[reverett123]

It is also strong support for the idea that cytokines from reactions to bacterial toxins not only cause long term damage, but also cause acute interference with neurotransmission. Also, a lot of things block TNF-a. This could be a very good year.

http://www.sciencedaily.com/releases...0109091102.htm

Reversal Of Alzheimer's Symptoms Within Minutes In Human Study

PET Scan of Alzheimer's Disease Brain. (Credit: NIH/National Institute On Aging)

ScienceDaily (Jan. 9, 2008) — An extraordinary new scientific study, which for the first time documents marked improvement in Alzheimer’s disease within minutes of administration of a therapeutic molecule, has just been published in the Journal of Neuroinflammation.

This new study highlights the importance of certain soluble proteins, called cytokines, in Alzheimer’s disease. The study focuses on one of these cytokines, tumor necrosis factor-alpha(TNF), a critical component of the brain’s immune system. Normally, TNF finely regulates the transmission of neural impulses in the brain. The authors hypothesized that elevated levels of TNF in Alzheimer’s disease interfere with this regulation. To reduce elevated TNF, the authors gave patients an injection of an anti-TNF therapeutic called etanercept. Excess TNF-alpha has been documented in the cerebrospinal fluid of patients with Alzheimer’s.

The new study documents a dramatic and unprecedented therapeutic effect in an Alzheimer’s patient: improvement within minutes following delivery of perispinal etanercept, which is etanercept given by injection in the spine. Etanercept (trade name Enbrel) binds and inactivates excess TNF. Etanercept is FDA approved to treat a number of immune-mediated disorders and is used off label in the study.

The use of anti-TNF therapeutics as a new treatment choice for many diseases, such as rheumatoid arthritis and potentially even Alzheimer’s, was recently chosen as one of the top 10 health stories of 2007 by the Harvard Health Letter.

Similarly, the Neurotechnology Industry Organization has recently selected new treatment targets revealed by neuroimmunology (such as excess TNF) as one of the top 10 Neuroscience Trends of 2007. And the Dana Alliance for Brain Initiatives has chosen the pilot study using perispinal etanercept for Alzheimer’s for inclusion and discussion in their 2007 Progress Report on Brain Research.

The lead author of the study, Edward Tobinick M.D., is an assistant clinical professor of medicine at the University of California, Los Angeles and director of the Institute for Neurological Research, a private medical group in Los Angeles. Hyman Gross, M.D., clinical professor of neurology at the University of Southern California, was co-author.

The study is accompanied by an extensive commentary by Sue Griffin, Ph.D., director of research at the Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences (UAMS) in Little Rock and at the Geriatric Research and Clinical Center at the VA Hospital in Little Rock, who along with Robert Mrak, M.D., chairman of pathology at University of Toledo Medical School, are editors-in-chief of the Journal of Neuroinflammation.

Griffin and Mrak are pioneers in the field of neuroinflammation. Griffin published a landmark study in 1989 describing the association of cytokine overexpression in the brain and Alzheimer’s disease. Her research helped pave the way for the findings of the present study. Griffin has recently been selected for membership in the Dana Alliance for Brain Initiatives, a nonprofit organization of more than 200 leading neuroscientists, including ten Nobel laureates.

“It is unprecedented that we can see cognitive and behavioral improvement in a patient with established dementia within minutes of therapeutic intervention,” said Griffin. “It is imperative that the medical and scientific communities immediately undertake to further investigate and characterize the physiologic mechanisms involved. This gives all of us in Alzheimer’s research a tremendous new clue about new avenues of research, which is so exciting and so needed in the field of Alzheimer’s. Even though this report predominantly discusses a single patient, it is of significant scientific interest because of the potential insight it may give into the processes involved in the brain dysfunction of Alzheimer’s.”

While the article discusses one patient, many other patients with mild to severe Alzheimer’s received the treatment and all have shown sustained and marked improvement.

The new study, entitled “Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration,” and the accompanying commentary, entitled “Perispinal etanercept: Potential as an Alzheimer’s therapeutic,” are available on the Web site of the Journal of Neuroinflammation.

[ZucchiniFlower]

Rick, it's involved in cancer, too.

Epigallocatechin gallate is EGCG, which is in green tea! I'm going to get some high EGCG green tea extract....


A New Process of Cancer Prevention Mediated through Inhibition of Tumor Necrosis Factor {alpha} Expression1

Mechanisms of cancer prevention were studied using structurally different cancer-preventive agents, sarcophytol A, canventol, (-)-epigallocatechin gallate, and tamoxifen, based on our evidence that tumor necrosis factor {alpha} (TNF-{alpha}) acts as an endogenous tumor promoter relevant to human carcinogenesis.

Pretreatment with the four preventive agents commonly inhibited TNF-{alpha} mRNA expression and TNF-{alpha} release in BALB/3T3 cells induced by a tumor promoter, okadaic acid, whereas the expression of early response genes (c-jun, junB, c-fos, and fosB) was enhanced.

These results strongly suggest that inhibition of TNF-{alpha} mRNA expression and its release is a new process of cancer prevention.

http://cancerres.aacrjournals.org/cg...act/56/16/3711

Green Tea Polyphenols Block Endotoxin-Induced Tumor Necrosis Factor-Production and Lethality in a Murine Model

Manuscript received 4 June 1998. Initial reviews completed 9 July 1998. Revision accepted 18 August 1998.
Fajun Yang*, Willem J. S. de Villiersdagger , Craig J. McClainDagger , and Gary W. Varilek**,


Green tea polyphenols are potent antioxidants. They have both anti-cancer and anti-inflammatory effects. However, their mechanisms of actions remain unclear. In inflammation, tumor necrosis factor-alpha (TNFalpha ) plays a pivotal role. NF-KB, an oxidative stress -sensitive nuclear transcription factor, controls the expression of many genes including the TNFalpha gene. We postulated that green tea polyphenols regulate TNFalpha gene expression by modulating NF-KB activation through their antioxidant properties. In the macrophage cell line, RAW264.7, (-)epigallocatechin gallate (EGCG), the major green tea polyphenol, decreased lipopolysaccharide (LPS)-induced TNFalpha production in a dose-dependent fashion (50% inhibition at 100 mmol/L). EGCG also inhibited LPS-induced TNFalpha mRNA expression and nuclear NF-KB-binding activity in RAW264.7 cells (30-40% inhibition at 100 mmol/L). Similarly, EGCG inhibited LPS-induced TNFalpha production in elicited mouse peritoneal macrophages. In male BALB/c mice, green tea polyphenols (given by oral gavage 2 h prior to an i.p. injection of 40 mg LPS/kg body wt) decreased LPS-induced TNFalpha production in serum in a dose-responsive fashion. At a dose of 0.5 g green tea polyphenols/kg body wt, serum TNFalpha was reduced by 80% of control. Moreover, 0.5 g green tea polyphenols/kg body wt completely inhibited LPS-induced lethality in male BALB/c mice. We conclude that the anti-inflammatory mechanism of green tea polyphenols is mediated at least in part through down-regulation of TNFalpha gene expression by blocking NF-KB activation. These findings suggest that green tea polyphenols may be effective therapy for a variety of inflammatory processes.

[ZucchiniFlower]

This is slightly off topic, but scary. Seems that ingesting broccoli and green tea together cancels out the benefits of both, in this study and in mice:

Frontiers in Polyphenols and Cancer Prevention

.....Epigenetics: the next major frontier for polyphenols?

Synergistic effects also are being considered for polyphenols with other dietary constituents. EGCG was reported to inhibit DNA methyltransferase (DNMT) activity in vitro, with a KI of 7 µmol/L; this led to reactivation of epigenetically silenced genes in cancer cells (13). These findings, coupled with work using dietary inhibitors of histone deacetylase (HDA), such as sulforaphane (14–17), suggested that an inhibitor of DNMT plus an HDA inhibitor might provide enhanced cancer chemoprevention. The latter hypothesis stems from recent advances in the field of epigenetics, indicating that unsilencing of tumor suppressor genes in cancer cells involves changes both in the methylation status of DNA and in the neighboring histone code (i.e., chromatin remodeling) (18). In Apcmin mice treated with sulforaphane, an isothiocyanate from broccoli, there was inhibition of HDA activity and suppression of intestinal polyps (17). In the same study, groups of mice were given EGCG alone or a combination of EGCG plus sulforaphane; no synergistic effects were seen when the test agents were combined (Fig. 1). On the contrary, it appeared that 1 compound counteracted the beneficial effects of the other so that no significant chemopreventive action was seen. Further work is needed to resolve these findings and the mechanisms involved, but they clearly demonstrate that observations made in vitro do not necessarily translate to the situation in vivo.

http://jn.nutrition.org/cgi/content/full/137/1/267S


Neuroinflammation and its Modulation by Flavonoids

Authors: Vafeiadou, K.; Vauzour, D.; Spencer, J. P.E.

Source: Endocrine, Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders), Volume 7, Number 3, September 2007 , pp. 211-224(14)

Abstract:
There is increasing evidence to suggest that neuroinflammatory processes contribute to the cascade of events that lead to the progressive neuronal damage observed in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Therefore, treatment regimes aimed at modulating neuroinflammatory processes may act to slow the progression of these debilitating brain disorders. Recently, a group of dietary polyphenols known as flavonoids have been shown to exert neuroprotective effects in vivo and in neuronal cell models. In this review we discuss the evidence relating to the modulation of neuroinflammation by flavonoids. We highlight the evidence which suggests their mechanism of action involves: 1) attenuation of the release of cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α); 2) an inhibitory action against inducible nitric oxide synthase (iNOS) induction and subsequent nitric oxide (NO.) production; 3) inhibition of the activation of NADPH oxidase and subsequent reactive oxygen species generation; 4) a capacity to down-regulate the activity of pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB); and 5) the potential to modulate signalling pathways such as mitogen-activated protein kinase (MAPK) cascade. We also consider the potential of these dietary compounds to represent novel therapeutic agents by considering their metabolism in the body and their ability to access the brain via the blood brain barrier. Finally, we discuss future areas of study which are necessary before dietary flavonoids can be established as therapeutic agents against neuroinflammation.

http://www.ingentaconnect.com/conten...00003/art00007

**********************

Vol. 142, No. 4, 2007

Epigallocatechin-3-Gallate Inhibits Secretion of TNF-alpha, IL-6 and IL-8 through the Attenuation of ERK and NF-kappaB in HMC-1 Cells

http://content.karger.com/ProdukteDB...oduktNr=224161

[Ronhutton]

Hi Rick,
Interesting that elevated levels of TNF also increase the permeability of the BBB. (It keps cropping up!).

Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice
Authors: Yang G.-Y.1; Gong C.; Qin Z.; Liu X.-H.; Lorris Betz A.

Source: Molecular Brain Research, Volume 69, Number 1, 21 May 1999 , pp. 135-143(9)

Publisher: Elsevier

Keywords: Blood-brain barrier; Ischemia; Middle cerebral artery occlusion; Reperfusion; Temporary; Tumor necrosis factor-alpha

Language: English

-------------------------------

I don't suppose we care about the mechanism, all we want is a cure, However, inflammation seems the main cause of BBB damage, so it all fits in.
Ron

[Ronhutton]

Just done a search on etanercept, the anti TNF drug used in Rick's reference. It is used against arthritis.
But surely there must have been someone with AD who has been treated with this drug for arthritis!!! Why have these resilts not been seen before??
Ron

PS Guess who markets etanercept.....Amgen!!

Data sheet
What is etanercept?
Etanercept (trade name Enbrel) is a type of drug known as anti-TNF. In people with rheumatoid arthritis and some other inflammatory diseases a protein called TNF is present in the blood and joints in excessive amounts, where it increases inflammation. Anti-TNF drugs block the action of TNF and so can reduce inflammation. In this way they can help people with active rheumatoid arthritis and other types of arthritis.

Why am I being prescribed etanercept?
Etanercept is available for people with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and for children with juvenile idiopathic arthritis (also known as JIA or JCA). It will only be prescribed if your arthritis is active. Also, if you have rheumatoid arthritis it will only be used if you have already tried methotrexate and another standard 'second-line' treatment (e.g. sulfasalazine, gold injections, penicillamine). It may also be prescribed if you cannot tolerate other treatments. Slightly different conditions may apply in the case of the other diseases. Etanercept is available only on prescription from a consultant rheumatologist.

[reverett123]

Good question. One answer might be the BBB. From what I gather, they infused the etanercept directly. Oral intake might not have the effect.

That doesn't mean that curcumin or green tea or whatever wouldn't get in though. And let's keep in mind that inflammation opens the BBB. So you might have an "open the door - slam the door" effect as anti-inflammatories penetrate the BBB, inflammation decreases enough to close it, inflammation goes back up, and so on. That could explain some of the more maddening things we encounter in terms of predictability.

Then there is the stress factor. Increases inflammation, etc. Explains NSAIDS protective effects, too. Of course, while the BBB is going back and forth it is letting other toxins in as well, further explaining why we vary so much yet are the same.

It comes down to two basic questions-

What starts the process? This answer would provide prevention. My vote is still the bacterial toxin and sensitization.

What stops it? We've got a good dozen candidates that we've identified on this forum alone.

So, anti-inflammatories that penetrate the BBB from oral intake and have a long enough track record to seem safe, relatively speaking.

Green tea: " Tea flavonoids (catechins) have been reported to possess divalent metal chelating, antioxidant, and anti-inflammatory activities, to penetrate the brain barrier and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. This review aims to shed light on the multipharmacological neuroprotective activities of green tea catechins with special emphasis on their brain-permeable, nontoxic, transitional metal (iron and copper)-chelatable/radical scavenger properties.
PMID: 16470637 [PubMed - indexed for MEDLINE]"

Curcumin / Turmeric: "In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. PMID: 15590663 [PubMed - indexed for MEDLINE]"

And we can probably add dextromethorphan to the list, too.

-Rick

Originally Posted by Ronhutton

Just done a search on etanercept, the anti TNF drug used in Rick's reference. It is used against arthritis.
But surely there must have been someone with AD who has been treated with this drug for arthritis!!! Why have these resilts not been seen before??
Ron

PS Guess who markets etanercept.....Amgen!!

Data sheet
What is etanercept?
Etanercept (trade name Enbrel) is a type of drug known as anti-TNF. In people with rheumatoid arthritis and some other inflammatory diseases a protein called TNF is present in the blood and joints in excessive amounts, where it increases inflammation. Anti-TNF drugs block the action of TNF and so can reduce inflammation. In this way they can help people with active rheumatoid arthritis and other types of arthritis.

Why am I being prescribed etanercept?
Etanercept is available for people with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and for children with juvenile idiopathic arthritis (also known as JIA or JCA). It will only be prescribed if your arthritis is active. Also, if you have rheumatoid arthritis it will only be used if you have already tried methotrexate and another standard 'second-line' treatment (e.g. sulfasalazine, gold injections, penicillamine). It may also be prescribed if you cannot tolerate other treatments. Slightly different conditions may apply in the case of the other diseases. Etanercept is available only on prescription from a consultant rheumatologist.

[Jaye]

If memory serves me well, I have reported here in the past that these same catechins that are found in green tea are also present in dark chocolate.

A story about that: My first neuro used to love to tell me after an exam that I didn't have PD (but all she meant was that my meds were well balanced). One time she concluded her exam with: "You're doing very well. Whatever you're doing, keep doing it." And I thought, "THAT much chocolate?!" for I had been enjoying a generous amount of the stuff. Sometimes the truth is too simple to see, I suppose.

Jaye

[aftermathman]

some time ago and he maintained the cells of PD people were not dead but dormant.

Does this support his statement or am I off the page here.

Neil.

[reverett123]

Educated guesses, but....
Inflammation is an action taken by the immune system rather than an invader. That action includes the release of chemicals called cytokines of which TNFa is one. Short term, these serve as signals to rally the troops and tell them where to look for invaders.

Long term, however, the situation becomes destructive from physical swelling and the chemical effects of the cytokines. Particularly troublesome for us are the immediate neuroactive effects as the cytokines interfere with the other brain chemicals. This is what I suspect clears up so quickly. I can't imagine that physical damage could respond so fast.

Originally Posted by aftermathman

some time ago and he maintained the cells of PD people were not dead but dormant.

Does this support his statement or am I off the page here.

Neil.