15 replies to this topic

[lynx]

The abstract doesn't list the flavonoids, so I got the full text from my library.

The gist is that NGF of course stimulates neurite outgrowth, and so does fisetin. Fisetin takes longer, hours versus minutes, but works quite well.

Fisetin is found in strawberries, other fruits and Folium Cotini. Right now folium cotini extract only seems to be available in Xenadrine, but the chinese are selling it so we should be able to get it.

Fisetin, like most other flavonoids has a host of other benefits.

J Neurochem. 2004 Sep;90(5):1144-55. Related Articles, Links 

 
Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation.

Sagara Y, Vanhnasy J, Maher P.

Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Many of the physiological benefits attributed to flavonoids are thought to stem from their potent antioxidant and free radical scavenging properties. Recently, it was shown that flavonoids protect nerve cells from oxidative stress by multiple mechanisms, only one of which is directly related to their antioxidant activity, suggesting that specific flavonoids may have other properties that could make them useful in the treatment of conditions that lead to nerve cell death. In particular, it was asked if any flavonoid could mimic neurotrophic proteins. To examine this possibility, we looked at the ability of flavonoids to induce nerve cell differentiation using PC12 cells. PC12 cells were treated with a variety of flavonoids to determine if there was a correlation between their neuroprotective activity and their neurite outgrowth-promoting activity. In addition, the signaling pathways required for flavonoid-induced differentiation were examined. We found that only a small subset of the flavonoids that were neuroprotective could induce neurite outgrowth by an extracellular signal-regulated kinase-dependent process. There was a strong correlation between the concentrations of the flavonoids that were neuroprotective and the concentrations that induced differentiation. These results suggest that the consumption of specific flavonoids could have further beneficial effects on nerve cells following injury, in pathological conditions or in normal aging. Copyright 2004 International Society for Neurochemistry

PMID: 15312169 [PubMed - indexed for MEDLINE]

Edit: I hadn't completely read the materials/methods when I wrote this, so the 40%, 2.5 numbers are wrong. It was nanograms for NGF, micrograms for Fisetin. Apologies to all who rushed out and ate a pound of strawberries.

Edited by lynx, 28 January 2005 - 11:10 PM.

[pinballwizard]

But is this "PC12 cells" a good sample of all brain cells? Or is only going to work on them? What are they anyway? Great, great post. thanks

[lynx]

You know that is good question, I had never really bothered to look into it, I just assumed it was a brain cell. Turns out I was wrong.

http://anatomy.med.u...ds/cellpc12.htm
"There are almost 5000 references to this well characterized cell line in the scientific literature(PubMed Dec 99). Generated by Greene and Tischler (1976) from a transplantable rat adrenal pheochromocytoma line, it is a single cell clonal line which responded reversibly to nerve growth factor (NGF). Different cell labs may have slightly different versions of these cells dependent upon passage number and selection criteria."

In the text of the study on NGF and Fisetin they say it is a good model for how brain cells respond to different chemicals. So it should work in the brain the same way as it did in these cells.

[eternaltraveler]

does it cross the blood brain barrier?

[Chip]

Hmmm, until there are well conducted clinical trials of in vivo testing, I don't place a lot of credibility on this but still, I strongly suspect no damaging repercussions to strawberry flavinoids. With ellagic acid I notice that the concentration is quite different for different strains of strawberry, being least in most commercially available varieties. A wild strawberry here in Northern California appears to have some of the highest concentration of ellagic acid in its seeds as well as in its leaves which I have picked and used as part of a fresh blender made tonic. I buy ellagic acid supplements from pomegranate seeds as being most cost effective. Is there any data on what parts of the plant and which strains of strawberry have the most of the Fisetin? Which other fruits have it and to what comparative concentrations?

[lynx]

Regarding BBB, quercetin dihydrate doesn't cross well because it is water insoluble, and fisetin is structurally similar to quercetin. Quercetin/lecithin combos, phytosomes cross the BBB quite well. Quercetin is soluble in alcohol.
The best source that I have seen is Folium Cotini. The data on the strawberries was from Japanese strawberries, not leaf etc. It is also present in apples and kiwi, but in much smaller amounts.
So, probably the best bet is strawberry wine or Folium Cotini alcohol extract.

Here are the compounds studied and the half-maximal concentrations

1. Fisetin -------5
2. Quercetin ---10
3. Luteolin------10
4. isohamentin-10
5. genistein-----50

I am sure that given the dramatic nature of the results, there will be follow up studies.

[eternaltraveler]

Brain damage induces neurogenesis as a repair response, but can one use this same process, artificially induced, to increase overall grey matter in the brain? While I ask this question sincerely, I presume this is not possible as outlined in the question. 

Cosmos, I would assume that in theory you could do this.

I suspect the mechanism is similar to muscular growth. When you exercise you cause microscopic tears in the muscle, and the response is to initiate a signaling pathway that causes more muscle to grow. It has been shown that you don't need to damage the muscle to make it grow, only initiate this signaling pathway (IGF-1). Some super mice were engineered so this pathway is more or less always on. I believe there is some kid in Germany who also has this signaling pathway initiated through some random mutation.

The trick is finding out exactly what the signaling pathway that induces neurogenesis and inducing it artificially (fibroblast growth factor-2 is one possibility, though it may take a whole cocktail of various growth factors and regulatory proteins to get it right).

Having a whole bunch of these growth factors just floating around your bloodstream is probably a bad idea as they might tend to induce growth in tissues that you don’t want to grow. In the case of brain injury the growth factors are primarily released locally, and remain in a somewhat local area.

I would imagine the best way to induce this would be in highly specific areas of the brain rather than all over, possibly through localized injection or gene therapy.

[stellar]

How about a combo of fisetin and ALCAR-Arginate

[scottl]

If you type fisetin into froogle there are some interesting cobos with other flavonoids as well as a source to buy bulk amounts (prob not...for human consumption).

[lynx]

I just discovered something else quite interesting about fiseting, it extends the lives of fruit flies MORE than RESVERATROL.

http://www.youngagai...isficotosl.html

Researchers discover the first compounds that slow aging across species
Three colleagues with a common interest in the biology of aging have determined that the compound resveratrol, an antioxidant found in red wine, can slow the aging process in yeast, fruit flies and nematodes. The three -- David Sinclair of Harvard, Marc Tatar of Brown, and Stephen Helfand of the University of Connecticut -- report their findings in the July 15, 2004, issue of Nature.

Last July, during a day trip to Boston, Brown biologist Marc Tatar popped into the lab of David Sinclair, a friend and pathology researcher at Harvard Medical School.

Tatar and Sinclair share a fundamental fascination: how and why living organisms age. Tatar experiments with fruit flies. Sinclair works with yeast -- and he wanted to share an interesting find. Sinclair put a teaspoonful of clear liquid in a vial and placed it in a box of ice. He handed the box to Tatar and said, ''We think it's safe. Try it out.''

Tatar, an associate professor in the Department of Ecology and Evolutionary Biology, was intrigued. Back at Brown, he cooked the compound into a sweet corn meal mush, fed his flies and waited. He was amazed. The flies lived longer -- some nearly 30 percent longer -- than the average Drosophila melanogaster.

This discovery prompted an unusual, three-university experiment that has netted a true scientific breakthrough: the discovery of the first compounds that slow aging across species. The results are published in the July 15, 2004, issue of Nature.

''To work across species, the mechanism behind how these compounds function must be very, very old -- predating the evolution of yeast,'' Tatar said. ''It's amazing stuff.''

The compound Sinclair gave Tatar was resveratrol, an antioxidant found in red wine. To put resveratrol to a more rigorous, far-reaching test, Tatar and Sinclair enlisted Stephen Helfand, a researcher at the University of Connecticut.

The trio tested resveratrol along with fisetin, a close cousin in its plant-based family. They fed the compounds to yeast, worms and flies. Results showed that molecules called sirtuins slowed aging in all organisms. Flies, for example, live an average of 43 days. But flies that ate resveratrol lived up to 51 days. Flies that ate fisetin lived as long as 53 days.

Why? Sirtuins mimic the life-extending effects of caloric restriction, a biochemical cascade known to slow aging in mammals. Scientists don't fully understand why caloric restriction prolongs life. Tatar said the best thinking is this: Living creatures are hard-wired to reproduce. But a severe, low-calorie diet trips physiological sensors, sending a message throughout the body that conditions aren't ripe for reproduction. Cellular defense systems go up and aging slows, preserving the body for better, more reproduction-friendly times.

''In this case, a little stress is actually beneficial,'' Tatar explained. ''It's evolution.''

What was startling about the experiment is that sirtuins don't extend life when coupled with real caloric restriction. In fact, when flies on a low-calorie diet ate resveratrol and fisetin, they didn't live any longer than average flies. Another surprising discovery was the fact that flies feasting on sirtuins didn't have problems reproducing -- a negative side effect of caloric restriction.

One practical application of the research is in prescription drug development. But Tatar said a ''Ponce de Leon pill'' won't be found in pharmacies any time soon. Because sirtuins dissipate quickly in the blood, Tatar predicted that it would take scientists at least five years to create compounds stable enough for use in drugs.

Consumers shouldn't expect a silver-bullet centenarian pill. ''We'd probably see these compounds used in drugs that target a specific age-related disease, such as diabetes or heart failure,'' he said. ''If those diseases are delayed, we'd live longer.''

[lynx]

Here are some the answers to BBB questions. Keep in mind that ethanol can probably do what liposomes do, but less healthfully.

Neurotox Res. 2004;6(7-8):543-53. Related Articles, Links 


Some Aspects of the in vivo Neuroprotective Capacity of Flavonoids: Bioavailability and Structure-Activity Relationship.

Rivera F, Urbanavicius J, Gervaz E, Morquio A, Dajas F.

Department of Neurochemistry, Instituto de Investigaciones Biologicas, Clemente Estable, Avenida Italia 3318, Montevideo, Uruguay.

On the basis of previous work showing that flavonoids structurally related to quercetin are neuroprotective for cells in culture, this work was directed towards determining if several flavonoids (quercetin, fisetin and catechin) could acutely and by an intraperitoneal (IP) route reach significant cerebral concentrations and either prevent or facilitate recovery from a brain lesion induced by focal ischemia in rats. Aqueous and liposomal preparations of quercetin, fisetin and catechin were administered IP in a single dose and assessed in the brain by HPLC at 30 min, 1 h, 2 h and 4 h. Ischemic damage from focal middle cerebral artery occlusion was assessed spectrophotometrically with 2,3,5,-triphenylltetrazolium chloride (TTC). Infarct volume was assessed by an image analysis system following perfusion with TTC. The status of the cerebral tissue was evaluated by hematoxylin-eosin. Flavonoids administered in aqueous preparations were undetected in the brain. Cerebral concentrations of catechin (10.5 ng/g), fisetin (8.23 ng/g) and quercetin (509 ng/g) were detected in the brain only after IP injection of the liposomal preparations. Spectrophotometric analysis of brain tissue with the TTC-technique showed that liposomal quercetin reduced ischemic damage and infarct volume after permanent occlusion of the middle cerebral artery (ischemic: 41.3 mm(3) vs liposomal quercetin: 17 mm(3)). In liposomal quercetin-treated animals there was also recovery of the cytoarchitecture in ischemic areas of striatum and cortex. Although a liposomal preparation of fisetin had similar effects, catechin failed to protect brain tissue. In conclusion, early administration of liposomal preparations of quercetin and structurally related flavonoids are beneficial and neuroprotective in experimental focal ischemia.

PMID: 15639786 [PubMed - in process]

[lynx]

Wow, it is a phase II enzyme inducer too. Remarkable stuff.

Int J Oncol. 2001 Jun;18(6):1175-9. Related Articles, Links 


Fisetin induces transcription of NADPH:quinone oxidoreductase gene through an antioxidant responsive element-involved activation.

Hou DX, Fukuda M, Johnson JA, Miyamori K, Ushikai M, Fujii M.

Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Kagoshima 890-0065, Japan. hou@chem.agri.kagoshima-u.ac.jp

Induction of phase II enzymes such as NADPH:quinone oxidoreductase (QR) can reduce carcinogen-induced mutagenesis and tumor formation. In our search for novel dietary anticarcinogens, fisetin, a flavonol widely distributed in fruits and vegetables was found to induce QR activity in murine hepatoma 1c1c7 cells. The cells were treated with various concentrations of fisetin, and then were assessed for cell growth, QR activity, QR mRNA expression and transcription activation of the QR gene. The results showed that fisetin induced QR activity in time- and dose-dependent manner in the concentration range of 0.1 to 10 microM, and the activity induction was associated with QR mRNA expression as detected by reverse transcription-PCR. Furthermore, transfection studies using a human QR antioxidant/electrophile-response element (ARE/EpRE) reporter construct demonstrated that fisetin activated the ARE/EpRE. These results show that fisetin increases QR activity by transcriptional activation of the ARE/EpRE, suggesting a novel mechanism by which dietary fisetin may be implicated in cancer chemoprevention.

PMID: 11351248 [PubMed - indexed for MEDLINE]

[power.bulls.x]

how to get decent level of this stuff into blood stream ?
also i am wondering how to get resveratrol that is truly effective/bioaviable at a good price ? (didnt found any sources yet) i am just taking 1 cup of grape juice/day.

[tracer]

Hey Lynx... how 'bout scanning in the Fulltext or something bro? I'd really like to have a look... I happen to have 250g of Quercetin sitting in my cupboard... maybe it'll be useful after all, maybe stacked with LiOr and Idebenone.