9]http://www.ncbi.nlm.nih.gov/pubmed/18375960?ordinalpos=6&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[Peter LeDrew]

Nobiletin




Nobiletin is a polymethoxylated flavonoid derived from the peels of certain citrus fruits. Due to its chemical structure, nobiletin does not suffer from rapid metabolism which may account for hydroxylated flavonoids poor en vivo results. More information can be found here, and the abstracts listed below.


* Positive NMDA allosteric modulator [1]
* Ameliorates beta-amyloid-induced memory impairment [2]
* Positive AMPA allosteric modulator via increased PKA phosphorylation [3]
* Neurotrophic [4]
* Ameliorates cholinergic neurodegeneration associated with chronic cognitive dysfunction [5]

-----
Non-Brain related benefits

* Interfers with gene expression of cartilage destroying enzymes [6]
* Exceptionally orally bioavailable anticancer agent [7,8,9, exc.]

[1]http://www.ncbi.nlm.nih.gov/pubmed/17289833?ordinalpos=32&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[2]http://www.ncbi.nlm.nih.gov/pubmed/18544674?ordinalpos=1&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[3]http://www.ncbi.nlm.nih.gov/pubmed/17976577?ordinalpos=12&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[4]http://www.ncbi.nlm.nih.gov/pubmed/16229458?ordinalpos=59&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[5]http://www.ncbi.nlm.nih.gov/pubmed/17895593?ordinalpos=23&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[6]http://www.ncbi.nlm.nih.gov/pubmed/18541144?ordinalpos=2&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[7]http://www.ncbi.nlm.nih.gov/pubmed/17574860?ordinalpos=20&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[8]http://www.ncbi.nlm.nih.gov/pubmed/18053806?ordinalpos=10&itool=EntrezSystem2.PEntrez .Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
[9]http://www.ncbi.nlm.nih.gov/pubmed/18375960?ordinalpos=6&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Awesome info and that is actually a site I frequent often over the past few years... can't remember checking Nobiletin out though.

Interesting too about the acne... something I went through 15yrs ago and prescribed harsh dose of accutane which did some nice damage to my healthy body at the time.

Love you posts here Neuron (triathlete before right?)

Appreciate it bud. Is this something any company has in a product yet?

[neuron]

Appreciate it bud. Is this something any company has in a product yet?

Formerly triathlete04.

And to my knowledge, no company has included nobiletin in their supplement line-up. I could be mistaken.

Curcumin (with piperine) is another amazing polyphenol (in conjuction with its metabolic inhibitor, piperine) that is disappointingly absent from the supplement market. The new product from AN does include it, however.

[Eversor]

Only product I found so far was ArthroMax With FruiteX B

http://www.bodybuilding.com/store/le/arth.html

But this is quite interesting nontheless.

[neuron]

curcumin has very bad bioavailability and i doubt that the intake of even a few grams of a 90+ % extract would provide levels high enough to have signifcant effects on the brain. I wish i were wrong on that since curcumin is indeed one of the "wow"-substances w/r to neuronal health and viability.


there is a new formulation (Biocurcumax) that claims a severalfold higher bioavaliability than the classical >90% curcumin extracts, but I haven't seen any independent research on it.

Piperine dramatically raises curcumin's bioavailability.

[Peter LeDrew]

curcumin has very bad bioavailability and i doubt that the intake of even a few grams of a 90+ % extract would provide levels high enough to have signifcant effects on the brain. I wish i were wrong on that since curcumin is indeed one of the "wow"-substances w/r to neuronal health and viability.


there is a new formulation (Biocurcumax) that claims a severalfold higher bioavaliability than the classical >90% curcumin extracts, but I haven't seen any independent research on it.

I use AOR's Curcumin with their Acta-Resveratrol which has piperine and luteolin for enhanced bioavailability... piperine by itself has been shown to increase bioavailability by 1000% or something. Also taking EGCG with Curcuminoids together significantly enhance anti-cancer effects and likely other benefits (anti-inflammatory and brain protection possibly?) through a very nice synergism.

[neuron]

@ neuron /triathlete04:

is there any in vivo research on nobiletin? and if yes, what was the route of administration and what were the effective dosages?

btw: fisetin is another awesome polyphenol, found in many berries, especially in strawberries. it has virtually the same effects as nobiletin.

Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass?Walle T.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, P.O. Box 250505, 173 Ashley Avenue, Charleston, SC 29425, USA. wallet@musc.edu

Dietary flavonoids and other polyphenols show great potential as cancer chemopreventive agents in cell culture studies. This does not translate well into in vivo activity, because of extensive conjugative metabolism of these compounds in the intestine and liver. This paper presents a review of a flavonoid subclass in which all hydroxyl groups are capped by methylation. This results in dramatically increased metabolic stability and membrane transport in the intestine/liver, thus improving oral bioavailability. The methoxyflavones also show increased cancer chemopreventive properties. At the cancer initiation stage, bioactivation of polyaromatic hydrocarbon carcinogens and binding to DNA are markedly diminished through effects on CYP1A1/1B1 transcription but also through direct interactions with the proteins. At the cancer promotion stage, the proliferation of cancer cells, but not normal cells, is inhibited with greater potency than with the unmethylated flavones. Limited mechanistic experiments, such as of effects on cell cycle regulation, indicate that the mechanisms of methoxyflavone activities are unique, including aromatase inhibition. The cancer preventive effects and mechanisms of the polymethoxyflavones, such as tangeretin and nobiletin, are discussed in comparison. It is concluded that the methoxyflavones have properties that may make them particularly useful as cancer chemopreventive agents.

There is an abundant amount of in vivo research done on nobiletin, but I do not know the specific's offhand (administration/dosages).

[neuron]

btw: fisetin is another awesome polyphenol, found in many berries, especially in strawberries. it has virtually the same effects as nobiletin.

Interesting.

Interestingly the signaling pathway activated by fisetin in neural differentiation also played a role in memory formation, a process neuroscientists call "long-term potentiation" or LTP.

I'd like to see the mechanisms elucidated, however.

[Eversor]

again, i am not aware of independent research on it, but i remember something i read at the Life Extension site. they presented some graphs (from their own testing i guess) where curcumin + piperine was definitively much better (with regards to plasma levels) than only curcumine, but still VERY poor. in contrast to that the biocurcumax (BCM)extract blew the other two candidates away.
the key finding was that you might even reach a nice peak with curcumin + piperine, but it degrades extremely quickly, so you are left with a very poor AUC (areao under the curve). actually it was the AUC that was (allegedly) much better with the novel BCM axtract.

Do you mean this graph?


http://www.lef.org/magazine/mag2007/...urcumin_01.htm

[Peter LeDrew]

again, i am not aware of independent research on it, but i remember something i read at the Life Extension site. they presented some graphs (from their own testing i guess) where curcumin + piperine was definitively much better (with regards to plasma levels) than only curcumine, but still VERY poor. in contrast to that the biocurcumax (BCM)extract blew the other two candidates away.
the key finding was that you might even reach a nice peak with curcumin + piperine, but it degrades extremely quickly, so you are left with a very poor AUC (areao under the curve). actually it was the AUC that was (allegedly) much better with the novel BCM axtract.

In Foods That Fight Cancer, the esteemed authors mention that piperine increases by a factor of one thousand the absorption of curcumin, which allows the amount of curcumin present in the body to achieve levels sufficient to modify the aggressive behaviour of cancerous cells.

[Peter LeDrew]

Do you mean this graph?


http://www.lef.org/magazine/mag2007/...urcumin_01.htm

Interesting... heard of this product, but didn't know they had compared it to curcumin with piperine.

[Peter LeDrew]

The graph I have shows a level of curcumin reaching ~225ng/ml with piperine and maybe ~5ng/ml without.

[neuron]

again, i am not aware of independent research on it, but i remember something i read at the Life Extension site. they presented some graphs (from their own testing i guess) where curcumin + piperine was definitively much better (with regards to plasma levels) than only curcumine, but still VERY poor. in contrast to that the biocurcumax (BCM)extract blew the other two candidates away.
the key finding was that you might even reach a nice peak with curcumin + piperine, but it degrades extremely quickly, so you are left with a very poor AUC (areao under the curve). actually it was the AUC that was (allegedly) much better with the novel BCM axtract.

There is a lot of research out there demonstrating piperines ability to reduce solubilization, which is the main source of deactivation/metabolism of curcumin. I assume Biocurcumax is the isolated mixture of curcuminoid derivatives which possess functional groups which don't allow easy metabolism.

[neuron]

Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB.

Wang R, Li YB, Li YH, Xu Y, Wu HL, Li XJ.
Department of Pharmacology, School of Basic Medical Sciences and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, PR China.

Curcumin is a major active component isolated from Curcuma longa. Previously, we have reported its significant antidepressant effect. However, the mechanisms underlying the antidepressant effects are still obscure. In the present study, we explored the effect of curcumin against glutamate excitotoxicity, mainly focusing on the neuroprotective effects of curcumin on the expression of Brain-Derived Neurotrophic Factor (BDNF), which is deeply involved in the etiology and treatment of depression. Exposure of rat cortical neurons to 10 microM glutamate for 24 h caused a significant decrease in BDNF level, accompanied with reduced cell viability and enhanced cell apoptosis. Pretreatment of neurons with curcumin reversed the BDNF expression and cell viability in a dose- and time-dependent manner. However, K252a, a Trk receptor inhibitor which is known to inhibit the activity of BDNF, could block the survival-promoting effect of curcumin. In addition, the up-regulation of BDNF levels by curcumin was also suppressed by K252a. Taken together, these results suggest that the neuroprotective effect of curcumin might be mediated via BDNF/TrkB signaling pathway.

Curcumin has a host of positively beneficial effects on the brain (including MAO-B inhibition), but this is one of the most interesting.

[Peter LeDrew]

We want curcumin that works!!!

[Peter LeDrew]

I have faith that the supps I use such as 1.5g 90%curcuminoids, 100mg Trans-Res. + piperine + Luteolin, high dose EGCG extract, Boswellia Ext., Hawthorn, Grape Seed Ext., etc... all add to some amazing synergy.
There is so much science behind showing some interesting synergy with many of these ingredients.

But like DRP7 states, it'd nice to have more definite answers.

[Bane]

this i cut and paste from the full text of the study you quoted above (Wang et al., 2008):



now, someone tell me how much curcumin (with or without piperine) i need to ingest in order to get 10 microMol constantly over 6-24 hours at the site of my neurons.

i am no chemist, so someone please teach me (serious). but even without being a chemist, a little voice in my gut tells me that these 10microMol are miles away from the plasma levels we get when ingesting several grams of 95% curcumine - not to mention that you need to keep these levels over at least 6 hours. look at the graphs above how quickly curcumin disappears from plasma....

10micromol are 3,68mg/litre of fluid. I'll have to llok more into the pharmacokinetics but from a start point it doesnt look "Impossible"

[NO HYPE]

10micromol are 3,68mg/litre of fluid. I'll have to llok more into the pharmacokinetics but from a start point it doesnt look "Impossible"

Smarty-pants.

[Peter LeDrew]

10micromol are 3,68mg/litre of fluid. I'll have to llok more into the pharmacokinetics but from a start point it doesnt look "Impossible"

According to Richard Beliveau and Denis Gingras, two leading authorities in the field of cancer research, it doesn't look impossible either...

In Foods That Fight Cancer, the esteemed authors mention that piperine increases by a factor of one thousand the absorption of curcumin, which allows the amount of curcumin present in the body to achieve levels sufficient to modify the aggressive behaviour of cancerous cells.

People that use curry are getting both Curcumin, piperine and other compounds that work in synergy.

[NO HYPE]

it doesnt look "Impossible"

Agreed.

Copyright - The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice
Shingo Miyamotoa, Yumiko Yasuib, Takuji Tanakab, Hajime Ohigashia,c and Akira Murakamia,d
a Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
b Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan
c Present address: Faculty of Biotechnology, Fukui Prefectural University, Japan

d Corresponding author. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan E-mail address: cancer@kais.kyoto-u.ac.jp

Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM, followed by 1% DSS in drinking water for 7 days. Nobiletin, a citrus flavonoid, was given in the diet (100 ppm) for 17 weeks. Thereafter, the incidence and number of colon tumors, and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was 6 times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin, and IL-6. Feeding with nobiletin abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, nobiletin suppressed the leptin-dependent, but not -independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activate protein kinase/ extracellular signaling-regulated kinase (MEK), but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, while nobiletin has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels. http://carcin.oxfordjournals.org/cgi...short/bgn080v1

Parts per million (PPM). Parts per million works like percent by mass, but is more convenient when there is only a small amount of solute present. PPM is defined as the mass of the component in solution divided by the total mass of the solution multiplied by 106 (one million):

A solution with a concentration of 1 ppm has 1 gram of substance for every million grams of solution. Because the density of water is 1 g per mL and we are adding such a tiny amount of solute, the density of a solution at such a low concentration is approximately 1 g per mL. Therefore, in general, one ppm implies one milligram of solute per liter of solution. http://www.ilpi.com/msds/ref/concentration.html

[NO HYPE]

In terms of supplements that contain nobiletin, they are all propietary blends.

Here's a list [the numbers do not indicate preference]....


[1] Sytrinol Plant Sterols and Pomegranite Extract, by Douglas Laboratories

[2] Best Cardiovascular Support, by Doctor's Best

[3] Sytrinol, by Doctor's Best, Carlson and Vitabase

[4] Arthromax W/ Fruitx-b, by Life Extension

[5] Lipo-Gen, by Metagenics

[6] SPZM, by Health Concerns

[NO HYPE]

Prevention of UVB-induced photoinflammation and photoaging by a polymethoxy flavonoid, nobiletin, in human keratinocytes in vivo and in vitro.
Biochem Pharmacol. 2004 Aug 1;68(3):433-9.
Tanaka S, Sato T, Akimoto N, Yano M, Ito A.
Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.

Exposure to ultraviolet B (UVB) irradiation induces acute skin inflammation such as erythema (sunburn) and edema, and prostaglandin (PG)E2 in the epidermis plays an important role as its prominent mediator. In the present study, we investigated the effect of nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) from Citrus depressa, on the production of PGE2 in UVB-irradiated human keratinocytes. When keratinocytes were irradiated with 60mJ of UVB/cm2, the production and gene expression of cyclooxygenase (COX)-2, but not COX-1, were augmented along with an increase in PGE2 levels. The augmented COX-2 production was transcriptionally suppressed by nobiletin. In addition, neither the release of [14C]arachidonic acid from membrane phospholipids nor the gene expression of cytosolic phospholipase A2 (cPLA2) was altered in UVB-irradiated human keratinocytes. However, nobiletin was found to inhibit the release of [14C]arachidonic acid by decreasing the Ca2+ -dependent activity of cPLA2. Furthermore, topical treatment of nobiletin on the skin of the back prevented the UVB-induced increase of transepidermal water loss and hyperplasia of the epidermis in hairless mice. Therefore, these results suggest that nobiletin inhibits the UVB-induced production of PGE2 not only by suppressing the expression of COX-2 but also by decreasing the activity of cPLA2 in human keratinocytes. Furthermore, nobiletin may be useful as a novel sunscreen reagent to be applied for protection against photoinflammation and photoaging.

[Peter LeDrew]

In terms of supplements that contain nobiletin, they are all propietary blends.


[3] Sytrinol, by Doctor's Best, Carlson and Vitabase

Ah, yes that is where i have seen it... I can get that sytrinol pretty easy.

[NO HYPE]

Ah, yes that is where i have seen it... I can get that sytrinol pretty easy.

[In terms of sunscreen], hopefully nobiletin will be produced as a topical cream.

In terms of oral administration.... I would like to see some standalones vs. the propietary blends.

[Peter LeDrew]

[In terms of sunscreen], hopefully nobiletin will be produced as a topical cream.

In terms of oral administration.... I would like to see some standalones vs. the propietary blends.

Or a cognitive formula with adequate dosing!

[NO HYPE]

Or a cognitive formula with adequate dosing!

Even better.

[Peter LeDrew]

Even better.

You never know.

[Eversor]

Turned out to be an underestimated product. It was a good find by neuron and I would like to try it.

[NO HYPE]

hopefully nobiletin will be produced as a topical cream.

A Citrus Polymethoxy Flavonoid, Nobiletin Inhibits Sebum Production and Sebocyte Proliferation, and Augments Sebum Excretion in Hamsters
Journal of Investigative Dermatology (2007) 127, 2740?2748; doi:10.1038/sj.jid.5700927; published online 28 June 2007
Takashi Sato1, Aiko Takahashi1, Mika Kojima1, Noriko Akimoto1, Masamichi Yano2,3 and Akira Ito1

Acne vulgaris is characterized by excess sebum production, and apart from all-trans retinoic acid (atRA) or 13-cis retinoic acid (13-cisRA), there are few effective agents for acne therapy that directly suppresses sebaceous lipogenesis. In this study, we demonstrated that topical application of a citrus polymethoxy flavonoid, nobiletin, to hamster auricles decreased skin surface triacylglycerols (TG) level and the size of sebaceous glands along with inhibition of diacylglycerol acyltransferase (DGAT)-dependent TG synthesis and sebocyte proliferation. The inhibitory actions were similar to that observed with atRA and 13-cisRA in hamster sebocytes. The antilipogenic and antiproliferative actions of nobiletin were also reproduced in UVB (5.4 kJ/m2)-irradiated hamsters, which showed aberrant enhancement of sebum accumulation and sebaceous enlargement. Furthermore, nobiletin, but not 13-cisRA, augmented sebum excretion along with increases in intracellular cAMP level, protein kinase A (PKA) activation, and apoptosis-independent phosphatidylserine (PS) externalization in cell membrane. These phenomena were reproduced by forskolin and inhibited by a PKA inhibitor, H-89. These results provide early evidence that nobiletin is an effective candidate for acne therapy through mechanisms that include the inhibition of DGAT-dependent TG synthesis and sebocyte proliferation, and the progression of apoptosis-independent and PS-externalization-dependent sebum excretion by PKA activation. http://www.nature.com/jid/journal/v1.../5700927a.html